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1
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Kabrani E, Rahjouei A, Berruezo-Llacuna M, Ebeling S, Saha T, Altwasser R, Delgado-Benito V, Pavri R, Di Virgilio M. RIF1 integrates DNA repair and transcriptional requirements during the establishment of humoral immune responses. Nat Commun 2025; 16:777. [PMID: 39824820 PMCID: PMC11742068 DOI: 10.1038/s41467-025-56166-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2024] [Accepted: 01/09/2025] [Indexed: 01/20/2025] Open
Abstract
The establishment of protective immune responses relies on the ability of terminally differentiated B cells to secrete a broad variety of antigen-specific antibodies with different effector functions. RIF1 is a multifunctional protein that promotes antibody isotype diversification via its DNA end protection activity during class switch recombination. In this study, we showed that RIF1 ablation resulted in increased plasmablast formation ex vivo and enhanced terminal differentiation into plasma cells upon immunization. Mechanistically, this phenotype is independent from RIF1's role in DNA repair and class switch recombination, and reflects its ability to modulate the transcriptional status of a subset of BLIMP1 target genes. Therefore, here we show that, in addition to promoting antibody diversification, RIF1 fine-tunes the kinetics of late B cell differentiation, thus providing an additional layer of control in the establishment of humoral immunity.
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Affiliation(s)
- Eleni Kabrani
- Laboratory of Genome Diversification & Integrity, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, 13125, Berlin, Germany
| | - Ali Rahjouei
- Laboratory of Genome Diversification & Integrity, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, 13125, Berlin, Germany
- Department of Anesthesiology and Intensive Care Medicine, and Experimental and Clinical Research Center, Charité-Universitätsmedizin Berlin, 10117, Berlin, Germany
| | - Maria Berruezo-Llacuna
- Laboratory of Genome Diversification & Integrity, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, 13125, Berlin, Germany
- Humboldt-Universität zu Berlin, 10117, Berlin, Germany
| | - Svenja Ebeling
- Laboratory of Genome Diversification & Integrity, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, 13125, Berlin, Germany
- Freie Universität Berlin, 14195, Berlin, Germany
| | - Tannishtha Saha
- Laboratory of Genome Diversification & Integrity, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, 13125, Berlin, Germany
- Freie Universität Berlin, 14195, Berlin, Germany
| | - Robert Altwasser
- Laboratory of Genome Diversification & Integrity, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, 13125, Berlin, Germany
- Department of Hematology, Oncology, and Cancer Immunology, Charité-Universitätsmedizin Berlin, 10117, Berlin, Germany
| | - Veronica Delgado-Benito
- Laboratory of Genome Diversification & Integrity, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, 13125, Berlin, Germany
| | - Rushad Pavri
- Peter Gorer Department of Immunobiology, School of Immunology & Microbial Sciences, King's College London, London, SE1 9RT, UK
| | - Michela Di Virgilio
- Laboratory of Genome Diversification & Integrity, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, 13125, Berlin, Germany.
- Charité-Universitätsmedizin Berlin, 10117, Berlin, Germany.
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Gong S, Beukema M, De Vries-Idema J, Huckriede A. Assessing human B cell responses to influenza virus vaccines and adjuvants in a PBMC-derived in vitro culture system. Vaccine 2025; 44:126563. [PMID: 39616951 DOI: 10.1016/j.vaccine.2024.126563] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2024] [Revised: 11/19/2024] [Accepted: 11/23/2024] [Indexed: 12/20/2024]
Abstract
In vitro systems based on human peripheral blood mononuclear cells (PBMCs) can bridge the gap between preclinical and clinical vaccine evaluation but have so far mainly been exploited to assess vaccine effects on antigen-presenting cells and T cells. Our study aimed to assess whether B cells present in PBMCs also respond to vaccines and reflect the effects of different vaccine formulations and adjuvants. We stimulated PBMCs with whole inactivated virus (WIV) or split virus (SIV) H5N1 influenza vaccine, with or without the addition of the adjuvant cytosine phosphoguanine (CpG) ODN 2395, and collected the cells and supernatants at different timepoints. B cell subsets were measured by flow cytometry, immunoglobulin (IgG) levels by ELISA, B cell-related genes by qPCR, and cytokine levels by intracellular staining. B cells differentiated more readily to plasmablasts and plasma cells and produced more IgG when PBMC cultures were stimulated with WIV than when stimulated with SIV. In line, PRDM1, XBP1, and AICDA, genes associated with the differentiation of B cells to antibody-secreting cells, were expressed at higher levels in WIV- than in SIV-stimulated PBMCs. The combination of WIV and CpG consistently induced the highest levels of antibody-secreting cell differentiation, IgG production, and B-cells secreting IL-6 and IL-10. Taken together, B cells in human PBMC cultures show distinct responses to different types of vaccines and vaccine/CpG combinations. This underlines the suitability of unfractionated PBMCs for evaluating vaccine effects on different types of human immune cells before running costly clinical trials.
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MESH Headings
- Humans
- Influenza Vaccines/immunology
- Adjuvants, Immunologic/administration & dosage
- Adjuvants, Immunologic/pharmacology
- Leukocytes, Mononuclear/immunology
- B-Lymphocytes/immunology
- Immunoglobulin G/immunology
- Immunoglobulin G/blood
- Oligodeoxyribonucleotides/immunology
- Oligodeoxyribonucleotides/pharmacology
- Antibodies, Viral/immunology
- Antibodies, Viral/blood
- Influenza A Virus, H5N1 Subtype/immunology
- Cytokines/metabolism
- Cells, Cultured
- Influenza, Human/prevention & control
- Influenza, Human/immunology
- X-Box Binding Protein 1/immunology
- X-Box Binding Protein 1/genetics
- Adult
- Vaccines, Inactivated/immunology
- Cell Differentiation/immunology
- Interleukin-10/metabolism
- Interleukin-10/immunology
- Positive Regulatory Domain I-Binding Factor 1
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Affiliation(s)
- Shuran Gong
- Department of Medical Microbiology & Infection Prevention, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Martin Beukema
- Department of Medical Microbiology & Infection Prevention, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Jacqueline De Vries-Idema
- Department of Medical Microbiology & Infection Prevention, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Anke Huckriede
- Department of Medical Microbiology & Infection Prevention, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
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3
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Oh T, Woo Y, Kim G, Koo BS, Baek SH, Hwang EH, An YJ, Kim Y, Kim DY, Hong JJ. Spatiotemporal Cellular Dynamics of Germinal Center Reaction in Coronavirus Disease 2019 Lung-Draining Lymph Node Based on Imaging-Based Spatial Transcriptomics. J Transl Med 2025; 105:102180. [PMID: 39522760 DOI: 10.1016/j.labinv.2024.102180] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Revised: 10/28/2024] [Accepted: 10/29/2024] [Indexed: 11/16/2024] Open
Abstract
Although lymph node structures may be compromised in severe SARS-CoV-2 infection, the extent and parameters of recovery in convalescing patients remain unclear. Therefore, this study aimed to elucidate the nuances of lymphoid structural recovery and their implications for immunologic memory in nonhuman primates infected with SARS-CoV-2. To do so, we utilized imaging-based spatial transcriptomics to delineate immune cell composition and tissue architecture formation in the lung-draining lymph nodes during primary infection, convalescence, and reinfection from COVID-19. We noted the establishment of a germinal center with memory B cell differentiation within lymphoid follicles during convalescence accompanied by contrasting transcriptome patterns indicative of the acquisition of follicular helper T cells versus the loss of regulatory T cells. Additionally, repopulation of germinal center-like B cells was observed in the medullary niche with accumulating plasma cells along with enhanced transcriptional expression of B cell-activating factor receptor over the course of reinfection. The spatial transcriptome atlas produced herein enhances our understanding of germinal center formation with immune cell dynamics during COVID-19 convalescence and lymphoid structural recovery with transcriptome dynamics following reinfection. These findings have the potential to inform the optimization of vaccine strategies and the development of precise therapeutic interventions in the spatial context.
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Affiliation(s)
- Taehwan Oh
- National Primate Research Centre, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Cheongju, Chungcheongbuk, Republic of Korea
| | - YoungMin Woo
- National Primate Research Centre, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Cheongju, Chungcheongbuk, Republic of Korea; KRIBB School of Bioscience, Korea University of Science & Technology (UST), Daejeon, Republic of Korea
| | - Green Kim
- National Primate Research Centre, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Cheongju, Chungcheongbuk, Republic of Korea
| | - Bon-Sang Koo
- National Primate Research Centre, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Cheongju, Chungcheongbuk, Republic of Korea
| | - Seung Ho Baek
- National Primate Research Centre, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Cheongju, Chungcheongbuk, Republic of Korea
| | - Eun-Ha Hwang
- National Primate Research Centre, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Cheongju, Chungcheongbuk, Republic of Korea
| | - You Jung An
- National Primate Research Centre, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Cheongju, Chungcheongbuk, Republic of Korea
| | - Yujin Kim
- National Primate Research Centre, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Cheongju, Chungcheongbuk, Republic of Korea
| | - Dong-Yeon Kim
- National Primate Research Centre, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Cheongju, Chungcheongbuk, Republic of Korea
| | - Jung Joo Hong
- National Primate Research Centre, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Cheongju, Chungcheongbuk, Republic of Korea; KRIBB School of Bioscience, Korea University of Science & Technology (UST), Daejeon, Republic of Korea.
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4
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Sun S, Chen Y, Ouyang Y, Tang Z. Regulatory Roles of SWI/SNF Chromatin Remodeling Complexes in Immune Response and Inflammatory Diseases. Clin Rev Allergy Immunol 2024; 68:2. [PMID: 39751934 DOI: 10.1007/s12016-024-09011-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/13/2024] [Indexed: 01/04/2025]
Abstract
The switch/sucrose non-fermentable (SWI/SNF) chromatin remodeling complexes (also referred to as BAF complexes) are composed of multiple subunits, which regulate the nucleosome translocation and chromatin accessibility. In recent years, significant advancements have been made in understanding mutated genes encoding subunits of the SWI/SNF complexes in cancer biology. Nevertheless, the role of SWI/SNF complexes in immune response and inflammatory diseases continues to attract significant attention. This review presents a summary of the significant functions of SWI/SNF complexes during the overall process from the development to the activation of innate and adaptive immune cells. In addition, the correlation between various SWI/SNF subunits and diverse inflammatory diseases is explored. Further investigations are warranted in terms of the mechanism of SWI/SNF complexes' preference for binding sites and opposite pro-/anti-inflammatory effects. In conclusion, further efforts are needed to evaluate the druggability of targeting SWI/SNF complexes in inflammatory diseases, and we hope this review will inspire the development of novel immune modulators in clinical practice.
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Affiliation(s)
- Shunan Sun
- Department of Dermatology, Second Affiliated Hospital, Zhejiang University School of Medicine, 88 Jiefang Road, Hangzhou, 310009, People's Republic of China
- Zhejiang University School of Medicine, Hangzhou, China
| | - Yu Chen
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Yuzhen Ouyang
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Zhenwei Tang
- Department of Dermatology, Second Affiliated Hospital, Zhejiang University School of Medicine, 88 Jiefang Road, Hangzhou, 310009, People's Republic of China.
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5
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Kurasawa T, Muto A, Matsumoto M, Ochiai K, Murayama K, Igarashi K. Absolute quantification of BACH1 and BACH2 transcription factors in B and plasma cells reveals their dynamic changes and unique roles. J Biochem 2024; 176:449-459. [PMID: 39323025 DOI: 10.1093/jb/mvae065] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Revised: 08/05/2024] [Accepted: 09/23/2024] [Indexed: 09/27/2024] Open
Abstract
Changes in the absolute protein amounts of transcription factors are important for regulating gene expression during cell differentiation and in responses to changes in the cellular and extracellular environment. However, few studies have focused on the absolute quantification of mammalian transcription factors. In this study, we established an absolute quantification method for the transcription factors BACH1 and BACH2, which are expressed in B cells and regulated by direct heme binding. The method used purified recombinant proteins as controls in western blotting and was applied to mouse naïve B cells in the spleen, as well as activated B cells and plasma cells. BACH1 was present in naïve B cells at approximately half the levels of BACH2. In activated B cells, BACH1 decreased compared to naïve B cells, whilst BACH2 increased. In plasma cells, BACH1 increased back to the same extent as in naïve B cells, whilst BACH2 was not detected. Their target genes, Prdm1 and Hmox1, were highly induced in plasma cells. BACH1 was found to undergo degradation with lower concentrations of heme than BACH2. Therefore, BACH1 and BACH2 are similarly abundant in B cells but differ in heme sensitivity, potentially regulating gene expression differently depending on their heme responsiveness.
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Affiliation(s)
- Takeshi Kurasawa
- Department of Biochemistry, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
| | - Akihiko Muto
- Department of Biochemistry, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
| | - Mitsuyo Matsumoto
- Department of Biochemistry, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
- Institute of Multidisciplinary Research for Advanced Materials, Tohoku University, 2-1-1 Katahira, Aoba-ku, Sendai 980-8577, Japan
| | - Kyoko Ochiai
- Department of Biochemistry, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
| | - Kazutaka Murayama
- Division of Biomedical Measurements and Diagnostics, Tohoku University Graduate School of Biomedical Engineering, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
| | - Kazuhiko Igarashi
- Department of Biochemistry, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
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6
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Masnikosa R, Cvetković Z, Pirić D. Tumor Biology Hides Novel Therapeutic Approaches to Diffuse Large B-Cell Lymphoma: A Narrative Review. Int J Mol Sci 2024; 25:11384. [PMID: 39518937 PMCID: PMC11545713 DOI: 10.3390/ijms252111384] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2024] [Revised: 10/13/2024] [Accepted: 10/16/2024] [Indexed: 11/16/2024] Open
Abstract
Diffuse large B-cell lymphoma (DLBCL) is a malignancy of immense biological and clinical heterogeneity. Based on the transcriptomic or genomic approach, several different classification schemes have evolved over the years to subdivide DLBCL into clinically (prognostically) relevant subsets, but each leaves unclassified samples. Herein, we outline the DLBCL tumor biology behind the actual and potential drug targets and address the challenges and drawbacks coupled with their (potential) use. Therapeutic modalities are discussed, including small-molecule inhibitors, naked antibodies, antibody-drug conjugates, chimeric antigen receptors, bispecific antibodies and T-cell engagers, and immune checkpoint inhibitors. Candidate drugs explored in ongoing clinical trials are coupled with diverse toxicity issues and refractoriness to drugs. According to the literature on DLBCL, the promise for new therapeutic targets lies in epigenetic alterations, B-cell receptor and NF-κB pathways. Herein, we present putative targets hiding in lipid pathways, ferroptosis, and the gut microbiome that could be used in addition to immuno-chemotherapy to improve the general health status of DLBCL patients, thus increasing the chance of being cured. It may be time to devote more effort to exploring DLBCL metabolism to discover novel druggable targets. We also performed a bibliometric and knowledge-map analysis of the literature on DLBCL published from 2014-2023.
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Affiliation(s)
- Romana Masnikosa
- Department of Physical Chemistry, Vinca Institute of Nuclear Sciences—National Institute of the Republic of Serbia, University of Belgrade, Mike Petrovica Alasa 12-14, 11000 Belgrade, Serbia;
| | - Zorica Cvetković
- Department of Hematology, Clinical Hospital Centre Zemun, Vukova 9, 11000 Belgrade, Serbia
- Faculty of Medicine, University of Belgrade, Dr Subotića 8, 11000 Belgrade, Serbia
| | - David Pirić
- Department of Physical Chemistry, Vinca Institute of Nuclear Sciences—National Institute of the Republic of Serbia, University of Belgrade, Mike Petrovica Alasa 12-14, 11000 Belgrade, Serbia;
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7
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Calmon MS, Lemos FFB, Silva Luz M, Rocha Pinheiro SL, de Oliveira Silva LG, Correa Santos GL, Rocha GR, Freire de Melo F. Immune pathway through endometriosis to ovarian cancer. World J Clin Oncol 2024; 15:496-522. [PMID: 38689629 PMCID: PMC11056862 DOI: 10.5306/wjco.v15.i4.496] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Revised: 01/29/2024] [Accepted: 03/18/2024] [Indexed: 04/22/2024] Open
Abstract
Endometriosis is an estrogen-dependent inflammatory disease, defined by the presence of functional endometrial tissue outside of the uterine cavity. This disease is one of the main gynecological diseases, affecting around 10%-15% women and girls of reproductive age, being a common gynecologic disorder. Although endometriosis is a benign disease, it shares several characteristics with invasive cancer. Studies support that it has been linked with an increased chance of developing endometrial ovarian cancer, representing an earlier stage of neoplastic processes. This is particularly true for women with clear cell carcinoma, low-grade serous carcinoma and endometrioid. However, the carcinogenic pathways between both pathologies remain poorly understood. Current studies suggest a connection between endometriosis and endometriosis-associated ovarian cancers (EAOCs) via pathways associated with oxidative stress, inflammation, and hyperestrogenism. This article aims to review current data on the molecular events linked to the development of EAOCs from endometriosis, specifically focusing on the complex relationship between the immune response to endometriosis and cancer, including the molecular mechanisms and their ramifications. Examining recent developments in immunotherapy and their potential to boost the effectiveness of future treatments.
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Affiliation(s)
- Mariana Santos Calmon
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Fabian Fellipe Bueno Lemos
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Marcel Silva Luz
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Samuel Luca Rocha Pinheiro
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | | | - Gabriel Lima Correa Santos
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Gabriel Reis Rocha
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Fabrício Freire de Melo
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
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8
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Xiang M, Li H, Zhan Y, Ma D, Gao Q, Fang Y. Functional CRISPR screens in T cells reveal new opportunities for cancer immunotherapies. Mol Cancer 2024; 23:73. [PMID: 38581063 PMCID: PMC10996278 DOI: 10.1186/s12943-024-01987-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Accepted: 03/25/2024] [Indexed: 04/07/2024] Open
Abstract
T cells are fundamental components in tumour immunity and cancer immunotherapies, which have made immense strides and revolutionized cancer treatment paradigm. However, recent studies delineate the predicament of T cell dysregulation in tumour microenvironment and the compromised efficacy of cancer immunotherapies. CRISPR screens enable unbiased interrogation of gene function in T cells and have revealed functional determinators, genetic regulatory networks, and intercellular interactions in T cell life cycle, thereby providing opportunities to revamp cancer immunotherapies. In this review, we briefly described the central roles of T cells in successful cancer immunotherapies, comprehensively summarised the studies of CRISPR screens in T cells, elaborated resultant master genes that control T cell activation, proliferation, fate determination, effector function, and exhaustion, and highlighted genes (BATF, PRDM1, and TOX) and signalling cascades (JAK-STAT and NF-κB pathways) that extensively engage in multiple branches of T cell responses. In conclusion, this review bridged the gap between discovering element genes to a specific process of T cell activities and apprehending these genes in the global T cell life cycle, deepened the understanding of T cell biology in tumour immunity, and outlined CRISPR screens resources that might facilitate the development and implementation of cancer immunotherapies in the clinic.
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Affiliation(s)
- Minghua Xiang
- Department of Obstetrics and Gynecology, National Clinical Research Center for Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Key Laboratory of Cancer Invasion and Metastasis (Ministry of Education), Hubei Key Laboratory of Tumor Invasion and Metastasis, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Huayi Li
- Department of Obstetrics and Gynecology, National Clinical Research Center for Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Key Laboratory of Cancer Invasion and Metastasis (Ministry of Education), Hubei Key Laboratory of Tumor Invasion and Metastasis, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yuanyuan Zhan
- Department of Plastic and Cosmetic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ding Ma
- Department of Obstetrics and Gynecology, National Clinical Research Center for Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Key Laboratory of Cancer Invasion and Metastasis (Ministry of Education), Hubei Key Laboratory of Tumor Invasion and Metastasis, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qinglei Gao
- Department of Obstetrics and Gynecology, National Clinical Research Center for Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
- Key Laboratory of Cancer Invasion and Metastasis (Ministry of Education), Hubei Key Laboratory of Tumor Invasion and Metastasis, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Yong Fang
- Department of Obstetrics and Gynecology, National Clinical Research Center for Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
- Key Laboratory of Cancer Invasion and Metastasis (Ministry of Education), Hubei Key Laboratory of Tumor Invasion and Metastasis, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
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9
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Koshkin A, Herbach U, Martínez MR, Gandrillon O, Crauste F. Stochastic modeling of a gene regulatory network driving B cell development in germinal centers. PLoS One 2024; 19:e0301022. [PMID: 38547073 PMCID: PMC10977792 DOI: 10.1371/journal.pone.0301022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2023] [Accepted: 03/08/2024] [Indexed: 04/02/2024] Open
Abstract
Germinal centers (GCs) are the key histological structures of the adaptive immune system, responsible for the development and selection of B cells producing high-affinity antibodies against antigens. Due to their level of complexity, unexpected malfunctioning may lead to a range of pathologies, including various malignant formations. One promising way to improve the understanding of malignant transformation is to study the underlying gene regulatory networks (GRNs) associated with cell development and differentiation. Evaluation and inference of the GRN structure from gene expression data is a challenging task in systems biology: recent achievements in single-cell (SC) transcriptomics allow the generation of SC gene expression data, which can be used to sharpen the knowledge on GRN structure. In order to understand whether a particular network of three key gene regulators (BCL6, IRF4, BLIMP1), influenced by two external stimuli signals (surface receptors BCR and CD40), is able to describe GC B cell differentiation, we used a stochastic model to fit SC transcriptomic data from a human lymphoid organ dataset. The model is defined mathematically as a piecewise-deterministic Markov process. We showed that after parameter tuning, the model qualitatively recapitulates mRNA distributions corresponding to GC and plasmablast stages of B cell differentiation. Thus, the model can assist in validating the GRN structure and, in the future, could lead to better understanding of the different types of dysfunction of the regulatory mechanisms.
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Affiliation(s)
- Alexey Koshkin
- Inria Dracula, Villeurbanne, France
- Laboratory of Biology and Modelling of the Cell, Universite de Lyon, ENS de Lyon, Université Claude Bernard, CNRS UMR 5239, INSERM U1210, Lyon, France
| | - Ulysse Herbach
- Université de Lorraine, CNRS, Inria, IECL, Nancy, France
| | | | - Olivier Gandrillon
- Inria Dracula, Villeurbanne, France
- Laboratory of Biology and Modelling of the Cell, Universite de Lyon, ENS de Lyon, Université Claude Bernard, CNRS UMR 5239, INSERM U1210, Lyon, France
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10
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Wang W, Fan Z, Yan Q, Pan T, Luo J, Wei Y, Li B, Fang Z, Lu W. Gut microbiota determines the fate of dietary fiber-targeted interventions in host health. Gut Microbes 2024; 16:2416915. [PMID: 39418223 PMCID: PMC11487953 DOI: 10.1080/19490976.2024.2416915] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2024] [Revised: 07/04/2024] [Accepted: 10/10/2024] [Indexed: 10/19/2024] Open
Abstract
Epidemiological investigation confirmed that the intake of dietary fiber (DF) is closely related to human health, and the most important factor affecting the physiological function of DF, besides its physicochemical properties, is the gut microbiota. This paper mainly summarizes the interaction between DF and gut microbiota, including the influence of DF on the colonization of gut microbiota based on its different physicochemical properties, and the physiological role of gut microbiota in destroying the complex molecular structure of DF by encoding carbohydrate-active enzymes, thus producing small molecular products that affect the metabolism of the host. Taking cardiovascular disease (Atherosclerosis and hypertension), liver disease, and immune diseases as examples, it is confirmed that some DF, such as fructo-oligosaccharide, galactooligosaccharide, xylo-oligosaccharide, and inulin, have prebiotic-like physiological effects. These effects are dependent on the metabolites produced by the gut microbiota. Therefore, this paper further explores how DF affects the gut microbiota's production of substances such as short-chain fatty acids, bile acids, and tryptophan metabolites, and provides a preliminary explanation of the mechanisms associated with their impact on host health. Finally, based on the structural properties of DF and the large heterogeneity in the composition of the population gut microbiota, it may be a future trend to utilize DF and the gut microbiota to correlate host health for precision nutrition by combining the information from population disease databases.
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Affiliation(s)
- Wenjing Wang
- School of Food Science and Technology, Shihezi University, Shihezi, China
| | - Zhexin Fan
- School of Food Science and Technology, Shihezi University, Shihezi, China
- Key Laboratory of Characteristics Agricultural Product Processing and Quality Control (Co-construction by Ministry and Province), Ministry of Agriculture and Rural Affairs, School of Food Science and Technology, Shihezi University, Shihezi, Xinjiang, China
- Key Laboratory for Food Nutrition and Safety Control of Xinjiang Production and Construction Corps, School of Food Science and Technology, Shihezi University, Shihezi, Xinjiang, China
- Engineering Research Center of Storage and Processing of Xinjiang Characteristic Fruits and Vegetables, Ministry of Education, School of Food Science and Technology, Shihezi University, Shihezi, Xinjiang, China
| | - Qingqing Yan
- School of Food Science and Technology, Shihezi University, Shihezi, China
| | - Tong Pan
- School of Food Science and Technology, Jiangnan University, Wuxi, China
| | - Jing Luo
- School of Food Science and Technology, Shihezi University, Shihezi, China
| | - Yijiang Wei
- School of Food Science and Technology, Shihezi University, Shihezi, China
| | - Baokun Li
- School of Food Science and Technology, Shihezi University, Shihezi, China
- Key Laboratory of Characteristics Agricultural Product Processing and Quality Control (Co-construction by Ministry and Province), Ministry of Agriculture and Rural Affairs, School of Food Science and Technology, Shihezi University, Shihezi, Xinjiang, China
- Key Laboratory for Food Nutrition and Safety Control of Xinjiang Production and Construction Corps, School of Food Science and Technology, Shihezi University, Shihezi, Xinjiang, China
- Engineering Research Center of Storage and Processing of Xinjiang Characteristic Fruits and Vegetables, Ministry of Education, School of Food Science and Technology, Shihezi University, Shihezi, Xinjiang, China
| | - Zhifeng Fang
- School of Food Science and Technology, Shihezi University, Shihezi, China
- Key Laboratory of Characteristics Agricultural Product Processing and Quality Control (Co-construction by Ministry and Province), Ministry of Agriculture and Rural Affairs, School of Food Science and Technology, Shihezi University, Shihezi, Xinjiang, China
- Key Laboratory for Food Nutrition and Safety Control of Xinjiang Production and Construction Corps, School of Food Science and Technology, Shihezi University, Shihezi, Xinjiang, China
- Engineering Research Center of Storage and Processing of Xinjiang Characteristic Fruits and Vegetables, Ministry of Education, School of Food Science and Technology, Shihezi University, Shihezi, Xinjiang, China
| | - Wenwei Lu
- School of Food Science and Technology, Jiangnan University, Wuxi, China
- National Engineering Research Center for Functional Food, Jiangnan University, Wuxi, China
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Zhang F, Cheng T, Zhang SX. Mechanistic target of rapamycin (mTOR): a potential new therapeutic target for rheumatoid arthritis. Arthritis Res Ther 2023; 25:187. [PMID: 37784141 PMCID: PMC10544394 DOI: 10.1186/s13075-023-03181-w] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Accepted: 09/25/2023] [Indexed: 10/04/2023] Open
Abstract
Rheumatoid arthritis (RA) is an autoimmune disease characterized by systemic synovitis and bone destruction. Proinflammatory cytokines activate pathways of immune-mediated inflammation, which aggravates RA. The mechanistic target of rapamycin (mTOR) signaling pathway associated with RA connects immune and metabolic signals, which regulates immune cell proliferation and differentiation, macrophage polarization and migration, antigen presentation, and synovial cell activation. Therefore, therapy strategies targeting mTOR have become an important direction of current RA treatment research. In the current review, we summarize the biological functions of mTOR, its regulatory effects on inflammation, and the curative effects of mTOR inhibitors in RA, thus providing references for the development of RA therapeutic targets and new drugs.
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Affiliation(s)
- Fen Zhang
- Department of Rheumatology, The Second Hospital of Shanxi Medical University, No. 382, Wuyi Road, Xinghualing District, Taiyuan, 030001, Shanxi Province, China
- Shanxi Provincial Key Laboratory of Rheumatism Immune Microecology, Taiyuan, Shanxi Province, China
- Key Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, Taiyuan, Shanxi Province, China
| | - Ting Cheng
- Department of Rheumatology, The Second Hospital of Shanxi Medical University, No. 382, Wuyi Road, Xinghualing District, Taiyuan, 030001, Shanxi Province, China
- Shanxi Provincial Key Laboratory of Rheumatism Immune Microecology, Taiyuan, Shanxi Province, China
- Key Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, Taiyuan, Shanxi Province, China
| | - Sheng-Xiao Zhang
- Department of Rheumatology, The Second Hospital of Shanxi Medical University, No. 382, Wuyi Road, Xinghualing District, Taiyuan, 030001, Shanxi Province, China.
- Shanxi Provincial Key Laboratory of Rheumatism Immune Microecology, Taiyuan, Shanxi Province, China.
- Key Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, Taiyuan, Shanxi Province, China.
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Jiménez-Guerrero R, Karlsen C, Boudinot P, Afanasyev S, Mørkøre T, Krasnov A. Differentiation and traffic of IgM + B cells between focal dark spots in skeletal muscle of Atlantic salmon, lymphoid and adipose tissues. FISH & SHELLFISH IMMUNOLOGY 2023:108858. [PMID: 37302676 DOI: 10.1016/j.fsi.2023.108858] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/13/2023] [Revised: 05/12/2023] [Accepted: 05/28/2023] [Indexed: 06/13/2023]
Abstract
Focal dark spots (DS) in farmed Atlantic salmon fillets contain a significant number of B cells as revealed by the high abundance of immunoglobulin (Ig) transcripts in transcriptome data. The immune response in DS remains unknown while they represent a major problem in commercial aquaculture. Here, we characterized the diversity and clonal composition of B cells in DS. Sixteen gene markers of immune cells and antigen presentation were analyzed with RT-qPCR. All genes expression showed a positive correlation with DS area and intensity. The flatter the DS, the higher the expression of cd28, csfr, ctla, igt, and sigm, the lower expression of cd83 and btla, and the larger the cumulative frequency within DS. The expression of most of the analyzed immune genes, including three Ig types and markers of B cells was lower in DS than in the lymphatic organs, head kidney and spleen, but significantly higher compared to skeletal muscle. High levels of ctla4 and cd28 in DS might indicate the recruitment of T cells. Sequencing of IgM repertoire (Ig-seq) assessed migration of B cells by co-occurrence of identical CDR3 sequences in different tissues. The combination of gene expression and Ig-seq revealed the presence of several stages of B cell differentiation in DS. B cells at the earliest stage, with high ratio of membrane to secretory IgM (migm and sigm), showed minor Ig repertoire overlap with other tissues. Further differentiation stage (increased sigm to migm ratio and high expression of pax5 and cd79) was associated with active movement of B cells from DS towards lymphatic organs and visceral fat. Traffic and expression of immune genes decreased at later stages. These B cells could be involved in a response directed against viruses, pathogenic or opportunistic bacteria in DS. Seven of eight fish were positive for salmon alphavirus, and levels were higher in DS than in unstained muscle. PCR with universal primers to the 16S rRNA gene did not detect bacteria in DS. Although the evolution of DS most likely implies local exposure to antigens, neither this nor previous studies have found a necessary association between DS and pathogens or self-antigens.
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Affiliation(s)
- Raúl Jiménez-Guerrero
- Department of Animal and Aquacultural Sciences, Norwegian University of Life Sciences, Ås, Norway.
| | | | - Pierre Boudinot
- Université Paris-Saclay, INRAE, UVSQ, VIM, Jouy-en-Josas, 78350, France
| | - Sergey Afanasyev
- Sechenov Institute of Evolutionary Physiology and Biochemistry, Saint Petersburg, Russia
| | - Turid Mørkøre
- Department of Animal and Aquacultural Sciences, Norwegian University of Life Sciences, Ås, Norway
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Li Q, Wang W, Wu S, Li J, Dong M, Wang L, Song L. CgBlimp-1 inhibits granulocytes proliferation and interleukin production in the immune response of oyster Crassostrea gigas. DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY 2023; 142:104652. [PMID: 36736934 DOI: 10.1016/j.dci.2023.104652] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Revised: 01/27/2023] [Accepted: 01/30/2023] [Indexed: 06/18/2023]
Abstract
B lymphocyte-inducible maturation protein 1 (Blimp-1) is a SET domain and zinc fingers containing transcriptional repressor, which is necessary for regulating the development of many immune cell lineages and keeping immune homeostasis. In the present study, a Blimp-1 homologue (designated as CgBlimp-1) was identified from oyster Crassostrea gigas, which contained a conserved SET domain and five ZnF_C2H2 domains and shared high homology with Blimp-1 from other species. The mRNA transcripts of CgBlimp-1 were highly expressed in gill and hepatopancreas. CgBlimp-1 protein was detected to be specifically expressed in granulocytes. After V. splendidus stimulation, the mRNA expression level of CgBlimp-1 in haemocytes up-regulated significantly at 24, 48, and 96 h, which was 4.39-fold (p < 0.05), 7.68-fold (p < 0.01) and 2.65-fold (p < 0.05) of that in control group, respectively. When the expression of CgBlimp-1 was knocked-down in vivo by RNAi, the mRNA expressions of downstream transcription factor CgMyc-A (1.63-fold of that in control group, p < 0.05) and cell cycle related gene CgCDK2 (1.70-fold, p < 0.05) increased significantly at 24 h after V. splendidus stimulation. Concomitantly, the ratio of EdU+ haemocytes increased notably (p < 0.01) while the proportion of haemocytes in G0/G1 phase decreased dramatically (p < 0.001), compared to that in control group. More specifically, the proportion of granulocytes in total haemocytes increased apparently (p < 0.05) in CgBlimp-1-RNAi oysters, together with up-regulation (p < 0.05) of the ratio of EdU+ granulocytes and down-regulation (p < 0.001) of the proportion of granulocytes in G0/G1 phase. Furthermore, the mRNA expression levels of CgIL17-1, CgIL17-2 and CgIL17-4 in haemocytes increased significantly in CgBlimp-1-RNAi oysters, which was 1.71-fold (p < 0.05), 144.70-fold (p < 0.01) and 1.93-fold (p < 0.05) of that in control group, respectively. Aforementioned results suggested that CgBlimp-1 could reduce the proliferation of granulocytes by arresting cell cycle in G1/G0 phase and avoid over-expression of interleukin to maintain homeostasis in the immune response of oyster.
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Affiliation(s)
- Qing Li
- Liaoning Key Laboratory of Marine Animal Immunology and Disease Control, Dalian Ocean University, Dalian, 116023, China; Liaoning Key Laboratory of Marine Animal Immunology, Dalian Ocean University, Dalian, 116023, China; Dalian Key Laboratory of Aquatic Animal Disease Prevention and Control, Dalian Ocean University, Dalian, 116023, China
| | - Weilin Wang
- Liaoning Key Laboratory of Marine Animal Immunology and Disease Control, Dalian Ocean University, Dalian, 116023, China; Liaoning Key Laboratory of Marine Animal Immunology, Dalian Ocean University, Dalian, 116023, China; Dalian Key Laboratory of Aquatic Animal Disease Prevention and Control, Dalian Ocean University, Dalian, 116023, China.
| | - Shasha Wu
- Liaoning Key Laboratory of Marine Animal Immunology and Disease Control, Dalian Ocean University, Dalian, 116023, China; Liaoning Key Laboratory of Marine Animal Immunology, Dalian Ocean University, Dalian, 116023, China; Dalian Key Laboratory of Aquatic Animal Disease Prevention and Control, Dalian Ocean University, Dalian, 116023, China
| | - Jialuo Li
- Liaoning Key Laboratory of Marine Animal Immunology and Disease Control, Dalian Ocean University, Dalian, 116023, China; Liaoning Key Laboratory of Marine Animal Immunology, Dalian Ocean University, Dalian, 116023, China; Dalian Key Laboratory of Aquatic Animal Disease Prevention and Control, Dalian Ocean University, Dalian, 116023, China
| | - Miren Dong
- Liaoning Key Laboratory of Marine Animal Immunology and Disease Control, Dalian Ocean University, Dalian, 116023, China; Liaoning Key Laboratory of Marine Animal Immunology, Dalian Ocean University, Dalian, 116023, China; Dalian Key Laboratory of Aquatic Animal Disease Prevention and Control, Dalian Ocean University, Dalian, 116023, China
| | - Lingling Wang
- Liaoning Key Laboratory of Marine Animal Immunology and Disease Control, Dalian Ocean University, Dalian, 116023, China; Liaoning Key Laboratory of Marine Animal Immunology, Dalian Ocean University, Dalian, 116023, China; Dalian Key Laboratory of Aquatic Animal Disease Prevention and Control, Dalian Ocean University, Dalian, 116023, China.
| | - Linsheng Song
- Liaoning Key Laboratory of Marine Animal Immunology and Disease Control, Dalian Ocean University, Dalian, 116023, China; Functional Laboratory of Marine Fisheries Science and Food Production Process, Qingdao National Laboratory for Marine Science and Technology, Qingdao, 266235, China; Liaoning Key Laboratory of Marine Animal Immunology, Dalian Ocean University, Dalian, 116023, China; Dalian Key Laboratory of Aquatic Animal Disease Prevention and Control, Dalian Ocean University, Dalian, 116023, China
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Melnik BC, Stadler R, Weiskirchen R, Leitzmann C, Schmitz G. Potential Pathogenic Impact of Cow’s Milk Consumption and Bovine Milk-Derived Exosomal MicroRNAs in Diffuse Large B-Cell Lymphoma. Int J Mol Sci 2023; 24:ijms24076102. [PMID: 37047075 PMCID: PMC10094152 DOI: 10.3390/ijms24076102] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Revised: 03/05/2023] [Accepted: 03/16/2023] [Indexed: 03/29/2023] Open
Abstract
Epidemiological evidence supports an association between cow’s milk consumption and the risk of diffuse large B-cell lymphoma (DLBCL), the most common non-Hodgkin lymphoma worldwide. This narrative review intends to elucidate the potential impact of milk-related agents, predominantly milk-derived exosomes (MDEs) and their microRNAs (miRs) in lymphomagenesis. Upregulation of PI3K-AKT-mTORC1 signaling is a common feature of DLBCL. Increased expression of B cell lymphoma 6 (BCL6) and suppression of B lymphocyte-induced maturation protein 1 (BLIMP1)/PR domain-containing protein 1 (PRDM1) are crucial pathological deviations in DLBCL. Translational evidence indicates that during the breastfeeding period, human MDE miRs support B cell proliferation via epigenetic upregulation of BCL6 (via miR-148a-3p-mediated suppression of DNA methyltransferase 1 (DNMT1) and miR-155-5p/miR-29b-5p-mediated suppression of activation-induced cytidine deaminase (AICDA) and suppression of BLIMP1 (via MDE let-7-5p/miR-125b-5p-targeting of PRDM1). After weaning with the physiological termination of MDE miR signaling, the infant’s BCL6 expression and B cell proliferation declines, whereas BLIMP1-mediated B cell maturation for adequate own antibody production rises. Because human and bovine MDE miRs share identical nucleotide sequences, the consumption of pasteurized cow’s milk in adults with the continued transfer of bioactive bovine MDE miRs may de-differentiate B cells back to the neonatal “proliferation-dominated” B cell phenotype maintaining an increased BLC6/BLIMP1 ratio. Persistent milk-induced epigenetic dysregulation of BCL6 and BLIMP1 expression may thus represent a novel driving mechanism in B cell lymphomagenesis. Bovine MDEs and their miR cargo have to be considered potential pathogens that should be removed from the human food chain.
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15
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Medina S, Ihrie RA, Irish JM. Learning cell identity in immunology, neuroscience, and cancer. Semin Immunopathol 2023; 45:3-16. [PMID: 36534139 PMCID: PMC9762661 DOI: 10.1007/s00281-022-00976-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Accepted: 11/19/2022] [Indexed: 12/23/2022]
Abstract
Suspension and imaging cytometry techniques that simultaneously measure hundreds of cellular features are powering a new era of cell biology and transforming our understanding of human tissues and tumors. However, a central challenge remains in learning the identities of unexpected or novel cell types. Cell identification rubrics that could assist trainees, whether human or machine, are not always rigorously defined, vary greatly by field, and differentially rely on cell intrinsic measurements, cell extrinsic tissue measurements, or external contextual information such as clinical outcomes. This challenge is especially acute in the context of tumors, where cells aberrantly express developmental programs that are normally time, location, or cell-type restricted. Well-established fields have contrasting practices for cell identity that have emerged from convention and convenience as much as design. For example, early immunology focused on identifying minimal sets of protein features that mark individual, functionally distinct cells. In neuroscience, features including morphology, development, and anatomical location were typical starting points for defining cell types. Both immunology and neuroscience now aim to link standardized measurements of protein or RNA to informative cell functions such as electrophysiology, connectivity, lineage potential, phospho-protein signaling, cell suppression, and tumor cell killing ability. The expansion of automated, machine-driven methods for learning cell identity has further created an urgent need for a harmonized framework for distinguishing cell identity across fields and technology platforms. Here, we compare practices in the fields of immunology and neuroscience, highlight concepts from each that might work well in the other, and propose ways to implement these ideas to study neural and immune cell interactions in brain tumors and associated model systems.
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Affiliation(s)
- Stephanie Medina
- Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, USA
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Rebecca A Ihrie
- Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, USA
- Department of Neurological Surgery, Vanderbilt University Medical Center, Nashville, TN, USA
- Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Jonathan M Irish
- Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, USA.
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.
- Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA.
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16
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The trehalose glycolipid C18Brar promotes antibody and T-cell immune responses to Mannheimia haemolytica and Mycoplasma ovipneumoniae whole cell antigens in sheep. PLoS One 2023; 18:e0278853. [PMID: 36656850 PMCID: PMC9851559 DOI: 10.1371/journal.pone.0278853] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Accepted: 11/23/2022] [Indexed: 01/20/2023] Open
Abstract
Bronchopneumonia is a common respiratory disease in livestock. Mannheimia haemolytica is considered the main causative pathogen leading to lung damage in sheep, with Mycoplasma ovipneumoniae and ParaInfluenza virus type 3, combined with adverse physical and physiological stress, being predisposing factors. A balance of humoral and cellular immunity is thought to be important for protection against developing respiratory disease. In the current study, we compared the ability of the trehalose glycolipid adjuvant C18Brar (C18-alkylated brartemicin analogue) and three commercially available adjuvant systems i.e., Quil-A, Emulsigen-D, and a combination of Quil-A and aluminium hydroxide gel, to stimulate antibody and cellular immune responses to antigens from inactivated whole cells of M. haemolytica and M. ovipneumoniae in sheep. C18Brar and Emulsigen-D induced the strongest antigen-specific antibody responses to both M. haemolytica and M. ovipneumoniae, while C18Brar and Quil-A promoted the strongest antigen-specific IL-17A responses. The expression of genes with known immune functions was determined in antigen-stimulated blood cultures using Nanostring nCounter technology. The expression levels of CD40, IL22, TGFB1, and IL2RA were upregulated in antigen-stimulated blood cultures from animals vaccinated with C18Brar, which is consistent with T-cell activation. Collectively, the results demonstrate that C18Brar can promote both antibody and cellular responses, notably Th17 immune responses in a ruminant species.
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17
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Jung SM, Baek IW, Park KS, Kim KJ. De novo molecular subtyping of salivary gland tissue in the context of Sjögren's syndrome heterogeneity. Clin Immunol 2022; 245:109171. [DOI: 10.1016/j.clim.2022.109171] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Revised: 10/26/2022] [Accepted: 10/27/2022] [Indexed: 11/08/2022]
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Gao L, Zhou J, Ye L. Role of CXCR5 + CD8 + T cells in human immunodeficiency virus-1 infection. Front Microbiol 2022; 13:998058. [PMID: 36452930 PMCID: PMC9701836 DOI: 10.3389/fmicb.2022.998058] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Accepted: 10/24/2022] [Indexed: 07/30/2023] Open
Abstract
Human immunodeficiency virus (HIV) infection can be effectively suppressed by life-long administration of combination antiretroviral therapy (cART). However, the viral rebound can occur upon cART cessation due to the long-term presence of HIV reservoirs, posing a considerable barrier to drug-free viral remission. Memory CD4+ T cell subsets, especially T follicular helper (T FH ) cells that reside in B-cell follicles within lymphoid tissues, are regarded as the predominant cellular compartment of the HIV reservoir. Substantial evidence indicates that HIV-specific CD8+ T cell-mediated cellular immunity can sustain long-term disease-free and transmission-free HIV control in elite controllers. However, most HIV cure strategies that rely on expanded HIV-specific CD8+ T cells for virus control are likely to fail due to cellular exhaustion and T FH reservoir-specialized anatomical structures that isolate HIV-specific CD8+ T cell entry into B-cell follicles. Loss of stem-like memory properties is a key feature of exhaustion. Recent studies have found that CXC chemokine receptor type 5 (CXCR5)-expressing HIV-specific CD8+ T cells are memory-like CD8+ T cells that can migrate into B-cell follicles to execute inhibition of viral replication. Furthermore, these unique CD8+ T cells can respond to immune checkpoint blockade (ICB) therapy. In this review, we discuss the functions of these CD8+ T cells as well as the translation of findings into viable HIV treatment and cure strategies.
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Affiliation(s)
- Leiqiong Gao
- Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Jing Zhou
- Institute of Immunology, Third Military Medical University, Chongqing, China
| | - Lilin Ye
- Institute of Immunology, Third Military Medical University, Chongqing, China
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19
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Zhao Y, Vartak SV, Conte A, Wang X, Garcia DA, Stevens E, Kyoung Jung S, Kieffer-Kwon KR, Vian L, Stodola T, Moris F, Chopp L, Preite S, Schwartzberg PL, Kulinski JM, Olivera A, Harly C, Bhandoola A, Heuston EF, Bodine DM, Urrutia R, Upadhyaya A, Weirauch MT, Hager G, Casellas R. "Stripe" transcription factors provide accessibility to co-binding partners in mammalian genomes. Mol Cell 2022; 82:3398-3411.e11. [PMID: 35863348 PMCID: PMC9481673 DOI: 10.1016/j.molcel.2022.06.029] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Revised: 04/06/2022] [Accepted: 06/22/2022] [Indexed: 10/17/2022]
Abstract
Regulatory elements activate promoters by recruiting transcription factors (TFs) to specific motifs. Notably, TF-DNA interactions often depend on cooperativity with colocalized partners, suggesting an underlying cis-regulatory syntax. To explore TF cooperativity in mammals, we analyze ∼500 mouse and human primary cells by combining an atlas of TF motifs, footprints, ChIP-seq, transcriptomes, and accessibility. We uncover two TF groups that colocalize with most expressed factors, forming stripes in hierarchical clustering maps. The first group includes lineage-determining factors that occupy DNA elements broadly, consistent with their key role in tissue-specific transcription. The second one, dubbed universal stripe factors (USFs), comprises ∼30 SP, KLF, EGR, and ZBTB family members that recognize overlapping GC-rich sequences in all tissues analyzed. Knockouts and single-molecule tracking reveal that USFs impart accessibility to colocalized partners and increase their residence time. Mammalian cells have thus evolved a TF superfamily with overlapping DNA binding that facilitate chromatin accessibility.
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Affiliation(s)
- Yongbing Zhao
- The NIH Regulome Project, National Institutes of Health, Bethesda, MD 20892, USA; Lymphocyte Nuclear Biology, NIAMS-NCI, NIH, Bethesda, MD 20892, USA.
| | - Supriya V Vartak
- The NIH Regulome Project, National Institutes of Health, Bethesda, MD 20892, USA; Lymphocyte Nuclear Biology, NIAMS-NCI, NIH, Bethesda, MD 20892, USA
| | - Andrea Conte
- The NIH Regulome Project, National Institutes of Health, Bethesda, MD 20892, USA; Lymphocyte Nuclear Biology, NIAMS-NCI, NIH, Bethesda, MD 20892, USA
| | - Xiang Wang
- The NIH Regulome Project, National Institutes of Health, Bethesda, MD 20892, USA; Lymphocyte Nuclear Biology, NIAMS-NCI, NIH, Bethesda, MD 20892, USA
| | - David A Garcia
- Laboratory of Receptor Biology and Gene Expression, NCI, NIH, Bethesda, MD 20893, USA; Department of Physics, University of Maryland, College Park, MD 20742, USA
| | - Evan Stevens
- Lymphocyte Nuclear Biology, NIAMS-NCI, NIH, Bethesda, MD 20892, USA
| | - Seol Kyoung Jung
- The NIH Regulome Project, National Institutes of Health, Bethesda, MD 20892, USA; Lymphocyte Nuclear Biology, NIAMS-NCI, NIH, Bethesda, MD 20892, USA
| | | | - Laura Vian
- Lymphocyte Nuclear Biology, NIAMS-NCI, NIH, Bethesda, MD 20892, USA
| | - Timothy Stodola
- Genomic Sciences and Precision Medicine Center (GSPMC), Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Francisco Moris
- EntreChem S.L., Vivero Ciencias de la Salud, 33011 Oviedo, Spain
| | - Laura Chopp
- Laboratory of Immune Cell Biology, NCI, NIH, Bethesda, MD 20892, USA
| | - Silvia Preite
- Laboratory of Immune System Biology, NIAID, NIH, Bethesda, MD 20892, USA
| | | | - Joseph M Kulinski
- Mast cell Biology Section, Laboratory of Allergic Diseases, NIAID, NIH, Bethesda, MD 20892, USA
| | - Ana Olivera
- Mast cell Biology Section, Laboratory of Allergic Diseases, NIAID, NIH, Bethesda, MD 20892, USA
| | - Christelle Harly
- Laboratory of Genome Integrity, NCI, NIH, Bethesda, MD 20892, USA
| | | | | | - David M Bodine
- Genetics and Molecular Biology Branch, NHGRI, NIH, Bethesda, MD 20892, USA
| | - Raul Urrutia
- Genomic Sciences and Precision Medicine Center (GSPMC), Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Arpita Upadhyaya
- Department of Physics, University of Maryland, College Park, MD 20742, USA
| | - Matthew T Weirauch
- Divisions of Biomedical Informatics and Developmental Biology, Center for Autoimmune Genomics and Etiology (CAGE), Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA
| | - Gordon Hager
- Laboratory of Receptor Biology and Gene Expression, NCI, NIH, Bethesda, MD 20893, USA
| | - Rafael Casellas
- The NIH Regulome Project, National Institutes of Health, Bethesda, MD 20892, USA; Lymphocyte Nuclear Biology, NIAMS-NCI, NIH, Bethesda, MD 20892, USA.
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20
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Qi F, Cao Y, Zhang S, Zhang Z. Single-cell analysis of the adaptive immune response to SARS-CoV-2 infection and vaccination. Front Immunol 2022; 13:964976. [PMID: 36119105 PMCID: PMC9478577 DOI: 10.3389/fimmu.2022.964976] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Accepted: 08/10/2022] [Indexed: 12/04/2022] Open
Abstract
Amid the ongoing Coronavirus Disease 2019 (COVID-19) pandemic, vaccination and early therapeutic interventions are the most effective means to combat and control the severity of the disease. Host immune responses to SARS-CoV-2 and its variants, particularly adaptive immune responses, should be fully understood to develop improved strategies to implement these measures. Single-cell multi-omic technologies, including flow cytometry, single-cell transcriptomics, and single-cell T-cell receptor (TCR) and B-cell receptor (BCR) profiling, offer a better solution to examine the protective or pathological immune responses and molecular mechanisms associated with SARS-CoV-2 infection, thus providing crucial support for the development of vaccines and therapeutics for COVID-19. Recent reviews have revealed the overall immune landscape of natural SARS-CoV-2 infection, and this review will focus on adaptive immune responses (including T cells and B cells) to SARS-CoV-2 revealed by single-cell multi-omics technologies. In addition, we explore how the single-cell analyses disclose the critical components of immune protection and pathogenesis during SARS-CoV-2 infection through the comparison between the adaptive immune responses induced by natural infection and by vaccination.
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Affiliation(s)
- Furong Qi
- Institute for Hepatology, National Clinical Research Center for Infectious Disease, Shenzhen Third People’s Hospital, The Second Affiliated Hospital, School of Medicine, Southern University of Science and Technology, Shenzhen, China
- Shenzhen Key Laboratory of Single-Cell Omics Reasearch and Application, Shenzhen, China
| | - Yingyin Cao
- Institute for Hepatology, National Clinical Research Center for Infectious Disease, Shenzhen Third People’s Hospital, The Second Affiliated Hospital, School of Medicine, Southern University of Science and Technology, Shenzhen, China
| | - Shuye Zhang
- Clinical Center for BioTherapy and Institutes of Biomedical Sciences, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Zheng Zhang
- Institute for Hepatology, National Clinical Research Center for Infectious Disease, Shenzhen Third People’s Hospital, The Second Affiliated Hospital, School of Medicine, Southern University of Science and Technology, Shenzhen, China
- Shenzhen Key Laboratory of Single-Cell Omics Reasearch and Application, Shenzhen, China
- Shenzhen Research Center for Communicable Disease Diagnosis and Treatment of Chinese Academy of Medical Science, Shenzhen, China
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21
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Yi SG, Gaber AO, Chen W. B-cell response in solid organ transplantation. Front Immunol 2022; 13:895157. [PMID: 36016958 PMCID: PMC9395675 DOI: 10.3389/fimmu.2022.895157] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2022] [Accepted: 07/11/2022] [Indexed: 11/21/2022] Open
Abstract
The transcriptional regulation of B-cell response to antigen stimulation is complex and involves an intricate network of dynamic signals from cytokines and transcription factors propagated from T-cell interaction. Long-term alloimmunity, in the setting of organ transplantation, is dependent on this B-cell response, which does not appear to be halted by current immunosuppressive regimens which are targeted at T cells. There is emerging evidence that shows that B cells have a diverse response to solid organ transplantation that extends beyond plasma cell antibody production. In this review, we discuss the mechanistic pathways of B-cell activation and differentiation as they relate to the transcriptional regulation of germinal center B cells, plasma cells, and memory B cells in the setting of solid organ transplantation.
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Affiliation(s)
- Stephanie G. Yi
- Division of Transplantation, Department of Surgery, Houston Methodist Hospital, Houston, TX, United States
- *Correspondence: Stephanie G. Yi,
| | - Ahmed Osama Gaber
- Division of Transplant Immunology, Houston Methodist Research Institute, Houston Methodist Hospital, Houston, TX, United States
| | - Wenhao Chen
- Division of Transplantation, Department of Surgery, Houston Methodist Hospital, Houston, TX, United States
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22
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Xia Y, Sandor K, Pai JA, Daniel B, Raju S, Wu R, Hsiung S, Qi Y, Yangdon T, Okamoto M, Chou C, Hiam-Galvez KJ, Schreiber RD, Murphy KM, Satpathy AT, Egawa T. BCL6-dependent TCF-1 + progenitor cells maintain effector and helper CD4 + T cell responses to persistent antigen. Immunity 2022; 55:1200-1215.e6. [PMID: 35637103 PMCID: PMC10034764 DOI: 10.1016/j.immuni.2022.05.003] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Revised: 03/04/2022] [Accepted: 05/04/2022] [Indexed: 12/12/2022]
Abstract
Soon after activation, CD4+ T cells are segregated into BCL6+ follicular helper (Tfh) and BCL6- effector (Teff) T cells. Here, we explored how these subsets are maintained during chronic antigen stimulation using the mouse chronic LCMV infection model. Using single cell-transcriptomic and epigenomic analyses, we identified a population of PD-1+ TCF-1+ CD4+ T cells with memory-like features. TCR clonal tracing and adoptive transfer experiments demonstrated that these cells have self-renewal capacity and continue to give rise to both Teff and Tfh cells, thus functioning as progenitor cells. Conditional deletion experiments showed Bcl6-dependent development of these progenitors, which were essential for sustaining antigen-specific CD4+ T cell responses to chronic infection. An analogous CD4+ T cell population developed in draining lymph nodes in response to tumors. Our study reveals the heterogeneity and plasticity of CD4+ T cells during persistent antigen exposure and highlights their population dynamics through a stable, bipotent intermediate state.
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Affiliation(s)
- Yu Xia
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Katalin Sandor
- Department of Pathology, Stanford University, Stanford, CA 94305, USA; Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA 94158, USA
| | - Joy A Pai
- Department of Pathology, Stanford University, Stanford, CA 94305, USA; Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA 94158, USA
| | - Bence Daniel
- Department of Pathology, Stanford University, Stanford, CA 94305, USA; Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA 94158, USA
| | - Saravanan Raju
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Renee Wu
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Sunnie Hsiung
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Yanyan Qi
- Department of Pathology, Stanford University, Stanford, CA 94305, USA
| | - Tenzin Yangdon
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Mariko Okamoto
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Chun Chou
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | | | - Robert D Schreiber
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Kenneth M Murphy
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Ansuman T Satpathy
- Department of Pathology, Stanford University, Stanford, CA 94305, USA; Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA 94158, USA.
| | - Takeshi Egawa
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
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23
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Dubreil L, Ledevin M, Hervet C, Menard D, Philippe C, Michel FJ, Larcher T, Meurens F, Bertho N. The Internal Conduit System of the Swine Inverted Lymph Node. Front Immunol 2022; 13:869384. [PMID: 35734172 PMCID: PMC9207403 DOI: 10.3389/fimmu.2022.869384] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Accepted: 05/12/2022] [Indexed: 12/04/2022] Open
Abstract
Lymph nodes (LN) are the crossroad where naïve lymphocytes, peripheral antigens and antigen presenting cells contact together in order to mount an adaptive immune response. For this purpose, LN are highly organized convergent hubs of blood and lymphatic vessels that, in the case of B lymphocytes, lead to the B cell follicles. Herein take place the selection and maturation of B cell clones producing high affinity antibodies directed against various antigens. Whereas the knowledge on the murine and human LN distribution systems have reached an exquisite precision those last years, the organization of the antigens and cells circulation into the inverted porcine LN remains poorly described. Using up to date microscopy tools, we described the complex interconnections between afferent lymphatics and blood vessels, perifollicular macrophages, follicular B cells and efferent blood vessels. We observed that afferent lymphatic sinuses presented an asymmetric Lyve-1 expression similar to the one observed in murine LN, whereas specialized perifollicular sinuses connect the main afferent lymphatic sinus to the B cell follicles. Finally, whereas it was long though that mature B cells egress from the inverted LN in the T cell zone through HEV, our observations are in agreement with mature B cells accessing the efferent blood circulation in the efferent, subcapsular area. This understanding of the inverted porcine LN circuitry will allow a more accurate exploration of swine pathogens interactions with the immune cells inside the LN structures. Moreover, the mix between similarities and differences of porcine inverted LN circuitry with mouse and human normal LN shall enable to better apprehend the functions and malfunctions of normal LN from a new perspective.
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Affiliation(s)
| | | | | | | | - Claire Philippe
- APEX, PAnTher, INRAE, Oniris, Nantes, France
- BIOEPAR, INRAE, Oniris, Nantes, France
| | | | | | - François Meurens
- BIOEPAR, INRAE, Oniris, Nantes, France
- Department of Veterinary Microbiology and Immunology, Western College of Veterinary Medicine, University of Saskatchewan, Saskatoon, Canada
| | - Nicolas Bertho
- BIOEPAR, INRAE, Oniris, Nantes, France
- *Correspondence: Nicolas Bertho,
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24
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Guo H, Wang M, Wang B, Guo L, Cheng Y, Wang Z, Sun YQ, Wang Y, Chang YJ, Huang XJ. PRDM1 Drives Human Primary T Cell Hyporesponsiveness by Altering the T Cell Transcriptome and Epigenome. Front Immunol 2022; 13:879501. [PMID: 35572579 PMCID: PMC9097451 DOI: 10.3389/fimmu.2022.879501] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2022] [Accepted: 04/04/2022] [Indexed: 11/29/2022] Open
Abstract
T cell hyporesponsiveness is crucial for the functional immune system and prevents the damage induced by alloreactive T cells in autoimmune pathology and transplantation. Here, we found low expression of PRDM1 in T cells from donor and recipients both related to the occurrence of acute graft-versus-host disease (aGVHD). Our systematic multiomics analysis found that the transcription factor PRDM1 acts as a master regulator during inducing human primary T cell hyporesponsiveness. PRDM1-overexpression in primary T cells expanded Treg cell subset and increased the expression level of FOXP3, while decreased expression had the opposite effects. Moreover, the binding motifs of key T cell function regulators, such as FOS, JUN and AP-1, were enriched in PRDM1 binding sites and that PRDM1 altered the chromatin accessibility of these regions. Multiomics analysis showed that PRDM1 directly upregulated T cell inhibitory genes such as KLF2 and KLRD1 and downregulated the T cell activation gene IL2, indicating that PRDM1 could promote a tolerant transcriptional profile. Further analysis showed that PRDM1 upregulated FOXP3 expression level directly by binding to FOXP3 upstream enhancer region and indirectly by upregulating KLF2. These results indicated that PRDM1 is sufficient for inducing human primary T cell hyporesponsiveness by transcriptomic and epigenetic manners.
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Affiliation(s)
- Huidong Guo
- Peking University People's Hospital & Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China
| | - Ming Wang
- Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Bixia Wang
- Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Liping Guo
- Peking University People's Hospital & Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China
| | - Yifei Cheng
- Peking University People's Hospital & Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China
| | - Zhidong Wang
- Peking University People's Hospital & Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China
| | - Yu-Qian Sun
- Peking University People's Hospital & Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China
| | - Yu Wang
- Peking University People's Hospital & Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China
| | - Ying-Jun Chang
- Peking University People's Hospital & Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China
| | - Xiao-Jun Huang
- Peking University People's Hospital & Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China.,Nanfang Hospital, Southern Medical University, Guangzhou, China.,Peking-Tsinghua Center for Life Sciences, School of Life Sciences, Peking University, Beijing, China.,Research Unit of Key Technique for Diagnosis and Treatments of Hematologic Malignancies (2019RU029), Chinese Academy of Medical Sciences, Beijing, China
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25
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Costa-Madeira JC, Trindade GB, Almeida PHP, Silva JS, Carregaro V. T Lymphocyte Exhaustion During Human and Experimental Visceral Leishmaniasis. Front Immunol 2022; 13:835711. [PMID: 35585983 PMCID: PMC9108272 DOI: 10.3389/fimmu.2022.835711] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Accepted: 04/07/2022] [Indexed: 11/18/2022] Open
Abstract
A key point of immunity against protozoan Leishmania parasites is the development of an optimal T cell response, which includes a low apoptotic rate, high proliferative activity and polyfunctionality. During acute infection, antigen-specific T cells recognize the pathogen resulting in pathogen control but not elimination, promoting the development and the maintenance of a population of circulating effector cells that mount rapid response quickly after re-exposure to the parasite. However, in the case of visceral disease, the functionality of specific T cells is lost during chronic infection, resulting in inferior effector functions, poor response to specific restimulation, and suboptimal homeostatic proliferation, a term referred to as T cell exhaustion. Multiple factors, including parasite load, infection duration and host immunity, affect T lymphocyte exhaustion. These factors contribute to antigen persistence by promoting inhibitory receptor expression and sustained production of soluble mediators, influencing suppressive cell function and the release of endogenous molecules into chronically inflamed tissue. Together, these signals encourage several changes, reprogramming cells into a quiescent state, which reflects disease progression to more severe forms, and development of acquired resistance to conventional drugs to treat the disease. These points are discussed in this review.
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Affiliation(s)
- Juliana C. Costa-Madeira
- Department of Biochemistry and Immunology, Ribeirão Preto Medical School, University from São Paulo, Ribeirão Preto, Brazil
| | - Gabrielly B. Trindade
- Department of Biochemistry and Immunology, Ribeirão Preto Medical School, University from São Paulo, Ribeirão Preto, Brazil
| | - Paulo H. P. Almeida
- Department of Biochemistry and Immunology, Ribeirão Preto Medical School, University from São Paulo, Ribeirão Preto, Brazil
| | - João S. Silva
- Department of Biochemistry and Immunology, Ribeirão Preto Medical School, University from São Paulo, Ribeirão Preto, Brazil
- Fiocruz-Bi-Institutional Translational Medicine Project, Ribeirão Preto, Brazil
| | - Vanessa Carregaro
- Department of Biochemistry and Immunology, Ribeirão Preto Medical School, University from São Paulo, Ribeirão Preto, Brazil
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26
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Wu YZ, Jiang HS, Han HF, Li PH, Lu MR, Tsai IJ, Wu YC. C. elegans BLMP-1 controls apical epidermal cell morphology by repressing expression of mannosyltransferase bus-8 and molting signal mlt-8. Dev Biol 2022; 486:96-108. [DOI: 10.1016/j.ydbio.2022.03.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Revised: 03/17/2022] [Accepted: 03/29/2022] [Indexed: 11/26/2022]
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27
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Shen L, Wu Y, Qi H, Jiang Y, Jin J, Cao F, Chen S, Yang Y, Huang T, Song Z, Chen Q, Zhang Y, Mo J, Li D, Zhang X, Fan W. Inducible Regulatory T Cell Predicts Efficacy of PD‐1 Blockade Therapy in Melanoma. ADVANCED THERAPEUTICS 2022. [DOI: 10.1002/adtp.202100098] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Affiliation(s)
- Lujun Shen
- Department of Minimally Invasive Interventional Therapy Sun Yat‐sen University Cancer Center Guangzhou 510060 P. R. China
- State Key Laboratory of Oncology in South China Collaborative Innovation Center of Cancer Medicine Sun Yat‐sen University Guangzhou 510060 P. R. China
| | - Ying Wu
- Department of Minimally Invasive Interventional Therapy Sun Yat‐sen University Cancer Center Guangzhou 510060 P. R. China
- State Key Laboratory of Oncology in South China Collaborative Innovation Center of Cancer Medicine Sun Yat‐sen University Guangzhou 510060 P. R. China
| | - Han Qi
- Department of Minimally Invasive Interventional Therapy Sun Yat‐sen University Cancer Center Guangzhou 510060 P. R. China
- State Key Laboratory of Oncology in South China Collaborative Innovation Center of Cancer Medicine Sun Yat‐sen University Guangzhou 510060 P. R. China
| | - Yiquan Jiang
- Department of Minimally Invasive Interventional Therapy Sun Yat‐sen University Cancer Center Guangzhou 510060 P. R. China
- State Key Laboratory of Oncology in South China Collaborative Innovation Center of Cancer Medicine Sun Yat‐sen University Guangzhou 510060 P. R. China
| | - Jietian Jin
- State Key Laboratory of Oncology in South China Collaborative Innovation Center of Cancer Medicine Sun Yat‐sen University Guangzhou 510060 P. R. China
- Department of Pathology Sun Yat‐sen University Cancer Center Guangzhou 510060 P. R. China
| | - Fei Cao
- Department of Minimally Invasive Interventional Therapy Sun Yat‐sen University Cancer Center Guangzhou 510060 P. R. China
- State Key Laboratory of Oncology in South China Collaborative Innovation Center of Cancer Medicine Sun Yat‐sen University Guangzhou 510060 P. R. China
| | - Shuanggang Chen
- Department of Minimally Invasive Interventional Therapy Sun Yat‐sen University Cancer Center Guangzhou 510060 P. R. China
- State Key Laboratory of Oncology in South China Collaborative Innovation Center of Cancer Medicine Sun Yat‐sen University Guangzhou 510060 P. R. China
| | - Yuanzhong Yang
- State Key Laboratory of Oncology in South China Collaborative Innovation Center of Cancer Medicine Sun Yat‐sen University Guangzhou 510060 P. R. China
- Department of Pathology Sun Yat‐sen University Cancer Center Guangzhou 510060 P. R. China
| | - Tao Huang
- Department of Minimally Invasive Interventional Therapy Sun Yat‐sen University Cancer Center Guangzhou 510060 P. R. China
- State Key Laboratory of Oncology in South China Collaborative Innovation Center of Cancer Medicine Sun Yat‐sen University Guangzhou 510060 P. R. China
| | - Ze Song
- Department of Medical Oncology Seventh Affiliated Hospital of Sun Yat‐sen University Shenzhen 518107 P. R. China
| | - Qifeng Chen
- Department of Minimally Invasive Interventional Therapy Sun Yat‐sen University Cancer Center Guangzhou 510060 P. R. China
- State Key Laboratory of Oncology in South China Collaborative Innovation Center of Cancer Medicine Sun Yat‐sen University Guangzhou 510060 P. R. China
| | - Yinqi Zhang
- Zhong Shan School of Medicine Sun Yat‐sen University Guangzhou 510080 P. R. China
| | - Jinqing Mo
- Zhong Shan School of Medicine Sun Yat‐sen University Guangzhou 510080 P. R. China
| | - Dandan Li
- State Key Laboratory of Oncology in South China Collaborative Innovation Center of Cancer Medicine Sun Yat‐sen University Guangzhou 510060 P. R. China
- Department of Biological Therapy Center Sun Yat‐sen University Cancer Center Guangzhou 510060 P. R. China
| | - Xiaoshi Zhang
- State Key Laboratory of Oncology in South China Collaborative Innovation Center of Cancer Medicine Sun Yat‐sen University Guangzhou 510060 P. R. China
- Department of Biological Therapy Center Sun Yat‐sen University Cancer Center Guangzhou 510060 P. R. China
| | - Weijun Fan
- Department of Minimally Invasive Interventional Therapy Sun Yat‐sen University Cancer Center Guangzhou 510060 P. R. China
- State Key Laboratory of Oncology in South China Collaborative Innovation Center of Cancer Medicine Sun Yat‐sen University Guangzhou 510060 P. R. China
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28
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Lee H, Huang DY, Chang HC, Lin CY, Ren WY, Dai YS, Lin WW. Blimp-1 Upregulation by Multiple Ligands via EGFR Transactivation Inhibits Cell Migration in Keratinocytes and Squamous Cell Carcinoma. Front Pharmacol 2022; 13:763678. [PMID: 35185556 PMCID: PMC8847214 DOI: 10.3389/fphar.2022.763678] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Accepted: 01/07/2022] [Indexed: 12/02/2022] Open
Abstract
B lymphocyte-induced maturation protein-1 (Blimp-1) is a transcriptional repressor and plays a crucial role in the regulation of development and functions of various immune cells. Currently, there is limited understanding about the regulation of Blimp-1 expression and cellular functions in keratinocytes and cancer cells. Previously we demonstrated that EGF can upregulate Blimp-1 gene expression in keratinocytes, playing a negative role in regulation of cell migration and inflammation. Because it remains unclear if Blimp-1 can be regulated by other stimuli beyond EGF, here we further investigated multiple stimuli for their regulation of Blimp-1 expression in keratinocytes and squamous cell carcinoma (SCC). We found that PMA, TNF-α, LPS, polyIC, H2O2 and UVB can upregulate the protein and/or mRNA levels of Blimp-1 in HaCaT and SCC cells. Concomitant EGFR activation was observed by these stimuli, and EGFR inhibitor gefitinib and Syk inhibitor can block Blimp-1 gene expression caused by PMA. Reporter assay of Blimp-1 promoter activity further indicated the involvement of AP-1 in PMA-, TNF-α-, LPS- and EGF-elicited Blimp-1 mRNA expression. Confocal microscopic data indicated the nuclear loclization of Blimp-1, and such localization was not changed by stimuli. Moreover, Blimp-1 silencing enhanced SCC cell migration. Taken together, Blimp-1 can be transcriptionally upregulated by several stimuli in keratinocytes and SCC via EGFR transactivation and AP-1 pathway. These include growth factor PMA, cytokine TNF-α, TLR ligands (LPS and polyIC), and ROS insults (H2O2 and UVB). The function of Blimp-1 as a negative regulator of cell migration in SCC can provide a new therapeutic target in SCC.
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Affiliation(s)
- Hyemin Lee
- Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Duen-Yi Huang
- Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Hua-Ching Chang
- Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan.,Department of Dermatology, Taipei Medical University Hospital, Taipei, Taiwan
| | - Chia-Yee Lin
- Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Wan-Yu Ren
- Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Yang-Shia Dai
- Department of Dermatology, National Taiwan University Hospital, Taipei, Taiwan
| | - Wan-Wan Lin
- Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan.,Department and Graduate Institute of Pharmacology, National Defense Medical Center, Taipei, Taiwan.,Graduate Institute of Medical Sciences, Taipei Medical University, Taipei, Taiwan
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29
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Integrated analysis of plasma and single immune cells uncovers metabolic changes in individuals with COVID-19. Nat Biotechnol 2022; 40:110-120. [PMID: 34489601 PMCID: PMC9206886 DOI: 10.1038/s41587-021-01020-4] [Citation(s) in RCA: 69] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Accepted: 07/16/2021] [Indexed: 02/07/2023]
Abstract
A better understanding of the metabolic alterations in immune cells during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may elucidate the wide diversity of clinical symptoms experienced by individuals with coronavirus disease 2019 (COVID-19). Here, we report the metabolic changes associated with the peripheral immune response of 198 individuals with COVID-19 through an integrated analysis of plasma metabolite and protein levels as well as single-cell multiomics analyses from serial blood draws collected during the first week after clinical diagnosis. We document the emergence of rare but metabolically dominant T cell subpopulations and find that increasing disease severity correlates with a bifurcation of monocytes into two metabolically distinct subsets. This integrated analysis reveals a robust interplay between plasma metabolites and cell-type-specific metabolic reprogramming networks that is associated with disease severity and could predict survival.
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30
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Martinez-Ruíz GU, Morales-Sánchez A, Bhandoola A. Transcriptional and epigenetic regulation in thymic epithelial cells. Immunol Rev 2022; 305:43-58. [PMID: 34750841 PMCID: PMC8766885 DOI: 10.1111/imr.13034] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Revised: 10/22/2021] [Accepted: 10/26/2021] [Indexed: 01/03/2023]
Abstract
The thymus is required for the development of both adaptive and innate-like T cell subsets. There is keen interest in manipulating thymic function for therapeutic purposes in circumstances of autoimmunity, immunodeficiency, and for purposes of immunotherapy. Within the thymus, thymic epithelial cells play essential roles in directing T cell development. Several transcription factors are known to be essential for thymic epithelial cell development and function, and a few transcription factors have been studied in considerable detail. However, the role of many other transcription factors is less well understood. Further, it is likely that roles exist for other transcription factors not yet known to be important in thymic epithelial cells. Recent progress in understanding of thymic epithelial cell heterogeneity has provided some new insight into transcriptional requirements in subtypes of thymic epithelial cells. However, it is unknown whether progenitors of thymic epithelial cells exist in the adult thymus, and consequently, developmental relationships linking putative precursors with differentiated cell types are poorly understood. While we do not presently possess a clear understanding of stage-specific requirements for transcription factors in thymic epithelial cells, new single-cell transcriptomic and epigenomic technologies should enable rapid progress in this field. Here, we review our current knowledge of transcription factors involved in the development, maintenance, and function of thymic epithelial cells, and the mechanisms by which they act.
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Affiliation(s)
- Gustavo Ulises Martinez-Ruíz
- T Cell Biology and Development Unit, Laboratory of Genome Integrity, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
- Research Division, Faculty of Medicine, National Autonomous University of Mexico, Mexico City, Mexico
- Children’s Hospital of Mexico Federico Gomez, Mexico City, Mexico
| | - Abigail Morales-Sánchez
- T Cell Biology and Development Unit, Laboratory of Genome Integrity, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
- Children’s Hospital of Mexico Federico Gomez, Mexico City, Mexico
| | - Avinash Bhandoola
- T Cell Biology and Development Unit, Laboratory of Genome Integrity, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
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31
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Li X, Dong Z, Liu Y, Song W, Pu J, Jiang G, Wu Y, Liu L, Huang X. A Novel Role for the Regulatory Nod-Like Receptor NLRP12 in Anti-Dengue Virus Response. Front Immunol 2021; 12:744880. [PMID: 34956178 PMCID: PMC8695442 DOI: 10.3389/fimmu.2021.744880] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Accepted: 11/22/2021] [Indexed: 11/14/2022] Open
Abstract
Dengue Virus (DENV) infection can cause severe illness such as highly fatality dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). Innate immune activation by Nod-like receptors (NLRs) is a critical part of host defense against viral infection. Here, we revealed a key mechanism of NLRP12-mediated regulation in DENV infection. Firstly, NLRP12 expression was inhibited in human macrophage following DENV or other flaviviruses (JEV, YFV, ZIKV) infection. Positive regulatory domain 1 (PRDM1) was induced by DENV or poly(I:C) and suppressed NLRP12 expression, which was dependent on TBK-1/IRF3 and NF-κB signaling pathways. Moreover, NLRP12 inhibited DENV and other flaviviruses (JEV, YFV, ZIKV) replication, which relied on the well-conserved nucleotide binding structures of its NACHT domain. Furthermore, NLRP12 could interact with heat shock protein 90 (HSP90) dependent on its Walker A and Walker B sites. In addition, NLRP12 enhanced the production of type I IFNs (IFN-α/β) and interferon-stimulated genes (ISGs), including IFITM3, TRAIL and Viperin. Inhibition of HSP90 with 17-DMAG impaired the upregulation of type I IFNs and ISGs induced by NLRP12. Taken together, we demonstrated a novel mechanism that NLRP12 exerted anti-viral properties in DENV and other flaviviruses (JEV, YFV, ZIKV) infection, which brings up a potential target for the treatment of DENV infection.
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Affiliation(s)
- Xingyu Li
- Center for Infection and Immunity and Guangdong Provincial Key Laboratory of Biomedical Imaging, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, China.,Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Zhuo Dong
- Center for Infection and Immunity and Guangdong Provincial Key Laboratory of Biomedical Imaging, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, China
| | - Yan Liu
- Department of Clinical Laboratory, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, China
| | - Weifeng Song
- Department of Pharmacy, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, China
| | - Jieying Pu
- Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Guanmin Jiang
- Department of Clinical Laboratory, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, China
| | - Yongjian Wu
- Center for Infection and Immunity and Guangdong Provincial Key Laboratory of Biomedical Imaging, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, China.,Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.,Department of Pharmacy, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, China
| | - Lei Liu
- National Clinical Research Center for Infectious Diseases, Shenzhen Third People's Hospital, Southern University of Science and Technology, Shenzhen, China
| | - Xi Huang
- Center for Infection and Immunity and Guangdong Provincial Key Laboratory of Biomedical Imaging, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, China.,Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.,National Clinical Research Center for Infectious Diseases, Shenzhen Third People's Hospital, Southern University of Science and Technology, Shenzhen, China
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32
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Ma Q, Caillier SJ, Muzic S, Wilson MR, Henry RG, Cree BAC, Hauser SL, Didonna A, Oksenberg JR. Specific hypomethylation programs underpin B cell activation in early multiple sclerosis. Proc Natl Acad Sci U S A 2021; 118:e2111920118. [PMID: 34911760 PMCID: PMC8713784 DOI: 10.1073/pnas.2111920118] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/04/2021] [Indexed: 12/12/2022] Open
Abstract
Epigenetic changes have been consistently detected in different cell types in multiple sclerosis (MS). However, their contribution to MS pathogenesis remains poorly understood partly because of sample heterogeneity and limited coverage of array-based methods. To fill this gap, we conducted a comprehensive analysis of genome-wide DNA methylation patterns in four peripheral immune cell populations isolated from 29 MS patients at clinical disease onset and 24 healthy controls. We show that B cells from new-onset untreated MS cases display more significant methylation changes than other disease-implicated immune cell types, consisting of a global DNA hypomethylation signature. Importantly, 4,933 MS-associated differentially methylated regions in B cells were identified, and this epigenetic signature underlies specific genetic programs involved in B cell differentiation and activation. Integration of the methylome to changes in gene expression and susceptibility-associated regions further indicates that hypomethylated regions are significantly associated with the up-regulation of cell activation transcriptional programs. Altogether, these findings implicate aberrant B cell function in MS etiology.
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Affiliation(s)
- Qin Ma
- Weill Institute for Neurosciences, Department of Neurology, University of California, San Francisco, CA 94158
| | - Stacy J Caillier
- Weill Institute for Neurosciences, Department of Neurology, University of California, San Francisco, CA 94158
| | - Shaun Muzic
- Weill Institute for Neurosciences, Department of Neurology, University of California, San Francisco, CA 94158
| | - Michael R Wilson
- Weill Institute for Neurosciences, Department of Neurology, University of California, San Francisco, CA 94158
| | - Roland G Henry
- Weill Institute for Neurosciences, Department of Neurology, University of California, San Francisco, CA 94158
| | - Bruce A C Cree
- Weill Institute for Neurosciences, Department of Neurology, University of California, San Francisco, CA 94158
| | - Stephen L Hauser
- Weill Institute for Neurosciences, Department of Neurology, University of California, San Francisco, CA 94158
| | - Alessandro Didonna
- Weill Institute for Neurosciences, Department of Neurology, University of California, San Francisco, CA 94158
| | - Jorge R Oksenberg
- Weill Institute for Neurosciences, Department of Neurology, University of California, San Francisco, CA 94158
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33
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Kim SH, Baek M, Park S, Shin S, Lee JS, Lee GM. Improving the secretory capacity of CHO producer cells: The effect of controlled Blimp1 expression, a master transcription factor for plasma cells. Metab Eng 2021; 69:73-86. [PMID: 34775077 DOI: 10.1016/j.ymben.2021.11.001] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2021] [Revised: 08/29/2021] [Accepted: 11/02/2021] [Indexed: 01/23/2023]
Abstract
With the advent of novel therapeutic proteins with complex structures, cellular bottlenecks in secretory pathways have hampered the high-yield production of difficult-to-express (DTE) proteins in CHO cells. To mitigate their limited secretory capacity, recombinant CHO (rCHO) cells were engineered to express Blimp1, a master regulator orchestrating B cell differentiation into professional secretory plasma cells, using the streamlined CRISPR/Cas9-based recombinase-mediated cassette exchange landing pad platform. The expression of Blimp1α or Blimp1β in rCHO cells producing DTE recombinant human bone morphogenetic protein-4 (rhBMP-4) increased specific rhBMP-4 productivity (qrhBMP-4). However, since Blimp1α expression suppressed cell growth more significantly than Blimp1β expression, only Blimp1β expression enhanced rhBMP-4 yield. In serum-free suspension culture, Blimp1β expression significantly increased the rhBMP-4 concentration (>3-fold) and qrhBMP-4 (>4-fold) without significant increase in hBMP-4 transcript levels. In addition, Blimp1β expression facilitated mature rhBMP-4 secretion by active proteolytic cleavage in the secretory pathway. Transcriptomic profiling (RNA-seq) revealed global changes in gene expression patterns that promote protein processing in secretory organelles. In-depth integrative analysis of the current RNA-seq data, public epigenome/RNA-seq data, and in silico analysis identified 45 potential key regulators of Blimp1 that are consistently up- or down-regulated in Blimp1β expressing rCHO cells and plasma cells. Blimp1β expression also enhanced the production of easy-to-express monoclonal antibodies (mAbs) and modulated the expression of key regulators in rCHO cells producing mAb. Taken together, the results show that controlled expression of Blimp1β improves the production capacity of rCHO cells by regulating secretory machinery and suggest new opportunities for engineering promising targets that are resting in CHO cells.
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Affiliation(s)
- Su Hyun Kim
- Department of Biological Sciences, KAIST, Daejeon, 34141, Republic of Korea
| | - Minhye Baek
- Department of Biological Sciences, KAIST, Daejeon, 34141, Republic of Korea
| | - Sungje Park
- Department of Biological Sciences, KAIST, Daejeon, 34141, Republic of Korea
| | - Seunghyeon Shin
- Department of Biological Sciences, KAIST, Daejeon, 34141, Republic of Korea
| | - Jae Seong Lee
- Department of Molecular Science and Technology, Ajou University, Suwon, 16499, Republic of Korea.
| | - Gyun Min Lee
- Department of Biological Sciences, KAIST, Daejeon, 34141, Republic of Korea.
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34
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Jiang HS, Ghose P, Han HF, Wu YZ, Tsai YY, Lin HC, Tseng WC, Wu JC, Shaham S, Wu YC. BLMP-1 promotes developmental cell death in C. elegans by timely repression of ced-9 transcription. Development 2021; 148:dev193995. [PMID: 34541605 PMCID: PMC8572009 DOI: 10.1242/dev.193995] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Accepted: 09/14/2021] [Indexed: 11/20/2022]
Abstract
Programmed cell death (PCD) is a common cell fate in metazoan development. PCD effectors are extensively studied, but how they are temporally regulated is less understood. Here, we report a mechanism controlling tail-spike cell death onset during Caenorhabditis elegans development. We show that the zinc-finger transcription factor BLMP-1, which controls larval development timing, also regulates embryonic tail-spike cell death initiation. BLMP-1 functions upstream of CED-9 and in parallel to DRE-1, another CED-9 and tail-spike cell death regulator. BLMP-1 expression is detected in the tail-spike cell shortly after the cell is born, and blmp-1 mutations promote ced-9-dependent tail-spike cell survival. BLMP-1 binds ced-9 gene regulatory sequences, and inhibits ced-9 transcription just before cell-death onset. BLMP-1 and DRE-1 function together to regulate developmental timing, and their mammalian homologs regulate B-lymphocyte fate. Our results, therefore, identify roles for developmental timing genes in cell-death initiation, and suggest conservation of these functions.
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Affiliation(s)
- Hang-Shiang Jiang
- Institute of Molecular and Cellular Biology, National Taiwan University, Taipei, 106216, Taiwan
| | - Piya Ghose
- Laboratory of Developmental Genetics, The Rockefeller University, New York, NY 10065, USA
- Department of Biology, The University of Texas at Arlington, Arlington, TX 76019, USA
| | - Hsiao-Fen Han
- Institute of Molecular and Cellular Biology, National Taiwan University, Taipei, 106216, Taiwan
| | - Yun-Zhe Wu
- Institute of Molecular and Cellular Biology, National Taiwan University, Taipei, 106216, Taiwan
| | - Ya-Yin Tsai
- Institute of Molecular and Cellular Biology, National Taiwan University, Taipei, 106216, Taiwan
| | - Huang-Chin Lin
- Institute of Molecular and Cellular Biology, National Taiwan University, Taipei, 106216, Taiwan
| | - Wei-Chin Tseng
- Institute of Molecular and Cellular Biology, National Taiwan University, Taipei, 106216, Taiwan
| | - Jui-Ching Wu
- Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, 100229, Taiwan
| | - Shai Shaham
- Laboratory of Developmental Genetics, The Rockefeller University, New York, NY 10065, USA
| | - Yi-Chun Wu
- Institute of Molecular and Cellular Biology, National Taiwan University, Taipei, 106216, Taiwan
- Department of Life Science, Center for Systems Biology, and Research Center for Developmental Biology and Regenerative Medicine, National Taiwan University, Taipei, 106216, Taiwan
- Institute of Atomic and Molecular Sciences, Academia Sinica, Taipei, 106216, Taiwan
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35
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Ma X, Somasundaram A, Qi Z, Hartman D, Singh H, Osmanbeyoglu H. SPaRTAN, a computational framework for linking cell-surface receptors to transcriptional regulators. Nucleic Acids Res 2021; 49:9633-9647. [PMID: 34500467 PMCID: PMC8464045 DOI: 10.1093/nar/gkab745] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 08/09/2021] [Accepted: 09/06/2021] [Indexed: 12/22/2022] Open
Abstract
The identity and functions of specialized cell types are dependent on the complex interplay between signaling and transcriptional networks. Recently single-cell technologies have been developed that enable simultaneous quantitative analysis of cell-surface receptor expression with transcriptional states. To date, these datasets have not been used to systematically develop cell-context-specific maps of the interface between signaling and transcriptional regulators orchestrating cellular identity and function. We present SPaRTAN (Single-cell Proteomic and RNA based Transcription factor Activity Network), a computational method to link cell-surface receptors to transcription factors (TFs) by exploiting cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) datasets with cis-regulatory information. SPaRTAN is applied to immune cell types in the blood to predict the coupling of signaling receptors with cell context-specific TFs. Selected predictions are validated by prior knowledge and flow cytometry analyses. SPaRTAN is then used to predict the signaling coupled TF states of tumor infiltrating CD8+ T cells in malignant peritoneal and pleural mesotheliomas. SPaRTAN enhances the utility of CITE-seq datasets to uncover TF and cell-surface receptor relationships in diverse cellular states.
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Affiliation(s)
- Xiaojun Ma
- Department of Biomedical Informatics, University of Pittsburgh, Pittsburgh, PA 15206, USA
- UPMC Hillman Cancer Center, Pittsburgh, PA 15213, USA
| | - Ashwin Somasundaram
- Department of Medicine, Division of Hematology/Oncology, University of Pittsburgh, Pittsburgh, PA 15213, USA
- UPMC Hillman Cancer Center, Pittsburgh, PA 15213, USA
| | - Zengbiao Qi
- UPMC Hillman Cancer Center, Pittsburgh, PA 15213, USA
| | - Douglas J Hartman
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA
- UPMC Hillman Cancer Center, Pittsburgh, PA 15213, USA
| | - Harinder Singh
- Center for Systems Immunology and Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15213, USA
| | - Hatice Ulku Osmanbeyoglu
- Department of Biomedical Informatics, University of Pittsburgh, Pittsburgh, PA 15206, USA
- Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA 15261, USA
- UPMC Hillman Cancer Center, Pittsburgh, PA 15213, USA
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36
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DiToro D, Basu R. Emerging Complexity in CD4 +T Lineage Programming and Its Implications in Colorectal Cancer. Front Immunol 2021; 12:694833. [PMID: 34489941 PMCID: PMC8417887 DOI: 10.3389/fimmu.2021.694833] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Accepted: 08/04/2021] [Indexed: 12/17/2022] Open
Abstract
The intestinal immune system has the difficult task of protecting a large environmentally exposed single layer of epithelium from pathogens without allowing inappropriate inflammatory responses. Unmitigated inflammation drives multiple pathologies, including the development of colorectal cancer. CD4+T cells mediate both the suppression and promotion of intestinal inflammation. They comprise an array of phenotypically and functionally distinct subsets tailored to a specific inflammatory context. This diversity of form and function is relevant to a broad array of pathologic and physiologic processes. The heterogeneity underlying both effector and regulatory T helper cell responses to colorectal cancer, and its impact on disease progression, is reviewed herein. Importantly, T cell responses are dynamic; they exhibit both quantitative and qualitative changes as the inflammatory context shifts. Recent evidence outlines the role of CD4+T cells in colorectal cancer responses and suggests possible mechanisms driving qualitative alterations in anti-cancer immune responses. The heterogeneity of T cells in colorectal cancer, as well as the manner and mechanism by which they change, offer an abundance of opportunities for more specific, and likely effective, interventional strategies.
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Affiliation(s)
- Daniel DiToro
- Brigham and Women's Hospital, Boston, MA, United States.,Harvard Medical School, Boston, MA, United States.,Ragon Institute of MGH MIT and Harvard, Cambridge, MA, United States
| | - Rajatava Basu
- Division of Molecular and Cellular Pathology, Department of Pathology, University of Alabama at Birmingham (UAB), Birmingham, AL, United States
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37
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Barker KA, Etesami NS, Shenoy AT, Arafa EI, Lyon de Ana C, Smith NM, Martin IM, Goltry WN, Barron AM, Browning JL, Kathuria H, Belkina AC, Guillon A, Zhong X, Crossland NA, Jones MR, Quinton LJ, Mizgerd JP. Lung-resident memory B cells protect against bacterial pneumonia. J Clin Invest 2021; 131:e141810. [PMID: 34060477 DOI: 10.1172/jci141810] [Citation(s) in RCA: 78] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Accepted: 04/14/2021] [Indexed: 12/22/2022] Open
Abstract
Lung-resident memory B cells (BRM cells) are elicited after influenza infections of mice, but connections to other pathogens and hosts - as well as their functional significance - have yet to be determined. We postulate that BRM cells are core components of lung immunity. To test this, we examined whether lung BRM cells are elicited by the respiratory pathogen pneumococcus, are present in humans, and are important in pneumonia defense. Lungs of mice that had recovered from pneumococcal infections did not contain organized tertiary lymphoid organs, but did have plasma cells and noncirculating memory B cells. The latter expressed distinctive surface markers (including CD69, PD-L2, CD80, and CD73) and were poised to secrete antibodies upon stimulation. Human lungs also contained B cells with a resident memory phenotype. In mice recovered from pneumococcal pneumonia, depletion of PD-L2+ B cells, including lung BRM cells, diminished bacterial clearance and the level of pneumococcus-reactive antibodies in the lung. These data define lung BRM cells as a common feature of pathogen-experienced lungs and provide direct evidence of a role for these cells in pulmonary antibacterial immunity.
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Affiliation(s)
| | | | | | | | | | - Nicole Ms Smith
- Pulmonary Center.,Department of Pathology and Laboratory Medicine, and
| | | | | | | | | | | | - Anna C Belkina
- Pulmonary Center.,Department of Pathology and Laboratory Medicine, and.,Flow Cytometry Core Facility, Boston University School of Medicine, Boston, Massachusetts, USA
| | - Antoine Guillon
- Pulmonary Center.,Centre Hospitalier Régional Universitaire de (CHRU) de Tours, Service de Médecine Intensive Réanimation, INSERM, Centre d'Etude des Pathologies Respiratoires (CEPR), UMR 1100, University of Tours, Tours, France
| | | | | | | | - Lee J Quinton
- Pulmonary Center.,Department of Microbiology.,Department of Medicine.,Department of Pathology and Laboratory Medicine, and
| | - Joseph P Mizgerd
- Pulmonary Center.,Department of Microbiology.,Department of Medicine.,Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts, USA
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38
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Holla P, Dizon B, Ambegaonkar AA, Rogel N, Goldschmidt E, Boddapati AK, Sohn H, Sturdevant D, Austin JW, Kardava L, Yuesheng L, Liu P, Moir S, Pierce SK, Madi A. Shared transcriptional profiles of atypical B cells suggest common drivers of expansion and function in malaria, HIV, and autoimmunity. SCIENCE ADVANCES 2021; 7:7/22/eabg8384. [PMID: 34039612 PMCID: PMC8153733 DOI: 10.1126/sciadv.abg8384] [Citation(s) in RCA: 82] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Accepted: 04/07/2021] [Indexed: 05/05/2023]
Abstract
Chronic infectious diseases have a substantial impact on the human B cell compartment including a notable expansion of B cells here termed atypical B cells (ABCs). Using unbiased single-cell RNA sequencing (scRNA-seq), we uncovered and characterized heterogeneities in naïve B cell, classical memory B cells, and ABC subsets. We showed remarkably similar transcriptional profiles for ABC clusters in malaria, HIV, and autoimmune diseases and demonstrated that interferon-γ drove the expansion of ABCs in malaria. These observations suggest that ABCs represent a separate B cell lineage with a common inducer that further diversifies and acquires disease-specific characteristics and functions. In malaria, we identified ABC subsets based on isotype expression that differed in expansion in African children and in B cell receptor repertoire characteristics. Of particular interest, IgD+IgMlo and IgD-IgG+ ABCs acquired a high antigen affinity threshold for activation, suggesting that ABCs may limit autoimmune responses to low-affinity self-antigens in chronic malaria.
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Affiliation(s)
- Prasida Holla
- Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, USA
| | - Brian Dizon
- National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Abhijit A Ambegaonkar
- Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, USA
| | - Noga Rogel
- Department of Pathology, Sackler School of Medicine, Tel Aviv University, Israel
| | - Ella Goldschmidt
- Department of Pathology, Sackler School of Medicine, Tel Aviv University, Israel
| | - Arun K Boddapati
- NIAID Collaborative Bioinformatics Resource, National Institutes of Health, Bethesda, MD, USA
| | - Haewon Sohn
- Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, USA
| | - Dan Sturdevant
- RML Genomics Unit, Research Technologies Section, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT, USA
| | - James W Austin
- Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Lela Kardava
- Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Li Yuesheng
- National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA
| | - Poching Liu
- National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA
| | - Susan Moir
- Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Susan K Pierce
- Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, USA.
| | - Asaf Madi
- Department of Pathology, Sackler School of Medicine, Tel Aviv University, Israel.
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39
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Johnson JS, De Veaux N, Rives AW, Lahaye X, Lucas SY, Perot BP, Luka M, Garcia-Paredes V, Amon LM, Watters A, Abdessalem G, Aderem A, Manel N, Littman DR, Bonneau R, Ménager MM. A Comprehensive Map of the Monocyte-Derived Dendritic Cell Transcriptional Network Engaged upon Innate Sensing of HIV. Cell Rep 2021; 30:914-931.e9. [PMID: 31968263 PMCID: PMC7039998 DOI: 10.1016/j.celrep.2019.12.054] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2019] [Revised: 06/25/2019] [Accepted: 12/13/2019] [Indexed: 01/12/2023] Open
Abstract
Transcriptional programming of the innate immune response is pivotal for host protection. However, the transcriptional mechanisms that link pathogen sensing with innate activation remain poorly under-stood. During HIV-1 infection, human dendritic cells (DCs) can detect the virus through an innate sensing pathway, leading to antiviral interferon and DC maturation. Here, we develop an iterative experimental and computational approach to map the HIV-1 innate response circuitry in monocyte-derived DCs (MDDCs). By integrating genome-wide chromatin accessibility with expression kinetics, we infer a gene regulatory network that links 542 transcription factors with 21,862 target genes. We observe that an interferon response is required, yet insufficient, to drive MDDC maturation and identify PRDM1 and RARA as essential regulators of the interferon response and MDDC maturation, respectively. Our work provides a resource for interrogation of regulators of HIV replication and innate immunity, highlighting complexity and cooperativity in the regulatory circuit controlling the response to infection. Pathogen sensing leads to host transcriptional reprogramming to protect against infection. However, it is unclear how transcription factor activity is coordinated across the genome. Johnson et al. integrate chromatin accessibility and gene expression data to infer and validate a gene regulatory network that directs the innate immune response to HIV.
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Affiliation(s)
- Jarrod S Johnson
- Department of Biochemistry, University of Utah, Salt Lake City, UT 84112, USA; Center for Infectious Disease Research, Seattle, WA 98109, USA.
| | - Nicholas De Veaux
- Flatiron Institute, Center for Computational Biology, Simons Foundation, New York, NY 10010, USA
| | - Alexander W Rives
- Flatiron Institute, Center for Computational Biology, Simons Foundation, New York, NY 10010, USA
| | - Xavier Lahaye
- Immunity and Cancer Department, Institut Curie, PSL Research University, INSERM U932, 75005 Paris, France
| | - Sasha Y Lucas
- Center for Infectious Disease Research, Seattle, WA 98109, USA
| | - Brieuc P Perot
- Laboratory of Inflammatory Responses and Transcriptomic Networks in Diseases, Imagine Institute, INSERM UMR 1163, ATIP-Avenir Team, Université de Paris, 24 Boulevard du Montparnasse, 75015 Paris, France
| | - Marine Luka
- Laboratory of Inflammatory Responses and Transcriptomic Networks in Diseases, Imagine Institute, INSERM UMR 1163, ATIP-Avenir Team, Université de Paris, 24 Boulevard du Montparnasse, 75015 Paris, France
| | - Victor Garcia-Paredes
- Laboratory of Inflammatory Responses and Transcriptomic Networks in Diseases, Imagine Institute, INSERM UMR 1163, ATIP-Avenir Team, Université de Paris, 24 Boulevard du Montparnasse, 75015 Paris, France
| | - Lynn M Amon
- Center for Infectious Disease Research, Seattle, WA 98109, USA
| | - Aaron Watters
- Flatiron Institute, Center for Computational Biology, Simons Foundation, New York, NY 10010, USA
| | - Ghaith Abdessalem
- Laboratory of Inflammatory Responses and Transcriptomic Networks in Diseases, Imagine Institute, INSERM UMR 1163, ATIP-Avenir Team, Université de Paris, 24 Boulevard du Montparnasse, 75015 Paris, France
| | - Alan Aderem
- Center for Infectious Disease Research, Seattle, WA 98109, USA; Department of Immunology, University of Washington School of Medicine, Seattle, WA 98109, USA
| | - Nicolas Manel
- Immunity and Cancer Department, Institut Curie, PSL Research University, INSERM U932, 75005 Paris, France
| | - Dan R Littman
- The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, NY 10016, USA; Howard Hughes Medical Institute, New York University School of Medicine, New York, NY 10016, USA
| | - Richard Bonneau
- Flatiron Institute, Center for Computational Biology, Simons Foundation, New York, NY 10010, USA; Department of Biology, Center for Genomics and Systems Biology, New York University, New York, NY 10003, USA; Center for Data Science, New York University, New York, NY 10011, USA
| | - Mickaël M Ménager
- Laboratory of Inflammatory Responses and Transcriptomic Networks in Diseases, Imagine Institute, INSERM UMR 1163, ATIP-Avenir Team, Université de Paris, 24 Boulevard du Montparnasse, 75015 Paris, France; The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, NY 10016, USA.
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40
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Ripperger TJ, Bhattacharya D. Transcriptional and Metabolic Control of Memory B Cells and Plasma Cells. Annu Rev Immunol 2021; 39:345-368. [PMID: 33556247 DOI: 10.1146/annurev-immunol-093019-125603] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
For many infections and almost all vaccines, neutralizing-antibody-mediated immunity is the primary basis and best functional correlate of immunological protection. Durable long-term humoral immunity is mediated by antibodies secreted by plasma cells that preexist subsequent exposures and by memory B cells that rapidly respond to infections once they have occurred. In the midst of the current pandemic of coronavirus disease 2019, it is important to define our current understanding of the unique roles of memory B cells and plasma cells in immunity and the factors that control the formation and persistence of these cell types. This fundamental knowledge is the basis to interpret findings from natural infections and vaccines. Here, we review transcriptional and metabolic programs that promote and support B cell fates and functions, suggesting points at which these pathways do and do not intersect.
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Affiliation(s)
- Tyler J Ripperger
- Department of Immunobiology, University of Arizona College of Medicine-Tucson, Tucson, Arizona 85724, USA; ,
| | - Deepta Bhattacharya
- Department of Immunobiology, University of Arizona College of Medicine-Tucson, Tucson, Arizona 85724, USA; ,
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41
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Reynolds G, Vegh P, Fletcher J, Poyner EFM, Stephenson E, Goh I, Botting RA, Huang N, Olabi B, Dubois A, Dixon D, Green K, Maunder D, Engelbert J, Efremova M, Polański K, Jardine L, Jones C, Ness T, Horsfall D, McGrath J, Carey C, Popescu DM, Webb S, Wang XN, Sayer B, Park JE, Negri VA, Belokhvostova D, Lynch MD, McDonald D, Filby A, Hagai T, Meyer KB, Husain A, Coxhead J, Vento-Tormo R, Behjati S, Lisgo S, Villani AC, Bacardit J, Jones PH, O'Toole EA, Ogg GS, Rajan N, Reynolds NJ, Teichmann SA, Watt FM, Haniffa M. Developmental cell programs are co-opted in inflammatory skin disease. Science 2021; 371:eaba6500. [PMID: 33479125 PMCID: PMC7611557 DOI: 10.1126/science.aba6500] [Citation(s) in RCA: 311] [Impact Index Per Article: 77.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2019] [Revised: 09/03/2020] [Accepted: 12/01/2020] [Indexed: 12/16/2022]
Abstract
The skin confers biophysical and immunological protection through a complex cellular network established early in embryonic development. We profiled the transcriptomes of more than 500,000 single cells from developing human fetal skin, healthy adult skin, and adult skin with atopic dermatitis and psoriasis. We leveraged these datasets to compare cell states across development, homeostasis, and disease. Our analysis revealed an enrichment of innate immune cells in skin during the first trimester and clonal expansion of disease-associated lymphocytes in atopic dermatitis and psoriasis. We uncovered and validated in situ a reemergence of prenatal vascular endothelial cell and macrophage cellular programs in atopic dermatitis and psoriasis lesional skin. These data illustrate the dynamism of cutaneous immunity and provide opportunities for targeting pathological developmental programs in inflammatory skin diseases.
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Affiliation(s)
- Gary Reynolds
- Biosciences Institute, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
| | - Peter Vegh
- Biosciences Institute, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
| | - James Fletcher
- Biosciences Institute, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
| | - Elizabeth F M Poyner
- Biosciences Institute, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
- Department of Dermatology and NIHR Newcastle Biomedical Research Centre, Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne NE2 4LP, UK
| | - Emily Stephenson
- Biosciences Institute, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
| | - Issac Goh
- Biosciences Institute, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
| | - Rachel A Botting
- Biosciences Institute, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
| | - Ni Huang
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK
| | - Bayanne Olabi
- Biosciences Institute, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
- Department of Dermatology, NHS Lothian, Lauriston Building, Edinburgh EH3 9EN, UK
| | - Anna Dubois
- Biosciences Institute, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
- Department of Dermatology and NIHR Newcastle Biomedical Research Centre, Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne NE2 4LP, UK
| | - David Dixon
- Biosciences Institute, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
| | - Kile Green
- Biosciences Institute, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
| | - Daniel Maunder
- Biosciences Institute, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
| | - Justin Engelbert
- Biosciences Institute, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
| | - Mirjana Efremova
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK
| | - Krzysztof Polański
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK
| | - Laura Jardine
- Biosciences Institute, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
| | - Claire Jones
- Biosciences Institute, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
| | - Thomas Ness
- Biosciences Institute, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
| | - Dave Horsfall
- Biosciences Institute, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
| | - Jim McGrath
- Biosciences Institute, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
| | - Christopher Carey
- Biosciences Institute, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
| | - Dorin-Mirel Popescu
- Biosciences Institute, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
| | - Simone Webb
- Biosciences Institute, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
| | - Xiao-Nong Wang
- Biosciences Institute, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
| | - Ben Sayer
- Biosciences Institute, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
| | - Jong-Eun Park
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK
| | - Victor A Negri
- Centre for Stem Cells and Regenerative Medicine, King's College London, Guy's Hospital Campus, London SE1 9RT, UK
| | - Daria Belokhvostova
- Centre for Stem Cells and Regenerative Medicine, King's College London, Guy's Hospital Campus, London SE1 9RT, UK
| | - Magnus D Lynch
- Centre for Stem Cells and Regenerative Medicine, King's College London, Guy's Hospital Campus, London SE1 9RT, UK
| | - David McDonald
- Biosciences Institute, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
| | - Andrew Filby
- Biosciences Institute, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
| | - Tzachi Hagai
- Shmunis School of Biomedicine and Cancer Research, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel
| | - Kerstin B Meyer
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK
| | - Akhtar Husain
- Department of Pathology, Royal Victoria Infirmary, Newcastle upon Tyne NE1 4LP, UK
| | - Jonathan Coxhead
- Biosciences Institute, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
| | - Roser Vento-Tormo
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK
| | - Sam Behjati
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK
- Department of Paediatrics, University of Cambridge, Cambridge CB2 0SP, UK
| | - Steven Lisgo
- Biosciences Institute, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
| | - Alexandra-Chloé Villani
- Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
- Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA 02129, USA
| | - Jaume Bacardit
- School of Computing, Newcastle University, Newcastle upon Tyne NE4 5TG, UK
| | - Philip H Jones
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK
- MRC Cancer Unit, University of Cambridge, Cambridge CB2 0XZ, UK
| | - Edel A O'Toole
- Centre for Cell Biology and Cutaneous Research, Blizard Institute, Queen Mary University of London, London, UK
| | - Graham S Ogg
- MRC Human Immunology Unit, Oxford Biomedical Research Centre, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK
| | - Neil Rajan
- Biosciences Institute, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
- Department of Dermatology and NIHR Newcastle Biomedical Research Centre, Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne NE2 4LP, UK
| | - Nick J Reynolds
- Department of Dermatology and NIHR Newcastle Biomedical Research Centre, Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne NE2 4LP, UK
- Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
| | - Sarah A Teichmann
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK.
- Theory of Condensed Matter Group, Cavendish Laboratory/Department of Physics, University of Cambridge, Cambridge CB3 0HE, UK
| | - Fiona M Watt
- Centre for Stem Cells and Regenerative Medicine, King's College London, Guy's Hospital Campus, London SE1 9RT, UK.
| | - Muzlifah Haniffa
- Biosciences Institute, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
- Department of Dermatology and NIHR Newcastle Biomedical Research Centre, Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne NE2 4LP, UK
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK
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Kusnadi A, Ramírez-Suástegui C, Fajardo V, Chee SJ, Meckiff BJ, Simon H, Pelosi E, Seumois G, Ay F, Vijayanand P, Ottensmeier CH. Severely ill COVID-19 patients display impaired exhaustion features in SARS-CoV-2-reactive CD8 + T cells. Sci Immunol 2021; 6:eabe4782. [PMID: 33478949 PMCID: PMC8101257 DOI: 10.1126/sciimmunol.abe4782] [Citation(s) in RCA: 171] [Impact Index Per Article: 42.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Accepted: 01/15/2021] [Indexed: 12/11/2022]
Abstract
The molecular properties of CD8+ T cells that respond to SARS-CoV-2 infection are not fully known. Here, we report on the single-cell transcriptomes of >80,000 virus-reactive CD8+ T cells, obtained using a modified Antigen-Reactive T cell Enrichment (ARTE) assay, from 39 COVID-19 patients and 10 healthy subjects. COVID-19 patients segregated into two groups based on whether the dominant CD8+ T cell response to SARS-CoV-2 was 'exhausted' or not. SARS-CoV-2-reactive cells in the exhausted subset were increased in frequency and displayed lesser cytotoxicity and inflammatory features in COVID-19 patients with mild compared to severe illness. In contrast, SARS-CoV-2-reactive cells in the dominant non-exhausted subset from patients with severe disease showed enrichment of transcripts linked to co-stimulation, pro-survival NF-κB signaling, and anti-apoptotic pathways, suggesting the generation of robust CD8+ T cell memory responses in patients with severe COVID-19 illness. CD8+ T cells reactive to influenza and respiratory syncytial virus from healthy subjects displayed polyfunctional features and enhanced glycolysis. Cells with such features were largely absent in SARS-CoV-2-reactive cells from both COVID-19 patients and healthy controls non-exposed to SARS-CoV-2. Overall, our single-cell analysis revealed substantial diversity in the nature of CD8+ T cells responding to SARS-CoV-2.
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Affiliation(s)
| | | | | | - Serena J Chee
- NIHR and CRUK Southampton Experimental Cancer Medicine Center, Faculty of Medicine, University of Southampton, Southampton, UK
| | | | - Hayley Simon
- La Jolla Institute for Immunology, La Jolla, CA 92037
| | - Emanuela Pelosi
- Southampton Specialist Virology Centre, Department of Infection, University Hospital Southampton NHS Foundation Trust, Southampton, UK
| | | | - Ferhat Ay
- La Jolla Institute for Immunology, La Jolla, CA 92037
| | - Pandurangan Vijayanand
- La Jolla Institute for Immunology, La Jolla, CA 92037.
- Liverpool Head and Neck Center, Institute of Translational Medicine, University of Liverpool & Clatterbridge Cancer Center NHS Foundation Trust, Liverpool, UK
- Department of Medicine, University of California San Diego, La Jolla, CA 92037
| | - Christian H Ottensmeier
- La Jolla Institute for Immunology, La Jolla, CA 92037.
- Liverpool Head and Neck Center, Institute of Translational Medicine, University of Liverpool & Clatterbridge Cancer Center NHS Foundation Trust, Liverpool, UK
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43
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Shen L, Chen Q, Yang C, Wu Y, Yuan H, Chen S, Ou S, Jiang Y, Huang T, Ke L, Mo J, Feng Z, Zhou P, Fan W. Role of PRDM1 in Tumor Immunity and Drug Response: A Pan-Cancer Analysis. Front Pharmacol 2020; 11:593195. [PMID: 33384601 PMCID: PMC7770985 DOI: 10.3389/fphar.2020.593195] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Accepted: 11/16/2020] [Indexed: 11/15/2022] Open
Abstract
Background: PR domain zinc finger protein 1 (PRDM1) is a regulator of both B cell and T cell differentiation and plays a critical role in immunosuppression. Its role in tumor immunity and correlation with drug response remain unknown. Methods: This work comprehensively analyzed the transcriptional expression pattern of the PRDM1 among 33 types of malignancies from The Cancer Genome Atlas and the Genotype-Tissue Expression projects. Besides, correlation of the PRDM1 with cancer prognosis, immune infiltrates, checkpoint markers, cancer stemness and drug response were explored. Results: High expression level of PRDM1 were observed in ACC, COAD, LAML, LGG, LUAD, OV, PAAD, STAD, TGCT. Cox regression model showed high expression of PRDM1 in tumor samples correlates with poor prognosis in LGG, PAAD, UVM while favorable prognosis in KIRC, SKCM and THCA. PRDM1 expression positively correlates with the expression of LAG3, CTLA4, PDCD1 (PD-1), CD274 (PD-L1), PDCD1LG2 (PD-L2), TIGIT in the majority of 33 cancer types. PRDM1 positively correlated with TNFRSF14 in LGG and UVM among cancers with unfavorable prognosis; this correlation were weak or even negative in cancers with favorable prognosis. The top negatively enriched KEGG terms in high PRDM1 subgroup were B cell receptor signaling, T cell receptor signaling, and the top negatively enriched HALLMARK terms included IL-2-STAT5 signaling and allograft rejection. The expression of PRDM1 was found positively correlated with cancer stemness in CHOL, KIRP, TGCT, THYM and UVM. A series of targeted drugs and small-molecule drugs with promising efficacy predicted by PRDM1 level were identified. Conclusion: The clinical significance and biological impact of high transcriptional expression of PRDM1 differs across different cancers. Inhibiting the PRDM1-dependent signaling could be a novel and promising strategy of immunotherapy in cancers including LGG, PAAD and UVM.
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Affiliation(s)
- Lujun Shen
- Department of Minimally Invasive Interventional Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China.,State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University, Guangzhou, China
| | - Qifeng Chen
- Department of Minimally Invasive Interventional Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China.,State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University, Guangzhou, China
| | - Changsheng Yang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University, Guangzhou, China.,Department of Spine Surgery, Third Affiliated Hospital of Southern Medical University, Guangzhou, China
| | - Ying Wu
- Department of Minimally Invasive Interventional Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China.,State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University, Guangzhou, China
| | - Hui Yuan
- Department of Minimally Invasive Interventional Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China.,State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University, Guangzhou, China
| | - Shuanggang Chen
- Department of Minimally Invasive Interventional Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China.,State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University, Guangzhou, China
| | - Shunling Ou
- Department of Minimally Invasive Interventional Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China.,State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University, Guangzhou, China
| | - Yiquan Jiang
- Department of Minimally Invasive Interventional Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China.,State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University, Guangzhou, China
| | - Tao Huang
- Department of Minimally Invasive Interventional Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China.,State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University, Guangzhou, China
| | - Liangru Ke
- Department of Radiology, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Jinqing Mo
- Zhong Shan Medical School, Sun Yat-sen University, M, China
| | - Ziqing Feng
- Zhong Shan Medical School, Sun Yat-sen University, M, China
| | - Penghui Zhou
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University, Guangzhou, China
| | - Weijun Fan
- Department of Minimally Invasive Interventional Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China.,State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University, Guangzhou, China
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44
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Perdiguero P, Goméz-Esparza MC, Martín D, Bird S, Soleto I, Morel E, Díaz-Rosales P, Tafalla C. Insights Into the Evolution of the prdm1/Blimp1 Gene Family in Teleost Fish. Front Immunol 2020; 11:596975. [PMID: 33193451 PMCID: PMC7662092 DOI: 10.3389/fimmu.2020.596975] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Accepted: 10/08/2020] [Indexed: 12/27/2022] Open
Abstract
In mammals, Blimp1 (B lymphocyte-induced maturation protein 1) encoded by the prdm1 gene and its homolog Hobit (homolog of Blimp1 in T cells) encoded by znf683, represent key transcriptional factors that control the development and differentiation of both B and T cells. Despite their essential role in the regulation of acquired immunity, this gene family has been largely unexplored in teleosts to date. Until now, one prdm1 gene has been identified in most teleost species, whereas a znf683 homolog has not yet been reported in any of these species. Focusing our analysis on rainbow trout (Oncorhynchus mykiss), an in silico identification and characterization of prdm1-like genes has been undertaken, confirming that prdm1 and znf683 evolved from a common ancestor gene, acquiring three gene copies after the teleost-specific whole genome duplication event (WGD) and six genes after the salmonid-specific WGD. Additional transcriptional studies to study how each of these genes are regulated in homeostasis, in response to a viral infection or in B cells in different differentiation stages, provide novel insights as to how this gene family evolved and how their encoded products might be implicated in the lymphocyte differentiation process in teleosts.
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Affiliation(s)
| | | | - Diana Martín
- Animal Health Research Center (CISA-INIA), Madrid, Spain
| | - Steve Bird
- Biomedical Unit, School of Science, University of Waikato, Hamilton, New Zealand
| | - Irene Soleto
- Animal Health Research Center (CISA-INIA), Madrid, Spain
| | - Esther Morel
- Animal Health Research Center (CISA-INIA), Madrid, Spain
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45
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Si J, Shi X, Sun S, Zou B, Li Y, An D, Lin X, Gao Y, Long F, Pang B, Liu X, Liu T, Chi W, Chen L, Dimitrov DS, Sun Y, Du X, Yin W, Gao G, Min J, Wei L, Liao X. Hematopoietic Progenitor Kinase1 (HPK1) Mediates T Cell Dysfunction and Is a Druggable Target for T Cell-Based Immunotherapies. Cancer Cell 2020; 38:551-566.e11. [PMID: 32860752 DOI: 10.1016/j.ccell.2020.08.001] [Citation(s) in RCA: 117] [Impact Index Per Article: 23.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2019] [Revised: 05/17/2020] [Accepted: 07/31/2020] [Indexed: 01/02/2023]
Abstract
Ameliorating T cell exhaustion and enhancing effector function are promising strategies for the improvement of immunotherapies. Here, we show that the HPK1-NFκB-Blimp1 axis mediates T cell dysfunction. High expression of MAP4K1 (which encodes HPK1) correlates with increased T cell exhaustion and with worse patient survival in several cancer types. In MAP4K1KO mice, tumors grow slower than in wild-type mice and infiltrating T cells are less exhausted and more active and proliferative. We further show that genetic depletion, pharmacological inhibition, or proteolysis targeting chimera (PROTAC)-mediated degradation of HPK1 improves the efficacy of CAR-T cell-based immunotherapies in diverse preclinical mouse models of hematological and solid tumors. These strategies are more effective than genetically depleting PD-1 in CAR-T cells. Thus, we demonstrate that HPK1 is a mediator of T cell dysfunction and an attractive druggable target to improve immune therapy responses.
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Affiliation(s)
- Jingwen Si
- School of Pharmaceutical Sciences, Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Beijing Advanced Innovation Center for Human Brain Protection, Tsinghua University, 100084 Beijing, China; Joint Graduate Program of Peking-Tsinghua-NIBS, School of Life Sciences, Tsinghua University, 100084 Beijing, China
| | - Xiangjun Shi
- School of Pharmaceutical Sciences, Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Beijing Advanced Innovation Center for Human Brain Protection, Tsinghua University, 100084 Beijing, China
| | - Shuhao Sun
- School of Pharmaceutical Sciences, Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Beijing Advanced Innovation Center for Human Brain Protection, Tsinghua University, 100084 Beijing, China
| | - Bin Zou
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, 510060 Guangzhou, China
| | - Yaopeng Li
- School of Pharmaceutical Sciences, Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Beijing Advanced Innovation Center for Human Brain Protection, Tsinghua University, 100084 Beijing, China
| | - Dongjie An
- School of Pharmaceutical Sciences, Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Beijing Advanced Innovation Center for Human Brain Protection, Tsinghua University, 100084 Beijing, China
| | - Xingyu Lin
- Zhuhai Yufan Biotechnologies Co., Ltd, Zhuhai, 519000 Guangdong, China
| | - Yan Gao
- School of Pharmaceutical Sciences, Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Beijing Advanced Innovation Center for Human Brain Protection, Tsinghua University, 100084 Beijing, China; Department of Central Laboratory, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, 100026 Beijing, China
| | - Fei Long
- Xi'an Yufan Biotechnologies Co., Ltd, Xi'an, 710032 Shaanxi, China
| | - Bo Pang
- Department of Clinical Laboratory, Guang'an Men Hospital, China Academy of Chinese Medical Sciences, 100053 Beijing, China
| | - Xing Liu
- Department of Anesthesiology, Third Xiangya Hospital, Central South University, Changsha, 410013 Hunan, China
| | - Tian Liu
- Department of Plastic Surgery, General Hospital of Southern Theater Command, PLA, Guangdong, 510010 Guangzhou, China
| | - Wenna Chi
- School of Pharmaceutical Sciences, Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Beijing Advanced Innovation Center for Human Brain Protection, Tsinghua University, 100084 Beijing, China
| | - Ligong Chen
- School of Pharmaceutical Sciences, Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Beijing Advanced Innovation Center for Human Brain Protection, Tsinghua University, 100084 Beijing, China
| | - Dimiter S Dimitrov
- Center for Antibody Therapeutics, University of Pittsburgh, Pittsburgh, PA 15216, USA
| | - Yan Sun
- Lanzhou Institute of Husbandry and Pharmaceutical Science of CAAS, Lanzhou, 730050 Gansu, China
| | - Xinru Du
- Department of Orthopaedics, Beijing Chao-Yang Hospital, Capita Medical University, 100020 Beijing, China
| | - Wen Yin
- Department of Transfusion Medicine, Xijing Hospital, Air Force Military Medical University, Xi'an, 710032 Shaanxi, China
| | - Guangxun Gao
- Department of Hematology, Xijing Hospital, Air Force Military Medical University, Xi'an, 710032 Shaanxi, China
| | - Junxia Min
- The First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University, Hangzhou, 310058 Zhejiang, China
| | - Lai Wei
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, 510060 Guangzhou, China.
| | - Xuebin Liao
- School of Pharmaceutical Sciences, Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Beijing Advanced Innovation Center for Human Brain Protection, Tsinghua University, 100084 Beijing, China.
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Liang T, Guo Y, Li M, Ding C, Sang S, Zhou T, Shao Q, Liu X, Lu J, Ji Z, Wang T, Kang Q. Cytoskeleton protein 4.1R regulates B-cell fate by modulating the canonical NF-κB pathway. Immunology 2020; 161:314-324. [PMID: 32852059 DOI: 10.1111/imm.13250] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2019] [Revised: 06/16/2020] [Accepted: 08/12/2020] [Indexed: 11/29/2022] Open
Abstract
During the immune response, B cells can enter the memory pathway, which is characterized by class switch recombination (CSR), or they may undergo plasma cell differentiation (PCD) to secrete immunoglobulin. Both of these processes occur in activated B cells, which are reported to relate to membrane-association proteins and adaptors. Protein 4.1R acts as an adaptor, linking membrane proteins to the cytoskeleton, and is involved in many cell events such as cell activation and differentiation, and cytokine secretion. However, the effect of 4.1R on regulating B-cell fate is unclear. Here, we show an important association between B-cell fate and 4.1R. In vitro, primary B cells were stimulated with lipopolysaccharide combined with interleukin-4; results showed that 4.1R-deficient (4.1R-/- ) cells compared with wild-type (4.1R+/+ ) B cells augmented expression of activation-induced cytidine deaminase and germline, resulting in increased IgG1+ B cells, whereas the secretion of IgG1 and IgM was reduced, and CD138+ B cells were also decreased. Throughout the process, 4.1R regulated canonical nuclear factor (NF-κB) rather than non-canonical NF-κB to promote the expression of CSR complex components, leading to up-regulation of B-cell CSR. In contrast, 4.1R-deficient B cells showed reduced expression of Blimp-1, which caused B cells to down-regulate PCD. Furthermore, over-activation of canonical NF-κB may induce apoptosis signaling to cause PCD apoptosis to reduce PCD number. In summary, our results suggest that 4.1R acts as a B-cell fate regulator by inhibiting the canonical NF-κB signaling pathway.
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Affiliation(s)
- Taotao Liang
- School of Life Sciences, Zhengzhou University, Zhengzhou, China
| | - Yuying Guo
- The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Mengjia Li
- School of Life Sciences, Zhengzhou University, Zhengzhou, China
| | - Cong Ding
- School of Life Sciences, Zhengzhou University, Zhengzhou, China
| | - Siyao Sang
- School of Life Sciences, Zhengzhou University, Zhengzhou, China
| | - Tingting Zhou
- School of Life Sciences, Zhengzhou University, Zhengzhou, China
| | - Qi Shao
- School of Life Sciences, Zhengzhou University, Zhengzhou, China
| | - Xin Liu
- School of Life Sciences, Zhengzhou University, Zhengzhou, China
| | - Jike Lu
- School of Life Sciences, Zhengzhou University, Zhengzhou, China
| | - Zhenyu Ji
- Henan Academy of Medical and Pharmaceutical Sciences, Zhengzhou, China
| | - Ting Wang
- School of Life Sciences, Zhengzhou University, Zhengzhou, China
| | - Qiaozhen Kang
- School of Life Sciences, Zhengzhou University, Zhengzhou, China
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Li N, Fan X, Wang X, Zhang X, Zhang K, Han Q, Lv Y, Liu Z. Genetic association of polymorphisms at the intergenic region between PRDM1 and ATG5 with hepatitis B virus infection in Han Chinese patients. J Med Virol 2020; 92:1198-1205. [PMID: 31729038 DOI: 10.1002/jmv.25629] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2019] [Accepted: 11/12/2019] [Indexed: 12/21/2022]
Abstract
Chronic hepatitis B virus (HBV) infection is related to chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC), and the interplay between the virus and host immune response leads to different outcomes of the infection. PR domain zinc finger protein 1 (PRDM1) and autophagy-related protein 5 (ATG5) are involved in immune response and HBV infection. An intergenic region between PRDM1 and ATG5 (PRDM1-ATG5 region) has been identified, and single-nucleotide polymorphisms (SNPs) in this region were shown to be involved in immune regulation. This study investigated the functionally relevant rs548234, rs6937876, and rs6568431 polymorphisms at the PRDM1-ATG5 region in a Han Chinese population (403 patients with chronic HBV infection [171 chronic hepatitis, 119 cirrhosis, and 113 HCC], 70 infection resolvers, and 196 healthy controls). The frequencies of the rs6568431 allele A in HBV patients (P = .005) and genotype CA in infection resolvers (P = .005) were significantly higher than in healthy controls. In the dominant model, HCC patients had significantly higher frequencies of rs548234 genotypes CC + TC than cirrhosis patients (P = .009). Rs548234 was an independent factor for HCC in comparison with either cirrhosis (P = .005) or all chronic HBV infection without HCC (P = .018). Functional annotation showed evidence of the role of the SNPs in gene regulation. In conclusion, through this study it is revealed for the first time that rs6568431 may be associated with susceptibility to HBV infection and that rs548234 may be associated with HCC risk in chronic HBV infection, supporting the presence of HBV-related disease-causing regulatory polymorphisms in the PRDM1-ATG5 intergenic region.
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Affiliation(s)
- Na Li
- Department of Infectious Diseases, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Xiude Fan
- Department of Infectious Diseases, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Xiaoyun Wang
- Department of Infectious Diseases, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Xiaoge Zhang
- Department of Infectious Diseases, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Kun Zhang
- Department of Infectious Diseases, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Qunying Han
- Department of Infectious Diseases, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Yi Lv
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
- Institute of Advanced Surgical Technology and Engineering, Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Zhengwen Liu
- Department of Infectious Diseases, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
- Institute of Advanced Surgical Technology and Engineering, Xi'an Jiaotong University, Xi'an, Shaanxi, China
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Kusnadi A, Ramírez-Suástegui C, Fajardo V, Chee SJ, Meckiff BJ, Simon H, Pelosi E, Seumois G, Ay F, Vijayanand P, Ottensmeier CH. Severely ill COVID-19 patients display augmented functional properties in SARS-CoV-2-reactive CD8 + T cells. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2020:2020.07.09.194027. [PMID: 32676602 PMCID: PMC7359524 DOI: 10.1101/2020.07.09.194027] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 04/25/2023]
Abstract
The molecular properties of CD8 + T cells that respond to SARS-CoV-2 infection are not fully known. Here, we report on the single-cell transcriptomes of >80,000 virus-reactive CD8 + T cells from 39 COVID-19 patients and 10 healthy subjects. COVID-19 patients segregated into two groups based on whether the dominant CD8 + T cell response to SARS-CoV-2 was 'exhausted' or not. SARS-CoV-2-reactive cells in the exhausted subset were increased in frequency and displayed lesser cytotoxicity and inflammatory features in COVID-19 patients with mild compared to severe illness. In contrast, SARS-CoV-2-reactive cells in the non-exhausted subsets from patients with severe disease showed enrichment of transcripts linked to co-stimulation, pro-survival NF-κB signaling, and anti-apoptotic pathways, suggesting the generation of robust CD8 + T cell memory responses in patients with severe COVID-19 illness. CD8 + T cells reactive to influenza and respiratory syncytial virus from healthy subjects displayed polyfunctional features. Cells with such features were mostly absent in SARS-CoV-2 responsive cells from both COVID-19 patients and healthy controls non-exposed to SARS-CoV-2. Overall, our single-cell analysis revealed substantial diversity in the nature of CD8 + T cells responding to SARS-CoV-2.
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Affiliation(s)
- Anthony Kusnadi
- La Jolla Institute for Immunology, La Jolla, CA, USA
- These authors jointly contributed to the work
| | - Ciro Ramírez-Suástegui
- La Jolla Institute for Immunology, La Jolla, CA, USA
- These authors jointly contributed to the work
| | - Vicente Fajardo
- La Jolla Institute for Immunology, La Jolla, CA, USA
- These authors jointly contributed to the work
| | - Serena J Chee
- NIHR and CRUK Southampton Experimental Cancer Medicine Center, Faculty of Medicine, University of Southampton, Southampton, UK
- These authors jointly contributed to the work
| | | | - Hayley Simon
- La Jolla Institute for Immunology, La Jolla, CA, USA
| | - Emanuela Pelosi
- Southampton Specialist Virology Centre, Department of Infection, University Hospital Southampton NHS Foundation Trust, Southampton, UK
| | | | - Ferhat Ay
- La Jolla Institute for Immunology, La Jolla, CA, USA
| | - Pandurangan Vijayanand
- La Jolla Institute for Immunology, La Jolla, CA, USA
- Liverpool Head and Neck Center, Institute of Translational Medicine, University of Liverpool & Clatterbridge Cancer Center NHS Foundation Trust, Liverpool, United Kingdom
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
- These authors jointly directed the work
| | - Christian H Ottensmeier
- La Jolla Institute for Immunology, La Jolla, CA, USA
- Liverpool Head and Neck Center, Institute of Translational Medicine, University of Liverpool & Clatterbridge Cancer Center NHS Foundation Trust, Liverpool, United Kingdom
- These authors jointly directed the work
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49
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Vigano S, Bobisse S, Coukos G, Perreau M, Harari A. Cancer and HIV-1 Infection: Patterns of Chronic Antigen Exposure. Front Immunol 2020; 11:1350. [PMID: 32714330 PMCID: PMC7344140 DOI: 10.3389/fimmu.2020.01350] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2020] [Accepted: 05/27/2020] [Indexed: 12/14/2022] Open
Abstract
The main role of the human immune system is to eliminate cells presenting foreign antigens and abnormal patterns, while maintaining self-tolerance. However, when facing highly variable pathogens or antigens very similar to self-antigens, this system can fail in completely eliminating the anomalies, leading to the establishment of chronic pathologies. Prototypical examples of immune system defeat are cancer and Human Immunodeficiency Virus-1 (HIV-1) infection. In both conditions, the immune system is persistently exposed to antigens leading to systemic inflammation, lack of generation of long-term memory and exhaustion of effector cells. This triggers a negative feedback loop where effector cells are unable to resolve the pathology and cannot be replaced due to the lack of a pool of undifferentiated, self-renewing memory T cells. In addition, in an attempt to reduce tissue damage due to chronic inflammation, antigen presenting cells and myeloid components of the immune system activate systemic regulatory and tolerogenic programs. Beside these homologies shared between cancer and HIV-1 infection, the immune system can be shaped differently depending on the type and distribution of the eliciting antigens with ultimate consequences at the phenotypic and functional level of immune exhaustion. T cell differentiation, functionality, cytotoxic potential and proliferation reserve, immune-cell polarization, upregulation of negative regulators (immune checkpoint molecules) are indeed directly linked to the quantitative and qualitative differences in priming and recalling conditions. Better understanding of distinct mechanisms and functional consequences underlying disease-specific immune cell dysfunction will contribute to further improve and personalize immunotherapy. In the present review, we describe relevant players of immune cell exhaustion in cancer and HIV-1 infection, and enumerate the best-defined hallmarks of T cell dysfunction. Moreover, we highlight shared and divergent aspects of T cell exhaustion and T cell activation to the best of current knowledge.
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Affiliation(s)
- Selena Vigano
- Ludwig Institute for Cancer Research, University of Lausanne and Department of Oncology, University Hospital of Lausanne, Lausanne, Switzerland
| | - Sara Bobisse
- Ludwig Institute for Cancer Research, University of Lausanne and Department of Oncology, University Hospital of Lausanne, Lausanne, Switzerland
| | - George Coukos
- Ludwig Institute for Cancer Research, University of Lausanne and Department of Oncology, University Hospital of Lausanne, Lausanne, Switzerland
| | - Matthieu Perreau
- Service of Immunology and Allergy, University Hospital of Lausanne, Lausanne, Switzerland
| | - Alexandre Harari
- Ludwig Institute for Cancer Research, University of Lausanne and Department of Oncology, University Hospital of Lausanne, Lausanne, Switzerland
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Cui ZW, Zhang XY, Wu CS, Zhang YA, Zhou Y, Zhang XJ. Membrane IgM + plasma cells in grass carp (Ctenopharyngodon idella): Insights into the conserved evolution of IgM + plasma cells in vertebrates. DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY 2020; 106:103613. [PMID: 31935401 DOI: 10.1016/j.dci.2020.103613] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/13/2019] [Revised: 01/10/2020] [Accepted: 01/10/2020] [Indexed: 06/10/2023]
Abstract
Teleost fish are the most primitive bony vertebrates that contain B cells; thus, comparative analysis of teleost naïve/mature B cells and plasma cells can provide helpful evidence for understanding the evolution paradigms of these two B-cell subpopulations in vertebrates. In this study, we developed monoclonal antibody against grass carp IgM and identified two different IgM+ cell subsets: IgM+ lymphocytes (Lym), resembling naïve/mature B cells, and IgM+ myeloid cells (Mye), resembling plasma cells. Like plasma cells in mammals, the size of IgM+ Mye is significantly larger than that of IgM+ Lym, as revealed by flow cytometric analysis and transmission electron microscopy. The IgM+ Mye were further verified as plasma cells because they showed gene expression patterns similar with those of human plasma cells and a great capacity to secrete IgM. Like mammalian IgM+ and IgA+ plasma cells, not IgG+ plasma cells, grass carp IgM+ Mye also expressed membrane immunoglobulins, a feature conserved in IgM+ plasma cells in vertebrates. Furthermore, recombinant CD40L or IL-21 alone could induce the plasma cell generation and IgM secretion, while the combination of CD40L and IL-21 had greater effect on IgM secretion, but not on plasma cell generation. This study fills an important gap in the knowledge of plasma cells in teleost fish and provides critical insights into the conserved evolution of IgM+ plasma cells in vertebrates.
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Affiliation(s)
- Zheng-Wei Cui
- State Key Laboratory of Agricultural Microbiology, College of Fisheries, Huazhong Agricultural University, Wuhan, 430070, China; Key Laboratory of Fishery Drug Development, Ministry of Agriculture, China, Pearl River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Guangzhou, 510380, China; Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, 430070, China
| | - Xiang-Yang Zhang
- Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, 430070, China
| | - Chang-Song Wu
- State Key Laboratory of Agricultural Microbiology, College of Fisheries, Huazhong Agricultural University, Wuhan, 430070, China
| | - Yong-An Zhang
- State Key Laboratory of Agricultural Microbiology, College of Fisheries, Huazhong Agricultural University, Wuhan, 430070, China; Laboratory for Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Qingdao, 266071, China; Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, 430070, China
| | - Yang Zhou
- State Key Laboratory of Agricultural Microbiology, College of Fisheries, Huazhong Agricultural University, Wuhan, 430070, China.
| | - Xu-Jie Zhang
- State Key Laboratory of Agricultural Microbiology, College of Fisheries, Huazhong Agricultural University, Wuhan, 430070, China.
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