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Chen Y, Wu X, Yang H, Liu Z, Chen Y, Wei Q, Lin J, Yu Y, Tu Q, Li H. Characterization, expression, and polymorphism of MHC II α and MHC II β in Sichuan taimen (Hucho bleekeri). Comp Biochem Physiol A Mol Integr Physiol 2025; 299:111767. [PMID: 39401690 DOI: 10.1016/j.cbpa.2024.111767] [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: 09/01/2024] [Revised: 10/10/2024] [Accepted: 10/11/2024] [Indexed: 10/19/2024]
Abstract
The major histocompatibility complex (MHC) is involved in antigen presentation and plays an essential role in regulating immune function. In the present study, we identified two MHC class II genes and investigated their potential roles in Hucho bleekeri. The MHC II α and MHC II β of H. bleekeri had typical leading peptides, extracellular domains, connecting peptides, transmembrane region, and cytoplasmic region. Amino acid sequence comparison revealed that MHC II of H. bleekeri has high homology with other vertebrates, among which homology with salmonid fish was the highest. Phylogenetic analysis showed that H. bleekeri MHC II clustered with salmonid fish; moreover they clustered with orthologous genes of other fish, whereas mammalian MHC II clustered into a separate branch. Tissue distribution analysis revealed MHC II was widely expressed in all tested tissues, with both MHC II α and MHC II β highly expressed in the spleen, gill, kidney, and hindgut. After lipopolysaccharide (LPS) and polyinosinic:polycytidylic acid (poly(I:C)) stimulation, the expression of MHC II in the head kidney and spleen of H. bleekeri was significantly upregulated. Compared with MHC II α, MHC II β acted faster in response to the stimulation. Polymorphism analysis of MHC II revealed that all the different alleles belonged to the same major type, and very limited polymorphisms were found in H. bleekeri MHC II α and II β. Selection pressure analysis showed signs of weak and non-significant positive selection in the MHC II α and MHC II β extracellular region. Our study reveals the potential role of MHC II in the immune response of H. bleekeri and provides a reference for studying the evolutionary model of teleost MHC II.
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Affiliation(s)
- Yeyu Chen
- Fisheries Research Institute, Sichuan Academy of Agricultural Sciences, Chengdu 611730, China; Fish Resources and Environment in the Upper Reaches of the Yangtze River Observation and Research Station of Sichuan Province, Chengdu 611730, China
| | - Xiaoyun Wu
- Fisheries Research Institute, Sichuan Academy of Agricultural Sciences, Chengdu 611730, China; Fish Resources and Environment in the Upper Reaches of the Yangtze River Observation and Research Station of Sichuan Province, Chengdu 611730, China
| | - Huanchao Yang
- Fisheries Research Institute, Sichuan Academy of Agricultural Sciences, Chengdu 611730, China; Fish Resources and Environment in the Upper Reaches of the Yangtze River Observation and Research Station of Sichuan Province, Chengdu 611730, China
| | - Zhao Liu
- Fisheries Research Institute, Sichuan Academy of Agricultural Sciences, Chengdu 611730, China; Fish Resources and Environment in the Upper Reaches of the Yangtze River Observation and Research Station of Sichuan Province, Chengdu 611730, China
| | - Yanling Chen
- Fisheries Research Institute, Sichuan Academy of Agricultural Sciences, Chengdu 611730, China; Fish Resources and Environment in the Upper Reaches of the Yangtze River Observation and Research Station of Sichuan Province, Chengdu 611730, China
| | - Qinyao Wei
- Fisheries Research Institute, Sichuan Academy of Agricultural Sciences, Chengdu 611730, China; Key Laboratory of Bio-Resources and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu 610065, China
| | - Jue Lin
- Fisheries Research Institute, Sichuan Academy of Agricultural Sciences, Chengdu 611730, China; Fish Resources and Environment in the Upper Reaches of the Yangtze River Observation and Research Station of Sichuan Province, Chengdu 611730, China
| | - Yi Yu
- Fisheries Research Institute, Sichuan Academy of Agricultural Sciences, Chengdu 611730, China; Fish Resources and Environment in the Upper Reaches of the Yangtze River Observation and Research Station of Sichuan Province, Chengdu 611730, China
| | - Quanyu Tu
- Fisheries Research Institute, Sichuan Academy of Agricultural Sciences, Chengdu 611730, China; Fish Resources and Environment in the Upper Reaches of the Yangtze River Observation and Research Station of Sichuan Province, Chengdu 611730, China
| | - Hua Li
- Fisheries Research Institute, Sichuan Academy of Agricultural Sciences, Chengdu 611730, China; Fish Resources and Environment in the Upper Reaches of the Yangtze River Observation and Research Station of Sichuan Province, Chengdu 611730, China.
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2
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Rane G, Kuan VLS, Wang S, Mok MMH, Khanchandani V, Hansen J, Norvaisaite I, Zulkaflee N, Yong WK, Jahn A, Mukundan VT, Shi Y, Osato M, Li F, Kappei D. ZBTB48 is a priming factor regulating B-cell-specific CIITA expression. EMBO J 2024; 43:6236-6263. [PMID: 39562739 PMCID: PMC11649694 DOI: 10.1038/s44318-024-00306-y] [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: 11/23/2023] [Revised: 09/26/2024] [Accepted: 10/16/2024] [Indexed: 11/21/2024] Open
Abstract
The class-II transactivator (CIITA) is the master regulator of MHC class-II gene expression and hence the adaptive immune response. Three cell type-specific promoters (pI, pIII, and pIV) are involved in the regulation of CIITA expression, which can be induced by IFN-γ in non-immune cells. While key regulatory elements have been identified within these promoters, our understanding of the transcription factors regulating CIITA expression is incomplete. Here, we demonstrate that the telomere-binding protein and transcriptional activator ZBTB48 directly binds to both critical activating elements within the B-cell-specific promoter CIITA pIII. ZBTB48 knockout impedes the CIITA/MHC-II expression program induced in non-APC cells by IFN-γ, and loss of ZBTB48 in mice silences MHC-II expression in pro-B and immature B cells. Transcriptional regulation of CIITA by ZBTB48 is enabled by ZBTB48-dependent chromatin opening at CIITA pIII upstream of activating H3K4me3 marks. We conclude that ZBTB48 primes CIITA pIII by acting as a molecular on-off-switch for B-cell-specific CIITA expression.
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Affiliation(s)
- Grishma Rane
- Cancer Science Institute of Singapore, National University of Singapore, 117599, Singapore, Singapore
| | - Vivian L S Kuan
- Cancer Science Institute of Singapore, National University of Singapore, 117599, Singapore, Singapore
| | - Suman Wang
- MOE Key Laboratory for Cellular Dynamics, School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Michelle Meng Huang Mok
- Cancer Science Institute of Singapore, National University of Singapore, 117599, Singapore, Singapore
| | - Vartika Khanchandani
- Cancer Science Institute of Singapore, National University of Singapore, 117599, Singapore, Singapore
| | - Julia Hansen
- Cancer Science Institute of Singapore, National University of Singapore, 117599, Singapore, Singapore
| | - Ieva Norvaisaite
- Cancer Science Institute of Singapore, National University of Singapore, 117599, Singapore, Singapore
| | - Naasyidah Zulkaflee
- Cancer Science Institute of Singapore, National University of Singapore, 117599, Singapore, Singapore
| | - Wai Khang Yong
- Cancer Science Institute of Singapore, National University of Singapore, 117599, Singapore, Singapore
| | - Arne Jahn
- Institute for Clinical Genetics, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany
- National Center for Tumor Diseases (NCT), Dresden, Germany
- German Cancer Research Center (DKFZ), Heidelberg, Germany
- ERN-GENTURIS, Hereditary Cancer Syndrome Center, Dresden, Germany
| | - Vineeth T Mukundan
- Cancer Science Institute of Singapore, National University of Singapore, 117599, Singapore, Singapore
| | - Yunyu Shi
- MOE Key Laboratory for Cellular Dynamics, School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Motomi Osato
- Cancer Science Institute of Singapore, National University of Singapore, 117599, Singapore, Singapore
| | - Fudong Li
- MOE Key Laboratory for Cellular Dynamics, School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Dennis Kappei
- Cancer Science Institute of Singapore, National University of Singapore, 117599, Singapore, Singapore.
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, 117596, Singapore, Singapore.
- NUS Center for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
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Cui Y, Zhang W, Zeng X, Yang Y, Park SJ, Nakai K. Computational analysis of the functional impact of MHC-II-expressing triple-negative breast cancer. Front Immunol 2024; 15:1497251. [PMID: 39664386 PMCID: PMC11631845 DOI: 10.3389/fimmu.2024.1497251] [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: 09/16/2024] [Accepted: 11/08/2024] [Indexed: 12/13/2024] Open
Abstract
The tumor microenvironment (TME) plays a crucial role in tumor progression and immunoregulation. Major histocompatibility complex class II (MHC-II) is essential for immune surveillance within the TME. While MHC-II genes are typically expressed by professional antigen-presenting cells, they are also expressed in tumor cells, potentially facilitating antitumor immune responses. To understand the role of MHC-II-expressing tumor cells, we analyzed triple-negative breast cancer (TNBC), an aggressive subtype with poor prognosis and limited treatment options, using public bulk RNA-seq, single-cell RNA-seq, and spatial transcriptomics datasets. Our analysis revealed a distinct tumor subpopulation that upregulates MHC-II genes and actively interacts with immune cells. We implicated that this subpopulation is preferentially present in proximity to regions in immune infiltration of TNBC patient cohorts with a better prognosis, suggesting the functional importance of MHC-II-expressing tumor cells in modulating the immune landscape and influencing patient survival outcomes. Remarkably, we identified a prognostic signature comprising 40 significant genes in the MHC-II-expressing tumors in which machine leaning models with the signature successfully predicted patient survival outcomes and the degree of immune infiltration. This study advances our understanding of the immunological basis of cancer progression and suggests promising new directions for therapeutic strategies.
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Affiliation(s)
- Yang Cui
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, University of Tokyo, Tokyo, Japan
| | - Weihang Zhang
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, University of Tokyo, Tokyo, Japan
| | - Xin Zeng
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, University of Tokyo, Tokyo, Japan
| | - Yitao Yang
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, University of Tokyo, Tokyo, Japan
| | - Sung-Joon Park
- Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan
| | - Kenta Nakai
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, University of Tokyo, Tokyo, Japan
- Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan
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Nagasubramanian K, Gupta K. Interactome analysis implicates class II transactivator (CIITA) in depression and other neuroinflammatory disorders. Int J Neurosci 2024; 134:1153-1171. [PMID: 37933915 DOI: 10.1080/00207454.2023.2279502] [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: 08/02/2023] [Revised: 10/24/2023] [Accepted: 10/31/2023] [Indexed: 11/08/2023]
Abstract
PURPOSE Inappropriate inflammatory responses within the nervous system (neuroinflammation) have been implicated in several neurological conditions. Class II transactivator (CIITA), a principal regulator of the major histocompatibility complex II (MHCII), is known to play essential roles in inflammation. Hence, CIITA and its interactors could be potentially involved in multiple neurological disorders. However, the molecular mechanisms underlying CIITA-mediated neuroinflammation (NI) are yet to be understood. MATERIALS AND METHODS In this regard, we analyzed the potential involvement of CIITA and its interactome in the regulation of neuroinflammation. In the present study, using various computational tools, we aimed (1) to identify NI-related proteins, (2) to filter the critical interactors in the CIITA-NI network, and (3) to analyze the protein-disease interactions and the associated molecular pathways through which CIITA could influence neuroinflammation. RESULTS CIITA was found to interact with P T GS2, GSK3B, and NR3C1 and may influence depressive disorders. Further, the IL4/IL13 pathway was found to be potentially underlying the CIITA-interactomemediated effects on neurological disorders. Moreover, CIITA was found to be connected to genes associated with depressive disorder through IL4, wherein CIITA was found to be potentially involved in depressive disorders through IL-4/IL-13 and hippo pathways. However, the present study is based on the existing data on protein interactomes and could be re-evaluated as newer interactions are discovered. Also, the functional mechanisms of CIITA's roles in neuroinflammation must be evaluated further. CONCLUSION Notwithstanding these limitations, the results presented here, could form a basis for further experimental studies to assess CIITA as a potential therapeutic target in managing depression and other neuroinflammatory disorders.
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Affiliation(s)
- Kishore Nagasubramanian
- School of Chemical and Biotechnology, SASTRA Deemed to be University, Thanjavur, Tamil Nadu, India
| | - Krishnakant Gupta
- School of Chemical and Biotechnology, SASTRA Deemed to be University, Thanjavur, Tamil Nadu, India
- NCCS, Pune, India
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Yang Y, Han X, Sun L, Shao F, Yin Y, Zhang W. ETS Transcription Factors in Immune Cells and Immune-Related Diseases. Int J Mol Sci 2024; 25:10004. [PMID: 39337492 PMCID: PMC11432452 DOI: 10.3390/ijms251810004] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2024] [Revised: 09/13/2024] [Accepted: 09/14/2024] [Indexed: 09/30/2024] Open
Abstract
The development, differentiation, and function of immune cells are precisely regulated by transcription factors. The E26 transformation-specific (ETS) transcription factor family is involved in various physiological and pathological processes by regulating cell proliferation, differentiation, and apoptosis. Emerging evidence has suggested that ETS family proteins are intimately involved in the development and function of immune cells. This review summarizes the role of the ETS family in immune cells and immune-related disorders. Seven transcription factors within the ETS family, including PU.1, ETV5, ETV6, ETS1/2, ELK3, and ELF1, play essential roles in the development and function of T cells, B cells, macrophages, neutrophils, and dendritic cells. Furthermore, they are involved in the occurrence and development of immune-related diseases, including tumors, allergies, autoimmune diseases, and arteriosclerosis. This review is conducive to a comprehensive overview of the role of the ETS family in immune cells, and thus is informative for the development of novel therapeutic strategies targeting the ETS family for immune-related diseases.
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Affiliation(s)
- Yaxu Yang
- Department of Physiology and Pathophysiology, State Key Laboratory of Vascular Homeostasis and Remodeling, School of Basic Medical Sciences, Peking University, Beijing 100191, China; (Y.Y.); (L.S.)
| | - Xue Han
- Department of Pharmacology, State Key Laboratory of Vascular Homeostasis and Remodeling, School of Basic Medical Sciences, Peking University, Beijing 100191, China; (X.H.); (F.S.)
| | - Lijun Sun
- Department of Physiology and Pathophysiology, State Key Laboratory of Vascular Homeostasis and Remodeling, School of Basic Medical Sciences, Peking University, Beijing 100191, China; (Y.Y.); (L.S.)
| | - Fangyu Shao
- Department of Pharmacology, State Key Laboratory of Vascular Homeostasis and Remodeling, School of Basic Medical Sciences, Peking University, Beijing 100191, China; (X.H.); (F.S.)
| | - Yue Yin
- Department of Pharmacology, State Key Laboratory of Vascular Homeostasis and Remodeling, School of Basic Medical Sciences, Peking University, Beijing 100191, China; (X.H.); (F.S.)
| | - Weizhen Zhang
- Department of Physiology and Pathophysiology, State Key Laboratory of Vascular Homeostasis and Remodeling, School of Basic Medical Sciences, Peking University, Beijing 100191, China; (Y.Y.); (L.S.)
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6
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Burdett NL, Willis MO, Pandey A, Twomey L, Alaei S, Bowtell DDL, Christie EL. Timing of whole genome duplication is associated with tumor-specific MHC-II depletion in serous ovarian cancer. Nat Commun 2024; 15:6069. [PMID: 39025846 PMCID: PMC11258338 DOI: 10.1038/s41467-024-50137-y] [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: 11/08/2023] [Accepted: 07/02/2024] [Indexed: 07/20/2024] Open
Abstract
Whole genome duplication is frequently observed in cancer, and its prevalence in our prior analysis of end-stage, homologous recombination deficient high grade serous ovarian cancer (almost 80% of samples) supports the notion that whole genome duplication provides a fitness advantage under the selection pressure of therapy. Here, we therefore aim to identify potential therapeutic vulnerabilities in primary high grade serous ovarian cancer with whole genome duplication by assessing differentially expressed genes and pathways in 79 samples. We observe that MHC-II expression is lowest in tumors which have acquired whole genome duplication early in tumor evolution, and further demonstrate that reduced MHC-II expression occurs in subsets of tumor cells rather than in canonical antigen-presenting cells. Early whole genome duplication is also associated with worse patient survival outcomes. Our results suggest an association between the timing of whole genome duplication, MHC-II expression and clinical outcome in high grade serous ovarian cancer that warrants further investigation for therapeutic targeting.
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Affiliation(s)
- Nikki L Burdett
- Peter MacCallum Cancer Centre, Melbourne, VIC, 3000, Australia
- Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, 3010, Australia
- Box Hill Hospital, Eastern Health, Box Hill, VIC, 3128, Australia
| | | | - Ahwan Pandey
- Peter MacCallum Cancer Centre, Melbourne, VIC, 3000, Australia
| | - Laura Twomey
- Peter MacCallum Cancer Centre, Melbourne, VIC, 3000, Australia
| | - Sara Alaei
- Peter MacCallum Cancer Centre, Melbourne, VIC, 3000, Australia
- Australian Regenerative Medicine Institute, Monash University, Clayton, VIC, 3168, Australia
| | - David D L Bowtell
- Peter MacCallum Cancer Centre, Melbourne, VIC, 3000, Australia
- Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, 3010, Australia
| | - Elizabeth L Christie
- Peter MacCallum Cancer Centre, Melbourne, VIC, 3000, Australia.
- Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, 3010, Australia.
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Clements RL, Kennedy EA, Song D, Campbell A, An HH, Amses KR, Miller-Ensminger T, Addison MM, Eisenlohr LC, Chou ST, Jurado KA. Human erythroid progenitors express antigen presentation machinery. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.06.27.601047. [PMID: 39005276 PMCID: PMC11244935 DOI: 10.1101/2024.06.27.601047] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/16/2024]
Abstract
Early-life immune exposures can profoundly impact lifelong health. However, functional mechanisms underlying fetal immune development remain incomplete. Erythrocytes are not typically considered active immune mediators, primarily because erythroid precursors discard their organelles as they mature, thus losing the ability to alter gene expression in response to stimuli. Erythroid progenitors and precursors circulate in human fetuses and neonates. Although there is limited evidence that erythroid precursors are immunomodulatory, our understanding of the underlying mechanisms remains inadequate. To define the immunobiological role of fetal and perinatal erythroid progenitors and precursors, we analyzed single cell RNA-sequencing data and found that transcriptomics support erythroid progenitors as putative immune mediators. Unexpectedly, we discovered that human erythroid progenitors constitutively express Major Histocompatibility Complex (MHC) class II antigen processing and presentation machinery, which are hallmarks of specialized antigen presenting immune cells. Furthermore, we demonstrate that erythroid progenitors internalize and cleave foreign proteins into peptide antigens. Unlike conventional antigen presenting cells, erythroid progenitors express atypical costimulatory molecules and immunoregulatory cytokines that direct the development of regulatory T cells, which are critical for establishing maternal-fetal tolerance. Expression of MHC II in definitive erythroid progenitors begins during the second trimester, coinciding with the appearance of mature T cells in the fetus, and is absent in primitive progenitors. Lastly, we demonstrate physical and molecular interaction potential of erythroid progenitors and T cells in the fetal liver. Our findings shed light on a unique orchestrator of fetal immunity and provide insight into the mechanisms by which erythroid cells contribute to host defense.
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Kust SA, Ustiuzhanina MO, Streltsova MA, Shelyakin PV, Kryukov MA, Lutsenko GV, Sudarikova AV, Merzlyak EM, Britanova OV, Sapozhnikov AM, Kovalenko EI. HLA-DR Expression in Natural Killer Cells Marks Distinct Functional States, Depending on Cell Differentiation Stage. Int J Mol Sci 2024; 25:4609. [PMID: 38731828 PMCID: PMC11083986 DOI: 10.3390/ijms25094609] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2024] [Revised: 04/17/2024] [Accepted: 04/19/2024] [Indexed: 05/13/2024] Open
Abstract
HLA-DR-positive NK cells, found in both healthy individuals and patients with different inflammatory diseases, are characterized as activated cells. However, data on their capacity for IFNγ production or cytotoxic response vary between studies. Thus, more precise investigation is needed of the mechanisms related to the induction of HLA-DR expression in NK cells, their associations with NK cell differentiation stage, and functional or metabolic state. In this work, HLA-DR-expressing NK cell subsets were investigated using transcriptomic analysis, metabolic activity assays, and analysis of intercellular signaling cascades. We demonstrated that HLA-DR+CD56bright NK cells were characterized by a proliferative phenotype, while HLA-DR+CD56dim NK cells exhibited features of adaptive cells and loss of inhibitory receptors with increased expression of MHC class II trans-activator CIITA. The activated state of HLA-DR-expressing NK cells was confirmed by higher levels of ATP and mitochondrial mass observed in this subset compared to HLA-DR- cells, both ex vivo and after stimulation in culture. We showed that HLA-DR expression in NK cells in vitro can be induced both through stimulation by exogenous IL-2 and IL-21, as well as through auto-stimulation by NK-cell-produced IFNγ. At the intracellular level, HLA-DR expression depended on the activation of STAT3- and ERK1/2-mediated pathways, with subsequent activation of isoform 3 of the transcription factor CIITA. The obtained results broaden the knowledge about HLA-DR-positive NK cell appearance, diversity, and functions, which might be useful in terms of understanding the role of this subset in innate immunity and assessing their possible implications in NK cell-based therapy.
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Affiliation(s)
- Sofya A. Kust
- Shemyakin & Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia; (S.A.K.); (M.O.U.); (M.A.S.); (M.A.K.); (G.V.L.); (E.M.M.); (O.V.B.); (A.M.S.)
| | - Maria O. Ustiuzhanina
- Shemyakin & Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia; (S.A.K.); (M.O.U.); (M.A.S.); (M.A.K.); (G.V.L.); (E.M.M.); (O.V.B.); (A.M.S.)
| | - Maria A. Streltsova
- Shemyakin & Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia; (S.A.K.); (M.O.U.); (M.A.S.); (M.A.K.); (G.V.L.); (E.M.M.); (O.V.B.); (A.M.S.)
| | | | - Maxim A. Kryukov
- Shemyakin & Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia; (S.A.K.); (M.O.U.); (M.A.S.); (M.A.K.); (G.V.L.); (E.M.M.); (O.V.B.); (A.M.S.)
- Federal State Autonomous Institution, N.N. Burdenko National Medical Research Center of Neurosurgery, the Ministry of Health of the Russian Federation, 125047 Moscow, Russia;
| | - Gennady V. Lutsenko
- Shemyakin & Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia; (S.A.K.); (M.O.U.); (M.A.S.); (M.A.K.); (G.V.L.); (E.M.M.); (O.V.B.); (A.M.S.)
| | - Anna V. Sudarikova
- Federal State Autonomous Institution, N.N. Burdenko National Medical Research Center of Neurosurgery, the Ministry of Health of the Russian Federation, 125047 Moscow, Russia;
| | - Ekaterina M. Merzlyak
- Shemyakin & Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia; (S.A.K.); (M.O.U.); (M.A.S.); (M.A.K.); (G.V.L.); (E.M.M.); (O.V.B.); (A.M.S.)
- Institute of Translational Medicine, Pirogov Russian National Research Medical University, 117997 Moscow, Russia
| | - Olga V. Britanova
- Shemyakin & Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia; (S.A.K.); (M.O.U.); (M.A.S.); (M.A.K.); (G.V.L.); (E.M.M.); (O.V.B.); (A.M.S.)
- Institute of Translational Medicine, Pirogov Russian National Research Medical University, 117997 Moscow, Russia
| | - Alexandr M. Sapozhnikov
- Shemyakin & Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia; (S.A.K.); (M.O.U.); (M.A.S.); (M.A.K.); (G.V.L.); (E.M.M.); (O.V.B.); (A.M.S.)
| | - Elena I. Kovalenko
- Shemyakin & Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia; (S.A.K.); (M.O.U.); (M.A.S.); (M.A.K.); (G.V.L.); (E.M.M.); (O.V.B.); (A.M.S.)
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9
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Sundaram B, Tweedell RE, Prasanth Kumar S, Kanneganti TD. The NLR family of innate immune and cell death sensors. Immunity 2024; 57:674-699. [PMID: 38599165 PMCID: PMC11112261 DOI: 10.1016/j.immuni.2024.03.012] [Citation(s) in RCA: 62] [Impact Index Per Article: 62.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2024] [Revised: 03/07/2024] [Accepted: 03/12/2024] [Indexed: 04/12/2024]
Abstract
Nucleotide-binding oligomerization domain (NOD)-like receptors, also known as nucleotide-binding leucine-rich repeat receptors (NLRs), are a family of cytosolic pattern recognition receptors that detect a wide variety of pathogenic and sterile triggers. Activation of specific NLRs initiates pro- or anti-inflammatory signaling cascades and the formation of inflammasomes-multi-protein complexes that induce caspase-1 activation to drive inflammatory cytokine maturation and lytic cell death, pyroptosis. Certain NLRs and inflammasomes act as integral components of larger cell death complexes-PANoptosomes-driving another form of lytic cell death, PANoptosis. Here, we review the current understanding of the evolution, structure, and function of NLRs in health and disease. We discuss the concept of NLR networks and their roles in driving cell death and immunity. An improved mechanistic understanding of NLRs may provide therapeutic strategies applicable across infectious and inflammatory diseases and in cancer.
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Affiliation(s)
- Balamurugan Sundaram
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Rebecca E Tweedell
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
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10
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Pitter MR, Kryczek I, Zhang H, Nagarsheth N, Xia H, Wu Z, Tian Y, Okla K, Liao P, Wang W, Zhou J, Li G, Lin H, Vatan L, Grove S, Wei S, Li Y, Zou W. PAD4 controls tumor immunity via restraining the MHC class II machinery in macrophages. Cell Rep 2024; 43:113942. [PMID: 38489266 PMCID: PMC11022165 DOI: 10.1016/j.celrep.2024.113942] [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: 09/08/2023] [Revised: 01/18/2024] [Accepted: 02/26/2024] [Indexed: 03/17/2024] Open
Abstract
Tumor-associated macrophages (TAMs) shape tumor immunity and therapeutic efficacy. However, it is poorly understood whether and how post-translational modifications (PTMs) intrinsically affect the phenotype and function of TAMs. Here, we reveal that peptidylarginine deiminase 4 (PAD4) exhibits the highest expression among common PTM enzymes in TAMs and negatively correlates with the clinical response to immune checkpoint blockade. Genetic and pharmacological inhibition of PAD4 in macrophages prevents tumor progression in tumor-bearing mouse models, accompanied by an increase in macrophage major histocompatibility complex (MHC) class II expression and T cell effector function. Mechanistically, PAD4 citrullinates STAT1 at arginine 121, thereby promoting the interaction between STAT1 and protein inhibitor of activated STAT1 (PIAS1), and the loss of PAD4 abolishes this interaction, ablating the inhibitory role of PIAS1 in the expression of MHC class II machinery in macrophages and enhancing T cell activation. Thus, the PAD4-STAT1-PIAS1 axis is an immune restriction mechanism in macrophages and may serve as a cancer immunotherapy target.
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Affiliation(s)
- Michael R Pitter
- Department of Surgery, University of Michigan Medical School, Ann Arbor, MI, USA; Center of Excellence for Cancer Immunology and Immunotherapy, Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA; Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA; Graduate Program in Molecular and Cellular Pathology, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Ilona Kryczek
- Department of Surgery, University of Michigan Medical School, Ann Arbor, MI, USA; Center of Excellence for Cancer Immunology and Immunotherapy, Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA
| | - Hongjuan Zhang
- Department of Surgery, University of Michigan Medical School, Ann Arbor, MI, USA; Center of Excellence for Cancer Immunology and Immunotherapy, Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA
| | - Nisha Nagarsheth
- Department of Surgery, University of Michigan Medical School, Ann Arbor, MI, USA; Center of Excellence for Cancer Immunology and Immunotherapy, Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA
| | - Houjun Xia
- Department of Surgery, University of Michigan Medical School, Ann Arbor, MI, USA; Center of Excellence for Cancer Immunology and Immunotherapy, Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA
| | - Zhenyu Wu
- Department of Surgery, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Yuzi Tian
- Department of Surgery, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Karolina Okla
- Department of Surgery, University of Michigan Medical School, Ann Arbor, MI, USA; Center of Excellence for Cancer Immunology and Immunotherapy, Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA
| | - Peng Liao
- Department of Surgery, University of Michigan Medical School, Ann Arbor, MI, USA; Center of Excellence for Cancer Immunology and Immunotherapy, Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA
| | - Weichao Wang
- Department of Surgery, University of Michigan Medical School, Ann Arbor, MI, USA; Center of Excellence for Cancer Immunology and Immunotherapy, Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA
| | - Jiajia Zhou
- Department of Surgery, University of Michigan Medical School, Ann Arbor, MI, USA; Center of Excellence for Cancer Immunology and Immunotherapy, Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA
| | - Gaopeng Li
- Department of Surgery, University of Michigan Medical School, Ann Arbor, MI, USA; Center of Excellence for Cancer Immunology and Immunotherapy, Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA
| | - Heng Lin
- Department of Surgery, University of Michigan Medical School, Ann Arbor, MI, USA; Center of Excellence for Cancer Immunology and Immunotherapy, Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA
| | - Linda Vatan
- Department of Surgery, University of Michigan Medical School, Ann Arbor, MI, USA; Center of Excellence for Cancer Immunology and Immunotherapy, Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA
| | - Sara Grove
- Department of Surgery, University of Michigan Medical School, Ann Arbor, MI, USA; Center of Excellence for Cancer Immunology and Immunotherapy, Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA
| | - Shuang Wei
- Department of Surgery, University of Michigan Medical School, Ann Arbor, MI, USA; Center of Excellence for Cancer Immunology and Immunotherapy, Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA
| | - Yongqing Li
- Department of Surgery, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Weiping Zou
- Department of Surgery, University of Michigan Medical School, Ann Arbor, MI, USA; Center of Excellence for Cancer Immunology and Immunotherapy, Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA; Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA; Graduate Programs in Immunology and Cancer Biology, University of Michigan Medical School, Ann Arbor, MI, USA.
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11
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Parsons BD, Medina-Luna D, Scur M, Pinelli M, Gamage GS, Chilvers RA, Hamon Y, Ahmed IHI, Savary S, Makrigiannis AP, Braverman NE, Rodriguez-Alcazar JF, Latz E, Karakach TK, Di Cara F. Peroxisome deficiency underlies failures in hepatic immune cell development and antigen presentation in a severe Zellweger disease model. Cell Rep 2024; 43:113744. [PMID: 38329874 DOI: 10.1016/j.celrep.2024.113744] [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: 11/10/2023] [Revised: 12/21/2023] [Accepted: 01/18/2024] [Indexed: 02/10/2024] Open
Abstract
Peroxisome biogenesis disorders (PBDs) represent a group of metabolic conditions that cause severe developmental defects. Peroxisomes are essential metabolic organelles, present in virtually every eukaryotic cell and mediating key processes in immunometabolism. To date, the full spectrum of PBDs remains to be identified, and the impact PBDs have on immune function is unexplored. This study presents a characterization of the hepatic immune compartment of a neonatal PBD mouse model at single-cell resolution to establish the importance and function of peroxisomes in developmental hematopoiesis. We report that hematopoietic defects are a feature in a severe PBD murine model. Finally, we identify a role for peroxisomes in the regulation of the major histocompatibility class II expression and antigen presentation to CD4+ T cells in dendritic cells. This study adds to our understanding of the mechanisms of PBDs and expands our knowledge of the role of peroxisomes in immunometabolism.
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Affiliation(s)
- Brendon D Parsons
- University of Alberta, Department of Laboratory Medicine and Pathology, Edmonton, AB T6G 1C9, Canada
| | - Daniel Medina-Luna
- Dalhousie University, Department of Microbiology and Immunology, Halifax, NS B3K 6R8, Canada
| | - Michal Scur
- Dalhousie University, Department of Microbiology and Immunology, Halifax, NS B3K 6R8, Canada
| | - Marinella Pinelli
- Dalhousie University, Department of Microbiology and Immunology, Halifax, NS B3K 6R8, Canada
| | - Gayani S Gamage
- Dalhousie University, Department of Microbiology and Immunology, Halifax, NS B3K 6R8, Canada
| | - Rebecca A Chilvers
- Dalhousie University, Department of Microbiology and Immunology, Halifax, NS B3K 6R8, Canada
| | - Yannick Hamon
- Aix Marseille University, CNRS, INSERM au Centre d'Immunologie de Marseille Luminy, 13288 Marseille, France
| | - Ibrahim H I Ahmed
- Dalhousie University, Department of Pharmacology, Halifax, NS B3H 4R2, Canada; Beatrice Hunter Cancer Research Institute, Halifax, NS, Canada
| | - Stéphane Savary
- University of Bourgogne, Laboratoire Bio-PeroxIL EA7270, Dijon, France
| | - Andrew P Makrigiannis
- Dalhousie University, Department of Microbiology and Immunology, Halifax, NS B3K 6R8, Canada; Beatrice Hunter Cancer Research Institute, Halifax, NS, Canada
| | - Nancy E Braverman
- Research Institute of the McGill University Children's Hospital, Montreal, QC H4A 3J1, Canada
| | | | - Eicke Latz
- University of Bonn, Institute of Innate Immunity, Medical Faculty, 53127 Bonn, Germany
| | - Tobias K Karakach
- Dalhousie University, Department of Pharmacology, Halifax, NS B3H 4R2, Canada; Beatrice Hunter Cancer Research Institute, Halifax, NS, Canada
| | - Francesca Di Cara
- University of Alberta, Department of Laboratory Medicine and Pathology, Edmonton, AB T6G 1C9, Canada; Beatrice Hunter Cancer Research Institute, Halifax, NS, Canada.
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12
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Tsankov BK, Luchak A, Carr C, Philpott DJ. The effects of NOD-like receptors on adaptive immune responses. Biomed J 2024; 47:100637. [PMID: 37541620 PMCID: PMC10796267 DOI: 10.1016/j.bj.2023.100637] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Revised: 07/19/2023] [Accepted: 07/20/2023] [Indexed: 08/06/2023] Open
Abstract
It has long been appreciated that cues from the innate immune system orchestrate downstream adaptive immune responses. Although previous work has focused on the roles of Toll-like receptors in this regard, relatively little is known about how Nod-like receptors instruct adaptive immunity. Here we review the functions of different members of the Nod-like receptor family in orchestrating effector and anamnestic adaptive immune responses. In particular, we address the ways in which inflammasome and non-inflammasome members of this family affect adaptive immunity under various infectious and environmental contexts. Furthermore, we identify several key mechanistic questions that studies in this field have left unaddressed. Our aim is to provide a framework through which immunologists in the adaptive immune field may view their questions through an innate-immune lens and vice-versa.
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Affiliation(s)
- Boyan K Tsankov
- Department of Immunology, University of Toronto, 1 King's College Circle, Toronto, Ontario, Canada
| | - Alexander Luchak
- Department of Immunology, University of Toronto, 1 King's College Circle, Toronto, Ontario, Canada
| | - Charles Carr
- Department of Immunology, University of Toronto, 1 King's College Circle, Toronto, Ontario, Canada
| | - Dana J Philpott
- Department of Immunology, University of Toronto, 1 King's College Circle, Toronto, Ontario, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, 1 King's College Circle, Toronto, Ontario, Canada.
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13
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Rodrigues WF, Miguel CB, de Abreu MCM, Neto JM, Oliveira CJF. Potential Associations between Vascular Biology and Hodgkin's Lymphoma: An Overview. Cancers (Basel) 2023; 15:5299. [PMID: 37958472 PMCID: PMC10649902 DOI: 10.3390/cancers15215299] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2023] [Revised: 10/24/2023] [Accepted: 11/03/2023] [Indexed: 11/15/2023] Open
Abstract
Hodgkin's lymphoma (HL) is a lymphatic neoplasm typically found in the cervical lymph nodes. The disease is multifactorial, and in recent years, the relationships between various vascular molecules have been explored in the field of vascular biology. The connection between vascular biology and HL is intricate and the roles of several pathways remain unclear. This review summarizes the cellular and molecular relationships between vascular biology and HL. Proteins associated with various functions in vascular biology, including cytokines (TNF-α, IL-1, IL-13, and IL-21), chemokines (CXCL10, CXCL12, and CCL21), adhesion molecules (ELAM-1/VCAM-1), and growth factors (BDNF/NT-3, platelet-derived growth factor receptor-α), have been linked to tumor activity. Notable tumor activities include the induction of paracrine activation of NF-kB-dependent pathways, upregulation of adhesion molecule regulation, genome amplification, and effective loss of antigen presentation mediated by MHC-II. Preclinical study models, primarily those using cell culture, have been optimized for HL. Animal models, particularly mice, are also used as alternatives to complex biological systems, with studies primarily focusing on the physiopathogenic evaluation of the disease. These biomolecules warrant further study because they may shed light on obscure pathways and serve as targets for prevention and/or treatment interventions.
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Affiliation(s)
- Wellington Francisco Rodrigues
- Postgraduate Course in Tropical Medicine and Infectious Diseases, Federal University of Triangulo Mineiro, UFTM, Uberaba 38025-440, MG, Brazil; (C.B.M.); (C.J.F.O.)
- University Center of Mineiros, Unifimes, Mineiros 75833-130, GO, Brazil; (M.C.M.d.A.); (J.M.N.)
| | - Camila Botelho Miguel
- Postgraduate Course in Tropical Medicine and Infectious Diseases, Federal University of Triangulo Mineiro, UFTM, Uberaba 38025-440, MG, Brazil; (C.B.M.); (C.J.F.O.)
- University Center of Mineiros, Unifimes, Mineiros 75833-130, GO, Brazil; (M.C.M.d.A.); (J.M.N.)
| | | | - Jamil Miguel Neto
- University Center of Mineiros, Unifimes, Mineiros 75833-130, GO, Brazil; (M.C.M.d.A.); (J.M.N.)
| | - Carlo José Freire Oliveira
- Postgraduate Course in Tropical Medicine and Infectious Diseases, Federal University of Triangulo Mineiro, UFTM, Uberaba 38025-440, MG, Brazil; (C.B.M.); (C.J.F.O.)
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14
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Forlani G, Shallak M, Gatta A, Shaik AKB, Accolla RS. The NLR member CIITA: Master controller of adaptive and intrinsic immunity and unexpected tool in cancer immunotherapy. Biomed J 2023; 46:100631. [PMID: 37467968 PMCID: PMC10505679 DOI: 10.1016/j.bj.2023.100631] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Revised: 07/11/2023] [Accepted: 07/12/2023] [Indexed: 07/21/2023] Open
Abstract
Human nucleotide-binding oligomerization domain (NOD)-like receptors (NLR) include a large family of proteins that have important functions in basic physio-pathological processes like inflammation, cell death and regulation of transcription of key molecules for the homeostasis of the immune system. They are all characterized by a common backbone structure (the STAND ATPase module consisting in a nucleotide-binding domain (NBD), an helical domain 1 (HD1) and a winged helix domain (WHD), used by both prokaryotes and eukaryotes as defense mechanism. In this review, we will focus on the MHC class II transactivator (CIITA), the master regulator of MHC class II (MHC-II) gene expression and the founding member of NLR. Although a consistent part of the described NLR family components is often recalled as innate or intrinsic immune sensors, CIITA in fact occupies a special place as a unique example of regulator of both intrinsic and adaptive immunity. The description of the discovery of CIITA and the genetic and molecular characterization of its expression will be followed by the most recent studies that have unveiled this dual role of CIITA, key molecule in intrinsic immunity as restriction factor for human retroviruses and precious tool to induce the expression of MHC-II molecules in cancer cells, rendering them potent surrogate antigen presenting cells (APC) for their own tumor antigens.
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Affiliation(s)
- Greta Forlani
- Laboratories of General Pathology and Immunology "Giovanna Tosi", Department of Medicine and Technological Innovation, School of Medicine, University of Insubria, 21100 Varese, Italy.
| | - Mariam Shallak
- Laboratories of General Pathology and Immunology "Giovanna Tosi", Department of Medicine and Technological Innovation, School of Medicine, University of Insubria, 21100 Varese, Italy
| | - Andrea Gatta
- Laboratories of General Pathology and Immunology "Giovanna Tosi", Department of Medicine and Technological Innovation, School of Medicine, University of Insubria, 21100 Varese, Italy
| | - Amruth K B Shaik
- Laboratories of General Pathology and Immunology "Giovanna Tosi", Department of Medicine and Technological Innovation, School of Medicine, University of Insubria, 21100 Varese, Italy
| | - Roberto S Accolla
- Laboratories of General Pathology and Immunology "Giovanna Tosi", Department of Medicine and Technological Innovation, School of Medicine, University of Insubria, 21100 Varese, Italy.
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15
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Nagasubramanian K, Jha S, Rathore AS, Gupta K. Identification of small molecule modulators of class II transactivator-I using computational approaches. J Biomol Struct Dyn 2023; 41:8349-8361. [PMID: 36224172 DOI: 10.1080/07391102.2022.2133011] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Accepted: 09/30/2022] [Indexed: 10/17/2022]
Abstract
Major histocompatibility complex II (MHCII), a mediator of the innate and adaptive immune system, plays a central role in regulating inflammation and its progression. Class II transactivator (CIITA) is a master regulator of MHCII expression and controls antigen presentation followed by T-cell activation. Regulation of inflammation by modulation of CIITA has been suggested as a promising intervention for several disorders, including neuroinflammation, rheumatoid arthritis and other autoimmune diseases. This study aimed to (i) identify possible pharmacological agents which could bind to and inhibit isoform I of CIITA (CIITA-I) and (ii) determine their strength of interactions. The structure of CIITA-I isoform was predicted using phyre2 and refined via 3D refine. Loops were refined using ModBase, followed by quality assessment based on ERRAT value. The refined 3D structure was subjected to docking via Maestro (from Schrodinger) using glide module against small molecule databases. Molecules having the least glide score and favorable ADME properties were subjected to molecular simulation by GROMACS. We used the 3D refined structure of CIITA-I, with a score of 83.4% in ERRAT for docking studies. The ligand 4-(2-((6-oxo-4-phenyl-1,6-dihydropyrimidin-2-yl) thio) acetamido) benzamide (ZINC5154833), showed maximum glide score (-6.591) followed by N-[4-(3-oxo-3-{4-[3-(trifluoromethyl) phenyl] piperazin-1-yl} propyl)-1,3-thiazol-2-yl] benzamide (F5254-0161, glide score -6.41). Simulation studies using GROMACS showed F5254-0161 to have a more stable interaction with CIITA-I. Based on our analysis, we propose ZINC5154833 and F5254-0161 as potential modulators for CIITA-I.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Kishore Nagasubramanian
- School of Chemical and Biotechnology, SASTRA Deemed to be University, Thanjavur, Tamil Nadu, India
| | - Shanker Jha
- School of Chemical and Biotechnology, SASTRA Deemed to be University, Thanjavur, Tamil Nadu, India
| | - Anuranjan Singh Rathore
- School of Chemical and Biotechnology, SASTRA Deemed to be University, Thanjavur, Tamil Nadu, India
| | - Krishnakant Gupta
- School of Chemical and Biotechnology, SASTRA Deemed to be University, Thanjavur, Tamil Nadu, India
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16
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Ner-Gaon H, Peleg R, Gazit R, Reiner-Benaim A, Shay T. Mapping the splicing landscape of the human immune system. Front Immunol 2023; 14:1116392. [PMID: 37711610 PMCID: PMC10499523 DOI: 10.3389/fimmu.2023.1116392] [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: 12/05/2022] [Accepted: 08/14/2023] [Indexed: 09/16/2023] Open
Abstract
Most human genes code for more than one transcript. Different ratios of transcripts of the same gene can be found in different cell types or states, indicating differential use of transcription start sites or differential splicing. Such differential transcript use (DTUs) events provide an additional layer of regulation and protein diversity. With the exceptions of PTPRC and CIITA, there are very few reported cases of DTU events in the immune system. To rigorously map DTUs between different human immune cell types, we leveraged four publicly available RNA sequencing datasets. We identified 282 DTU events between five human healthy immune cell types that appear in at least two datasets. The patterns of the DTU events were mostly cell-type-specific or lineage-specific, in the context of the five cell types tested. DTUs correlated with the expression pattern of potential regulators, namely, splicing factors and transcription factors. Of the several immune related conditions studied, only sepsis affected the splicing of more than a few genes and only in innate immune cells. Taken together, we map the DTUs landscape in human peripheral blood immune cell types, and present hundreds of genes whose transcript use changes between cell types or upon activation.
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Affiliation(s)
- Hadas Ner-Gaon
- Department of Life Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Ronnie Peleg
- The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Roi Gazit
- The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Anat Reiner-Benaim
- Department of Epidemiology, Biostatistics and Community Health Sciences, School of Public Health, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Tal Shay
- Department of Life Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
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17
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Macy AM, Herrmann LM, Adams AC, Hastings KT. Major histocompatibility complex class II in the tumor microenvironment: functions of nonprofessional antigen-presenting cells. Curr Opin Immunol 2023; 83:102330. [PMID: 37130456 PMCID: PMC10524529 DOI: 10.1016/j.coi.2023.102330] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Revised: 03/30/2023] [Accepted: 04/02/2023] [Indexed: 05/04/2023]
Abstract
Major histocompatibility complex class-II-restricted presentation by nonprofessional antigen-presenting cells in the tumor microenvironment can regulate antitumor T-cell responses. In murine models, tumor cell-specific MHC class II expression decreases in vivo tumor growth, dependent on T cells. Tumor cell-specific MHC class II expression is associated with improved survival and response to immune checkpoint inhibitors in human cancers. Antigen-presenting cancer-associated fibroblasts (apCAF) present MHC class-II-restricted antigens and activate CD4 T cells. The role of MHC class II on apCAFs depends on the cell of origin. MHC class II on tumoral lymphatic endothelial cells leads to expansion of regulatory T cells and increased in vivo tumor growth.
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Affiliation(s)
- Anne M Macy
- University of Arizona College of Medicine Phoenix, 425 N. 5th St., Phoenix, AZ 85004, USA; Phoenix Veterans Affairs Health Care System, 650 E. Indian School Rd., Phoenix, AZ 85023, USA
| | - Lauren M Herrmann
- University of Arizona College of Medicine Phoenix, 425 N. 5th St., Phoenix, AZ 85004, USA; Phoenix Veterans Affairs Health Care System, 650 E. Indian School Rd., Phoenix, AZ 85023, USA
| | - Anngela C Adams
- University of Arizona College of Medicine Phoenix, 425 N. 5th St., Phoenix, AZ 85004, USA; Phoenix Veterans Affairs Health Care System, 650 E. Indian School Rd., Phoenix, AZ 85023, USA
| | - K Taraszka Hastings
- University of Arizona College of Medicine Phoenix, 425 N. 5th St., Phoenix, AZ 85004, USA; Phoenix Veterans Affairs Health Care System, 650 E. Indian School Rd., Phoenix, AZ 85023, USA; University of Arizona Cancer Center, University of Arizona, 1515 N. Campbell Ave., Tucson, AZ 85724, USA.
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18
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Yang Y, Li G, Zhong Y, Xu Q, Chen BJ, Lin YT, Chapkin R, Cai JJ. Gene knockout inference with variational graph autoencoder learning single-cell gene regulatory networks. Nucleic Acids Res 2023; 51:6578-6592. [PMID: 37246643 PMCID: PMC10359630 DOI: 10.1093/nar/gkad450] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Revised: 05/02/2023] [Accepted: 05/11/2023] [Indexed: 05/30/2023] Open
Abstract
In this paper, we introduce Gene Knockout Inference (GenKI), a virtual knockout (KO) tool for gene function prediction using single-cell RNA sequencing (scRNA-seq) data in the absence of KO samples when only wild-type (WT) samples are available. Without using any information from real KO samples, GenKI is designed to capture shifting patterns in gene regulation caused by the KO perturbation in an unsupervised manner and provide a robust and scalable framework for gene function studies. To achieve this goal, GenKI adapts a variational graph autoencoder (VGAE) model to learn latent representations of genes and interactions between genes from the input WT scRNA-seq data and a derived single-cell gene regulatory network (scGRN). The virtual KO data is then generated by computationally removing all edges of the KO gene-the gene to be knocked out for functional study-from the scGRN. The differences between WT and virtual KO data are discerned by using their corresponding latent parameters derived from the trained VGAE model. Our simulations show that GenKI accurately approximates the perturbation profiles upon gene KO and outperforms the state-of-the-art under a series of evaluation conditions. Using publicly available scRNA-seq data sets, we demonstrate that GenKI recapitulates discoveries of real-animal KO experiments and accurately predicts cell type-specific functions of KO genes. Thus, GenKI provides an in-silico alternative to KO experiments that may partially replace the need for genetically modified animals or other genetically perturbed systems.
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Affiliation(s)
- Yongjian Yang
- Department of Electrical and Computer Engineering, Texas A&M University, College Station, TX 77843, USA
| | - Guanxun Li
- Department of Statistics, Texas A&M University, College Station, TX 77843, USA
| | - Yan Zhong
- Key Laboratory of Advanced Theory and Application in Statistics and Data Science-MOE, School of Statistics, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, China
| | - Qian Xu
- Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, TX 77843, USA
| | - Bo-Jia Chen
- Graduate Institute of Microbiology and Public Health, College of Veterinary Medicine, National Chung Hsing University, Taichung 402, Taiwan
| | - Yu-Te Lin
- Graduate Institute of Biomedical Electronics and Bioinformatics, National Taiwan University, Taipei, Taiwan
| | - Robert S Chapkin
- Program in Integrative & Complex Diseases, Department of Nutrition, Texas A&M University, College Station, TX 77843, USA
| | - James J Cai
- Department of Electrical and Computer Engineering, Texas A&M University, College Station, TX 77843, USA
- Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, TX 77843, USA
- Interdisciplinary Program of Genetics, Texas A&M University, College Station, TX 77843, USA
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19
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Arroyo Hornero R, Idoyaga J. Plasmacytoid dendritic cells: A dendritic cell in disguise. Mol Immunol 2023; 159:38-45. [PMID: 37269733 PMCID: PMC10625168 DOI: 10.1016/j.molimm.2023.05.007] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Accepted: 05/20/2023] [Indexed: 06/05/2023]
Abstract
Since their discovery, the identity of plasmacytoid dendritic cells (pDCs) has been at the center of a continuous dispute in the field, and their classification as dendritic cells (DCs) has been recently re-challenged. pDCs are different enough from the rest of the DC family members to be considered a lineage of cells on their own. Unlike the exclusive myeloid ontogeny of cDCs, pDCs may have dual origin developing from myeloid and lymphoid progenitors. Moreover, pDCs have the unique ability to quickly secrete abundant levels of type I interferon (IFN-I) in response to viral infections. In addition, pDCs undergo a differentiation process after pathogen recognition that allows them to activate T cells, a feature that has been shown to be independent of presumed contaminating cells. Here, we aim to provide an overview of the historic and current understanding of pDCs and argue that their classification as either lymphoid or myeloid may be an oversimplification. Instead, we propose that the capacity of pDCs to link the innate and adaptive immune response by directly sensing pathogens and activating adaptive immune responses justify their inclusion within the DC network.
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Affiliation(s)
- Rebeca Arroyo Hornero
- Microbiology & Immunology Department, and Immunology Program, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Juliana Idoyaga
- Microbiology & Immunology Department, and Immunology Program, Stanford University School of Medicine, Stanford, CA 94305, USA.
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20
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Czaja AJ. Incorporating the Molecular Mimicry of Environmental Antigens into the Causality of Autoimmune Hepatitis. Dig Dis Sci 2023:10.1007/s10620-023-07967-5. [PMID: 37160542 PMCID: PMC10169207 DOI: 10.1007/s10620-023-07967-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2023] [Accepted: 05/01/2023] [Indexed: 05/11/2023]
Abstract
Molecular mimicry between foreign and self-antigens has been implicated as a cause of autoimmune hepatitis in experimental models and cross-reacting antibodies in patients. This review describes the experimental and clinical evidence for molecular mimicry as a cause of autoimmune hepatitis, indicates the limitations and uncertainties of this premise, and encourages investigations that assess diverse environmental antigens as sources of disease-relevant molecular mimics. Pertinent articles were identified in PubMed using multiple search phrases. Several pathogens have linear or conformational epitopes that mimic the self-antigens of autoimmune hepatitis. The occurrence of an acute immune-mediated hepatitis after vaccination for severe acute respiratory syndrome (SARS)-associated coronavirus 2 (SARS-CoV-2) has suggested that vaccine-induced peptides may mimic disease-relevant tissue antigens. The intestinal microbiome is an under-evaluated source of gut-derived antigens that could also engage in molecular mimicry. Chaperone molecules may enhance the pathogenicity of molecular mimics, and they warrant investigation. Molecular mimics of immune dominant epitopes within cytochrome P450 IID6, the autoantigen most closely associated with autoimmune hepatitis, should be sought in diverse environmental antigens and assessed for pathogenicity. Avoidance strategies, dietary adjustments, vaccine improvement, and targeted manipulation of the intestinal microbiota may emerge as therapeutic possibilities. In conclusion, molecular mimicry may be a missing causality of autoimmune hepatitis. Molecular mimics of key immune dominant epitopes of disease-specific antigens must be sought in diverse environmental antigens. The ubiquity of molecular mimicry compels rigorous assessments of peptide mimics for immunogenicity and pathogenicity in experimental models. Molecular mimicry may complement epigenetic modifications as causative mechanisms of autoimmune hepatitis.
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Affiliation(s)
- Albert J Czaja
- Professor Emeritus of Medicine, Mayo Clinic College of Medicine and Science, 200 First Street SW, Rochester, MN, 55905, USA.
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21
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Massa C, Wang Y, Marr N, Seliger B. Interferons and Resistance Mechanisms in Tumors and Pathogen-Driven Diseases—Focus on the Major Histocompatibility Complex (MHC) Antigen Processing Pathway. Int J Mol Sci 2023; 24:ijms24076736. [PMID: 37047709 PMCID: PMC10095295 DOI: 10.3390/ijms24076736] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Revised: 02/22/2023] [Accepted: 02/25/2023] [Indexed: 04/08/2023] Open
Abstract
Interferons (IFNs), divided into type I, type II, and type III IFNs represent proteins that are secreted from cells in response to various stimuli and provide important information for understanding the evolution, structure, and function of the immune system, as well as the signaling pathways of other cytokines and their receptors. They exert comparable, but also distinct physiologic and pathophysiologic activities accompanied by pleiotropic effects, such as the modulation of host responses against bacterial and viral infections, tumor surveillance, innate and adaptive immune responses. IFNs were the first cytokines used for the treatment of tumor patients including hairy leukemia, renal cell carcinoma, and melanoma. However, tumor cells often develop a transient or permanent resistance to IFNs, which has been linked to the escape of tumor cells and unresponsiveness to immunotherapies. In addition, loss-of-function mutations in IFN signaling components have been associated with susceptibility to infectious diseases, such as COVID-19 and mycobacterial infections. In this review, we summarize general features of the three IFN families and their function, the expression and activity of the different IFN signal transduction pathways, and their role in tumor immune evasion and pathogen clearance, with links to alterations in the major histocompatibility complex (MHC) class I and II antigen processing machinery (APM). In addition, we discuss insights regarding the clinical applications of IFNs alone or in combination with other therapeutic options including immunotherapies as well as strategies reversing the deficient IFN signaling. Therefore, this review provides an overview on the function and clinical relevance of the different IFN family members, with a specific focus on the MHC pathways in cancers and infections and their contribution to immune escape of tumors.
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Affiliation(s)
- Chiara Massa
- Medical Faculty, Martin Luther University Halle-Wittenberg, Magdeburger Str. 2, 06112 Halle, Germany
- Institute for Translational Immunology, Brandenburg Medical School Theodor Fontane, Hochstr. 29, 14770 Brandenburg an der Havel, Germany
| | - Yuan Wang
- Medical Faculty, Martin Luther University Halle-Wittenberg, Magdeburger Str. 2, 06112 Halle, Germany
| | - Nico Marr
- Institute for Translational Immunology, Brandenburg Medical School Theodor Fontane, Hochstr. 29, 14770 Brandenburg an der Havel, Germany
- College of Health and Life Sciences, Hamad Bin Khalifa University, Doha P.O. Box 34110, Qatar
| | - Barbara Seliger
- Medical Faculty, Martin Luther University Halle-Wittenberg, Magdeburger Str. 2, 06112 Halle, Germany
- Institute for Translational Immunology, Brandenburg Medical School Theodor Fontane, Hochstr. 29, 14770 Brandenburg an der Havel, Germany
- Fraunhofer Institute for Cell Therapy and Immunology, Perlickstr. 1, 04103 Leipzig, Germany
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22
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Scholand KK, Mack AF, Guzman GU, Maniskas ME, Sampige R, Govindarajan G, McCullough LD, de Paiva CS. Heterochronic Parabiosis Causes Dacryoadenitis in Young Lacrimal Glands. Int J Mol Sci 2023; 24:4897. [PMID: 36902330 PMCID: PMC10003158 DOI: 10.3390/ijms24054897] [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: 01/29/2023] [Revised: 02/25/2023] [Accepted: 02/28/2023] [Indexed: 03/06/2023] Open
Abstract
Aging is associated with inflammation and oxidative stress in the lacrimal gland (LG). We investigated if heterochronic parabiosis of mice could modulate age-related LG alterations. In both males and females, there were significant increases in total immune infiltration in isochronic aged LGs compared to that in isochronic young LGs. Male heterochronic young LGs were significantly more infiltrated compared to male isochronic young LGs. While both females and males had significant increases in inflammatory and B-cell-related transcripts in isochronic and heterochronic aged LGs compared to levels isochronic and heterochronic young LGs, females had a greater fold expression of some of these transcripts than males. Through flow cytometry, specific subsets of B cells were increased in the male heterochronic aged LGs compared to those in male isochronic aged LGs. Our results indicate that serum soluble factors from young mice were not enough to reverse inflammation and infiltrating immune cells in aged tissues and that there were specific sex-related differences in parabiosis treatment. This suggests that age-related changes in the LG microenvironment/architecture participate in perpetuating inflammation, which is not reversible by exposure to youthful systemic factors. In contrast, male young heterochronic LGs were significantly worse than their isochronic counterparts, suggesting that aged soluble factors can enhance inflammation in the young host. Therapies that aim at improving cellular health may have a stronger impact on improving inflammation and cellular inflammation in LGs than parabiosis.
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Affiliation(s)
- Kaitlin K. Scholand
- Ocular Surface Center, Cullen Eye Institute, Department of Ophthalmology, Baylor College of Medicine, Houston, TX 77030, USA
- Biochemistry and Cell Biology Graduate Program, Department of BioSciences, Rice University, Houston, TX 77005, USA
| | - Alexis F. Mack
- BRAINS Research Laboratory, Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - Gary U. Guzman
- BRAINS Research Laboratory, Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - Michael E. Maniskas
- BRAINS Research Laboratory, Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - Ritu Sampige
- Ocular Surface Center, Cullen Eye Institute, Department of Ophthalmology, Baylor College of Medicine, Houston, TX 77030, USA
| | - Gowthaman Govindarajan
- Ocular Surface Center, Cullen Eye Institute, Department of Ophthalmology, Baylor College of Medicine, Houston, TX 77030, USA
| | - Louise D. McCullough
- BRAINS Research Laboratory, Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - Cintia S. de Paiva
- Ocular Surface Center, Cullen Eye Institute, Department of Ophthalmology, Baylor College of Medicine, Houston, TX 77030, USA
- Biochemistry and Cell Biology Graduate Program, Department of BioSciences, Rice University, Houston, TX 77005, USA
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23
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The relevance of HLA class II genes in JAK2 V617F-positive myeloproliferative neoplasms. Hum Immunol 2023; 84:199-207. [PMID: 36707384 DOI: 10.1016/j.humimm.2023.01.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Revised: 12/29/2022] [Accepted: 01/17/2023] [Indexed: 01/27/2023]
Abstract
In the present study we analyzed the relevance of HLA class II in JAK2 V617F-positive (JAK2 V617F+) myeloproliferative neoplasms (MPNs) focusing on genotype diversity, associations with specific alleles and haplotypes and the level of gene expression. One hundred and thirty-nine JAK2 V617F+ MPN patients and 1083 healthy controls, typed by Next generation sequencing (NGS) were included in the study. Multivariate generalized linear models with age as a covariate were applied for analysis of HLA-II allele and haplotype associations. Publicly available gene expression datasets were used to analyze HLA-II pathway genes expression in CD34+ stem cells (SCs) from MPN patients and healthy controls. We did not observe differences in HLA evolutionary divergence (HED) between JAK2 V617F+ MPNs and healthy controls. Two alleles: HLA-DPB1*03:01, DQB1*04:02 and 4 haplotypes: DPB1*02:01-DQA1*05:05-DQB1*03:01-DRB1*11:01, DPB1*04:02-DQA1*05:05-DQB1*03:01-DRB1*11:03, DPB1*02:01-DQA1*01:04-DQB1*05:03-DRB1*14:04, and DPB1*04:01-DQA1*03:01-DQB1*03:02-DRB1*04:01 had significantly lower frequency in MPN patients compared to controls. Additionally, we observed HLA-II alleles and haplotypes with statistically higher frequencies in JAK2 V617F+ patients. Differential gene expression analysis showed down-regulation of HLA-DRB1, -DRA, -DMA, -DMB, -DOA,-DRB4, CIITA, and CD74 genes in JAK2 V617F+ MPN CD34+ SCs as compared to normal CD34 + SCs. In conclusion, this study provides evidence for the pleiotropic effects of HLA-II genes in JAK2 V617F-driven MPNs.
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24
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Zeng Z, Gu SS, Ouardaoui N, Tymm C, Yang L, Wong CJ, Li D, Zhang W, Wang X, Weirather JL, Rodig SJ, Hodi FS, Brown M, Liu XS. Hippo Signaling Pathway Regulates Cancer Cell-Intrinsic MHC-II Expression. Cancer Immunol Res 2022; 10:1559-1569. [PMID: 36219700 DOI: 10.1158/2326-6066.cir-22-0227] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2022] [Revised: 07/02/2022] [Accepted: 10/06/2022] [Indexed: 01/10/2023]
Abstract
MHC-II is known to be mainly expressed on the surface of antigen-presenting cells. Evidence suggests MHC-II is also expressed by cancer cells and may be associated with better immunotherapy responses. However, the role and regulation of MHC-II in cancer cells remain unclear. In this study, we leveraged data mining and experimental validation to elucidate the regulation of MHC-II in cancer cells and its role in modulating the response to immunotherapy. We collated an extensive collection of omics data to examine cancer cell-intrinsic MHC-II expression and its association with immunotherapy outcomes. We then tested the functional relevance of cancer cell-intrinsic MHC-II expression using a syngeneic transplantation model. Finally, we performed data mining to identify pathways potentially involved in the regulation of MHC-II expression, and experimentally validated candidate regulators. Analyses of preimmunotherapy clinical samples in the CheckMate 064 trial revealed that cancer cell-intrinsic MHC-II protein was positively correlated with more favorable immunotherapy outcomes. Comprehensive meta-analyses of multiomics data from an exhaustive collection of data revealed that MHC-II is heterogeneously expressed in various solid tumors, and its expression is particularly high in melanoma. Using a syngeneic transplantation model, we further established that melanoma cells with high MHC-II responded better to anti-PD-1 treatment. Data mining followed by experimental validation revealed the Hippo signaling pathway as a potential regulator of melanoma MHC-II expression. In summary, we identified the Hippo signaling pathway as a novel regulator of cancer cell-intrinsic MHC-II expression. These findings suggest modulation of MHC-II in melanoma could potentially improve immunotherapy response.
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Affiliation(s)
- Zexian Zeng
- Department of Data Science, Dana Farber Cancer Institute, Boston, Massachusetts
- Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
| | - Shengqing Stan Gu
- Department of Data Science, Dana Farber Cancer Institute, Boston, Massachusetts
- Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
- Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Nofal Ouardaoui
- Department of Data Science, Dana Farber Cancer Institute, Boston, Massachusetts
| | - Carly Tymm
- Department of Data Science, Dana Farber Cancer Institute, Boston, Massachusetts
| | - Lin Yang
- Department of Data Science, Dana Farber Cancer Institute, Boston, Massachusetts
| | - Cheryl J Wong
- Department of Data Science, Dana Farber Cancer Institute, Boston, Massachusetts
- Department of Biomedical Informatics, Harvard Medical School, Boston, Massachusetts
| | - Dian Li
- Department of Data Science, Dana Farber Cancer Institute, Boston, Massachusetts
| | - Wubing Zhang
- Department of Data Science, Dana Farber Cancer Institute, Boston, Massachusetts
- School of Life Science and Technology, Tongji University, Shanghai, China
| | - Xiaoqing Wang
- Department of Data Science, Dana Farber Cancer Institute, Boston, Massachusetts
- Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
- Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Jason L Weirather
- Department of Data Science, Dana Farber Cancer Institute, Boston, Massachusetts
- Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Scott J Rodig
- Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
- Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts
| | - F Stephen Hodi
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
- Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Myles Brown
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
- Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - X Shirley Liu
- Department of Data Science, Dana Farber Cancer Institute, Boston, Massachusetts
- Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
- Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts
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25
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Inoue A, Watanabe M, Kondo T, Hirano S, Hatakeyama S. TRIM22 negatively regulates MHC-II expression. BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR CELL RESEARCH 2022; 1869:119318. [PMID: 35777501 DOI: 10.1016/j.bbamcr.2022.119318] [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: 02/18/2022] [Revised: 06/01/2022] [Accepted: 06/16/2022] [Indexed: 06/15/2023]
Abstract
The development of cancer treatment has recently achieved a remarkable breakthrough, and checkpoint blockade immunotherapy has received much attention. To enhance the therapeutic efficacy of checkpoint blockade immunotherapy, recent studies have revealed the importance of activation of CD4+ T cells via an increase in major histocompatibility complex (MHC) class II molecules in cancer cells. Here, we demonstrate that tripartite motif-containing (TRIM) 22, negatively regulates MHC-II expression. Gene knockout of TRIM22 using Cas9-sgRNAs led to an increase of MHC-II proteins, while TRIM22 overexpression remarkably decreased MHC-II proteins. mRNA levels of MHC-II and class II transactivator (CIITA), which plays an essential role in the regulation of MHC-II transcription, were not affected by TRIM22. Furthermore, TRIM22 knockout did not suppress the degradation of MHC-II protein but rather promoted it. These results suggest that TRIM22 decreases MHC-II protein levels through a combination of multiple mechanisms other than transcription or degradation. We showed that inhibition of TRIM22 can increase the amount of MHC-II expression in cancer cells, suggesting a possibility of providing the biological basis for a possible therapeutic target to potentiate checkpoint blockade immunotherapy.
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Affiliation(s)
- Ayano Inoue
- Department of Biochemistry, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Kita 15, Nishi 7, Kita-ku, Sapporo, Hokkaido 060-8638, Japan; Department of Gastroenterological Surgery II, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Kita 15, Nishi 7, Kita-ku, Sapporo, Hokkaido 060-8638, Japan
| | - Masashi Watanabe
- Department of Biochemistry, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Kita 15, Nishi 7, Kita-ku, Sapporo, Hokkaido 060-8638, Japan
| | - Takeshi Kondo
- Department of Biochemistry, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Kita 15, Nishi 7, Kita-ku, Sapporo, Hokkaido 060-8638, Japan
| | - Satoshi Hirano
- Department of Gastroenterological Surgery II, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Kita 15, Nishi 7, Kita-ku, Sapporo, Hokkaido 060-8638, Japan
| | - Shigetsugu Hatakeyama
- Department of Biochemistry, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Kita 15, Nishi 7, Kita-ku, Sapporo, Hokkaido 060-8638, Japan.
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26
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Alvarez-Simon D, Ait Yahia S, de Nadai P, Audousset C, Chamaillard M, Boneca IG, Tsicopoulos A. NOD-like receptors in asthma. Front Immunol 2022; 13:928886. [PMID: 36189256 PMCID: PMC9515552 DOI: 10.3389/fimmu.2022.928886] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Accepted: 08/23/2022] [Indexed: 12/28/2022] Open
Abstract
Asthma is an extremely prevalent chronic inflammatory disease of the airway where innate and adaptive immune systems participate collectively with epithelial and other structural cells to cause airway hyperresponsiveness, mucus overproduction, airway narrowing, and remodeling. The nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) are a family of intracellular innate immune sensors that detect microbe-associated molecular patterns and damage-associated molecular patterns, well-recognized for their central roles in the maintenance of tissue homeostasis and host defense against bacteria, viruses and fungi. In recent times, NLRs have been increasingly acknowledged as much more than innate sensors and have emerged also as relevant players in diseases classically defined by their adaptive immune responses such as asthma. In this review article, we discuss the current knowledge and recent developments about NLR expression, activation and function in relation to asthma and examine the potential interventions in NLR signaling as asthma immunomodulatory therapies.
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Affiliation(s)
- Daniel Alvarez-Simon
- Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019-UMR9017-CIIL-Centre d’Infection et d’Immunité de Lille, Lille, France
| | - Saliha Ait Yahia
- Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019-UMR9017-CIIL-Centre d’Infection et d’Immunité de Lille, Lille, France
| | - Patricia de Nadai
- Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019-UMR9017-CIIL-Centre d’Infection et d’Immunité de Lille, Lille, France
| | - Camille Audousset
- Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019-UMR9017-CIIL-Centre d’Infection et d’Immunité de Lille, Lille, France
| | - Mathias Chamaillard
- Laboratory of Cell Physiology, INSERM U1003, University of Lille, Lille, France
| | - Ivo Gomperts Boneca
- Institut Pasteur, Université Paris Cité, CNRS UMR 6047, INSERM U1306, Unité Biologie et génétique de la paroi bactérienne, Paris, France
| | - Anne Tsicopoulos
- Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019-UMR9017-CIIL-Centre d’Infection et d’Immunité de Lille, Lille, France
- *Correspondence: Anne Tsicopoulos,
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27
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Meijer M, Agirre E, Kabbe M, van Tuijn CA, Heskol A, Zheng C, Mendanha Falcão A, Bartosovic M, Kirby L, Calini D, Johnson MR, Corces MR, Montine TJ, Chen X, Chang HY, Malhotra D, Castelo-Branco G. Epigenomic priming of immune genes implicates oligodendroglia in multiple sclerosis susceptibility. Neuron 2022; 110:1193-1210.e13. [PMID: 35093191 PMCID: PMC9810341 DOI: 10.1016/j.neuron.2021.12.034] [Citation(s) in RCA: 48] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Revised: 11/05/2021] [Accepted: 12/27/2021] [Indexed: 01/05/2023]
Abstract
Multiple sclerosis (MS) is characterized by a targeted attack on oligodendroglia (OLG) and myelin by immune cells, which are thought to be the main drivers of MS susceptibility. We found that immune genes exhibit a primed chromatin state in single mouse and human OLG in a non-disease context, compatible with transitions to immune-competent states in MS. We identified BACH1 and STAT1 as transcription factors involved in immune gene regulation in oligodendrocyte precursor cells (OPCs). A subset of immune genes presents bivalency of H3K4me3/H3K27me3 in OPCs, with Polycomb inhibition leading to their increased activation upon interferon gamma (IFN-γ) treatment. Some MS susceptibility single-nucleotide polymorphisms (SNPs) overlap with these regulatory regions in mouse and human OLG. Treatment of mouse OPCs with IFN-γ leads to chromatin architecture remodeling at these loci and altered expression of interacting genes. Thus, the susceptibility for MS may involve OLG, which therefore constitutes novel targets for immunological-based therapies for MS.
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Affiliation(s)
- Mandy Meijer
- Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 77 Stockholm, Sweden
| | - Eneritz Agirre
- Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 77 Stockholm, Sweden
| | - Mukund Kabbe
- Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 77 Stockholm, Sweden
| | - Cassandra A van Tuijn
- Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 77 Stockholm, Sweden
| | - Abeer Heskol
- Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 77 Stockholm, Sweden; Instituto Gulbenkian de Ciência, 2780-156 Oeiras, Portugal
| | - Chao Zheng
- Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 77 Stockholm, Sweden
| | - Ana Mendanha Falcão
- Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 77 Stockholm, Sweden; Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal; ICVS/3B's Associate Laboratory, PT Government Associate Laboratory, 4710-057 Braga/Guimarães, Portugal
| | - Marek Bartosovic
- Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 77 Stockholm, Sweden
| | - Leslie Kirby
- Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 77 Stockholm, Sweden
| | - Daniela Calini
- Roche Pharma Research and Early Development, 4070 Basel, Switzerland
| | - Michael R Johnson
- Faculty of Medicine, Department of Brain Sciences, Imperial College of London, SW7 2AZ London, UK
| | - M Ryan Corces
- Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA; Center for Personal Dynamic Regulomes and Howard Hughes Medical Institute, Stanford University, Stanford, CA, USA; Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA
| | - Thomas J Montine
- Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA
| | - Xingqi Chen
- Center for Personal Dynamic Regulomes and Howard Hughes Medical Institute, Stanford University, Stanford, CA, USA; Department of Immunology, Genetics, and Pathology, Uppsala University, 751 85 Uppsala, Sweden
| | - Howard Y Chang
- Center for Personal Dynamic Regulomes and Howard Hughes Medical Institute, Stanford University, Stanford, CA, USA; Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305-5101, USA
| | - Dheeraj Malhotra
- Roche Pharma Research and Early Development, 4070 Basel, Switzerland
| | - Gonçalo Castelo-Branco
- Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 77 Stockholm, Sweden; Ming Wai Lau Centre for Reparative Medicine, Stockholm node, Karolinska Institutet, 171 77 Stockholm, Sweden.
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28
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Brar HK, Roy G, Kanojia A, Madan E, Madhubala R, Muthuswami R. Chromatin-Remodeling Factor BRG1 Is a Negative Modulator of L. donovani in IFNγ Stimulated and Infected THP-1 Cells. Front Cell Infect Microbiol 2022; 12:860058. [PMID: 35433496 PMCID: PMC9011159 DOI: 10.3389/fcimb.2022.860058] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2022] [Accepted: 03/14/2022] [Indexed: 11/13/2022] Open
Abstract
Intracellular pathogens manipulate the host cell for their own survival by contributing to modifications of host epigenome, and thus, altering expression of genes involved in the pathogenesis. Both ATP-dependent chromatin remodeling complex and histone modifications has been shown to be involved in the activation of IFNγ responsive genes. Leishmania donovani is an intracellular pathogen that causes visceral leishmaniasis. The strategies employed by Leishmania donovani to modulate the host epigenome in order to overcome the host defense for their persistence has been worked out in this study. We show that L. donovani negatively affects BRG1, a catalytic subunit of mammalian SWI/SNF chromatin remodeling complex, to alter IFNγ induced host responses. We observed that L. donovani infection downregulates BRG1 expression both at transcript and protein levels in cells stimulated with IFNγ. We also observed a significant decrease in IFNγ responsive gene, Class II transactivator (CIITA), as well as its downstream genes, MHC-II (HLA-DR and HLA-DM). Also, the occupancy of BRG1 at CIITA promoters I and IV was disrupted. A reversal in CIITA expression and decreased parasite load was observed with BRG1 overexpression, thus, suggesting BRG1 is a potential negative regulator for the survival of intracellular parasites in an early phase of infection. We also observed a decrease in H3 acetylation at the promoters of CIITA, post parasite infection. Silencing of HDAC1, resulted in increased CIITA expression, and further decreased parasite load. Taken together, we suggest that intracellular parasites in an early phase of infection negatively regulates BRG1 by using host HDAC1 for its survival inside the host.
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Affiliation(s)
- Harsimran Kaur Brar
- Molecular Parasitology Laboratory, School of Life Sciences, Jawaharlal Nehru University, New Delhi, India
| | - Gargi Roy
- Molecular Parasitology Laboratory, School of Life Sciences, Jawaharlal Nehru University, New Delhi, India
| | - Akanksha Kanojia
- Chromatin Remodeling Laboratory, School of Life Sciences, Jawaharlal Nehru University, New Delhi, India
| | - Evanka Madan
- Molecular Parasitology Laboratory, School of Life Sciences, Jawaharlal Nehru University, New Delhi, India
| | - Rentala Madhubala
- Molecular Parasitology Laboratory, School of Life Sciences, Jawaharlal Nehru University, New Delhi, India
- *Correspondence: Rentala Madhubala, ; Rohini Muthuswami,
| | - Rohini Muthuswami
- Chromatin Remodeling Laboratory, School of Life Sciences, Jawaharlal Nehru University, New Delhi, India
- *Correspondence: Rentala Madhubala, ; Rohini Muthuswami,
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29
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Regulation of the antigen presentation machinery in cancer and its implication for immune surveillance. Biochem Soc Trans 2022; 50:825-837. [PMID: 35343573 PMCID: PMC9162455 DOI: 10.1042/bst20210961] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Revised: 02/10/2022] [Accepted: 03/14/2022] [Indexed: 12/20/2022]
Abstract
Evading immune destruction is one of the hallmarks of cancer. A key mechanism of immune evasion deployed by tumour cells is to reduce neoantigen presentation through down-regulation of the antigen presentation machinery. MHC-I and MHC-II proteins are key components of the antigen presentation machinery responsible for neoantigen presentation to CD8+ and CD4+ T lymphocytes, respectively. Their expression in tumour cells is modulated by a complex interplay of genomic, transcriptomic and post translational factors involving multiple intracellular antigen processing pathways. Ongoing research investigates mechanisms invoked by cancer cells to abrogate MHC-I expression and attenuate anti-tumour CD8+ cytotoxic T cell response. The discovery of MHC-II on tumour cells has been less characterized. However, this finding has triggered further interest in utilising tumour-specific MHC-II to harness sustained anti-tumour immunity through the activation of CD4+ T helper cells. Tumour-specific expression of MHC-I and MHC-II has been associated with improved patient survival in most clinical studies. Thus, their reactivation represents an attractive way to unleash anti-tumour immunity. This review provides a comprehensive overview of physiologically conserved or novel mechanisms utilised by tumour cells to reduce MHC-I or MHC-II expression. It outlines current approaches employed at the preclinical and clinical trial interface towards reversing these processes in order to improve response to immunotherapy and survival outcomes for patients with cancer.
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30
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Thirmanne HN, Wu F, Janssens DH, Swanger J, Diab A, Feldman H, Amezquita RA, Gottardo R, Paddison PJ, Henikoff S, Clurman BE. Global and context-specific transcriptional consequences of oncogenic Fbw7 mutations. eLife 2022; 11:74338. [PMID: 35225231 PMCID: PMC8926403 DOI: 10.7554/elife.74338] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Accepted: 02/16/2022] [Indexed: 11/30/2022] Open
Abstract
The Fbw7 ubiquitin ligase targets many proteins for proteasomal degradation, which include oncogenic transcription factors (TFs) (e.g., c-Myc, c-Jun, and Notch). Fbw7 is a tumor suppressor and tumors often contain mutations in FBXW7, the gene that encodes Fbw7. The complexity of its substrate network has obscured the mechanisms of Fbw7-associated tumorigenesis, yet this understanding is needed for developing therapies. We used an integrated approach employing RNA-Seq and high-resolution mapping (cleavage under target and release using nuclease) of histone modifications and TF occupancy (c-Jun and c-Myc) to examine the combinatorial effects of misregulated Fbw7 substrates in colorectal cancer (CRC) cells with engineered tumor-associated FBXW7 null or missense mutations. Both Fbw7 mutations caused widespread transcriptional changes associated with active chromatin and altered TF occupancy: some were common to both Fbw7 mutant cell lines, whereas others were mutation specific. We identified loci where both Jun and Myc were coregulated by Fbw7, suggesting that substrates may have synergistic effects. One coregulated gene was CIITA, the master regulator of MHC Class II gene expression. Fbw7 loss increased MHC Class II expression and Fbw7 mutations were correlated with increased CIITA expression in TCGA colorectal tumors and cell lines, which may have immunotherapeutic implications for Fbw7-associated cancers. Analogous studies in neural stem cells in which FBXW7 had been acutely deleted closely mirrored the results in CRC cells. Gene set enrichment analyses revealed Fbw7-associated pathways that were conserved across both cell types that may reflect fundamental Fbw7 functions. These analyses provide a framework for understanding normal and neoplastic context-specific Fbw7 functions.
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Affiliation(s)
| | - Feinan Wu
- Genomics and Bioinformatics Resource, Fred Hutchinson Cancer Research Center, Seattle, United States
| | - Derek H Janssens
- Basic Science Division, Fred Hutchinson Cancer Research Center, Seattle, United States
| | - Jherek Swanger
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, United States
| | - Ahmed Diab
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, United States
| | - Heather Feldman
- Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, United States
| | - Robert A Amezquita
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, United States
| | - Raphael Gottardo
- Vaccine and Infectious Disease Division, University of Washington, Seattle, United States
| | - Patrick J Paddison
- Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, United States
| | - Steven Henikoff
- Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, United States
| | - Bruce E Clurman
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, United States
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31
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Mizuno N, Yanagawa Y. Tofacitinib enhances interferon-γ-induced expression of major histocompatibility complex class II in macrophages. Eur J Pharmacol 2022; 915:174564. [PMID: 34919889 DOI: 10.1016/j.ejphar.2021.174564] [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: 04/27/2021] [Revised: 09/30/2021] [Accepted: 10/11/2021] [Indexed: 11/21/2022]
Abstract
Tofacitinib is the first selective Janus kinase (JAK) 1/3 inhibitor approved for the treatment of rheumatoid arthritis and has been demonstrated to exhibit its efficacy through suppression of lymphocyte activation. Although macrophages are critically involved in the pathogenesis of rheumatoid arthritis, little is known about the influence of tofacitinib on macrophage activation especially expression of major histocompatibility complex class II (MHC II) and co-stimulatory molecule CD86. In the present study, we examined the effect of tofacitinib on the expression of MHC II and CD86 in RAW264.7 murine macrophages. Interferon (IFN)-γ induces the cell surface expression of MHC II and CD86. The treatment of tofacitinib at 0.5 μM significantly upregulated IFN-γ-induced expression of MHC II, while decreased the expression of CD86. Hence the population of CD86- MHC II+ cells that induced by tofacitinib at 0.5 μM in the presence of IFN-γ were approximately three times larger than that of IFN-γ alone. Consistent with the surface expression, tofacitinib enhanced IFN-γ-induced mRNA expression of MHC II, and contrarily, decreased that of CD86. Similarly, tofacitinib increased the mRNA expression of MHC II transactivator (CIITA), especially CIITA type I, which is a key regulator of MHC II gene transcription. These findings suggested that tofacitinib enhanced IFNγ-induced MHC II expression by transcriptional regulation through induction of CIITA in macrophages and raise the possibility that a novel action of tofacitinib.
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Affiliation(s)
- Natsumi Mizuno
- Department of Pharmacology, School of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Kanazawa 1757, Ishikari-Tobetsu, 061-0293, Japan.
| | - Yoshiki Yanagawa
- Department of Pharmacology, School of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Kanazawa 1757, Ishikari-Tobetsu, 061-0293, Japan
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32
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Chang H, Zou Z, Li J, Shen Q, Liu L, An X, Yang S, Xing D. Photoactivation of mitochondrial reactive oxygen species-mediated Src and protein kinase C pathway enhances MHC class II-restricted T cell immunity to tumours. Cancer Lett 2021; 523:57-71. [PMID: 34563641 DOI: 10.1016/j.canlet.2021.09.032] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 09/08/2021] [Accepted: 09/21/2021] [Indexed: 10/20/2022]
Abstract
High fluence low-level laser (HF-LLL), a mitochondria-targeted tumour phototherapy, results in oxidative damage and apoptosis of tumour cells, as well as damage to normal tissue. To circumvent this, the therapeutic effect of low fluence LLL (LFL), a non-invasive and drug-free therapeutic strategy, was identified for tumours and the underlying molecular mechanisms were investigated. We observed that LFL enhanced antigen-specific immune response of macrophages and dendritic cells by upregulating MHC class II, which was induced by mitochondrial reactive oxygen species (ROS)-activated signalling, suppressing tumour growth in both CD11c-DTR and C57BL/6 mice. Mechanistically, LFL upregulated MHC class II in an MHC class II transactivator (CIITA)-dependent manner. LFL-activated protein kinase C (PKC) promoted the nuclear translocation of CIITA, as inhibition of PKC attenuated the DNA-binding efficiency of CIITA to MHC class II promoter. CIITA mRNA and protein expression also improved after LFL treatment, characterised by direct binding of Src and STAT1, and subsequent activation of STAT1. Notably, scavenging of ROS downregulated LFL-induced Src and PKC activation and antagonised the effects of LFL treatment. Thus, LFL treatment altered the adaptive immune response via the mitochondrial ROS-activated signalling pathway to control the progress of neoplastic disease.
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Affiliation(s)
- Haocai Chang
- MOE Key Laboratory of Laser Life Science & Institute of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, 510631, China; Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, 510631, China.
| | - Zhengzhi Zou
- MOE Key Laboratory of Laser Life Science & Institute of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, 510631, China; Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, 510631, China.
| | - Jie Li
- MOE Key Laboratory of Laser Life Science & Institute of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, 510631, China; Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, 510631, China.
| | - Qi Shen
- MOE Key Laboratory of Laser Life Science & Institute of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, 510631, China; Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, 510631, China.
| | - Lei Liu
- Institute for Brain Research and Rehabilitation, South China Normal University, Guangzhou, 510631, China.
| | - Xiaorui An
- MOE Key Laboratory of Laser Life Science & Institute of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, 510631, China; Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, 510631, China.
| | - Sihua Yang
- MOE Key Laboratory of Laser Life Science & Institute of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, 510631, China; Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, 510631, China.
| | - Da Xing
- MOE Key Laboratory of Laser Life Science & Institute of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, 510631, China; Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, 510631, China.
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Chen L, Zhang M, Wang X, Liu Y, Bian J, Yan D, Yin W. Cardiac steroid ouabain transcriptionally increases human leukocyte antigen DR expression on monocytes. Steroids 2021; 175:108915. [PMID: 34508735 DOI: 10.1016/j.steroids.2021.108915] [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: 04/27/2021] [Revised: 07/31/2021] [Accepted: 08/30/2021] [Indexed: 01/18/2023]
Abstract
Sepsis is a life-threatening disease characterized by acute multiple organ dysfunction and immunosuppression that is also called as immunoparalysis. Increasing evidence suggests that immunoparalysis largely contributes to the high mortality of sepsis, but the effective remedies are lacking. As an important antigen presentation molecule, human leukocyte antigen DR (HLA-DR) is remarkably down-regulated in sepsis-induced immunoparalysis, therefore, re-stimulation of HLA-DR expression is expected to be useful in reversing immunoparalysis. We previously described that ouabain, as a Na+, K+-ATPase ligand, is able to counteract immunoparalysis by regulating TH1 cytokines expression. Here, we expanded the finding that ouabain not only prevents LPS-induced down-regulation of HLA-DR on monocytes, but also transcriptionally activates HLA-DR α/β expression mediated by CIITA4, IRF1, c-Src, and Stat1 phosphorylation. Since ouabain can improve sepsis-induced immunoparalysis by multiple mechanisms, we propose that ouabain may be a promising agent in septic therapy that deserves further investigation.
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Affiliation(s)
- Lili Chen
- State Key Lab of Pharmaceutical Biotechnology, College of Life Sciences, Nanjing University, Nanjing, China
| | - Manli Zhang
- State Key Lab of Pharmaceutical Biotechnology, College of Life Sciences, Nanjing University, Nanjing, China
| | - Xiya Wang
- State Key Lab of Pharmaceutical Biotechnology, College of Life Sciences, Nanjing University, Nanjing, China
| | - Yongjian Liu
- State Key Lab of Pharmaceutical Biotechnology, College of Life Sciences, Nanjing University, Nanjing, China
| | - Jinjun Bian
- Department of Anesthesiology and Critical Care, Changhai Hospital, Naval Medical University, Shanghai, China.
| | - Dong Yan
- Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, China.
| | - Wu Yin
- State Key Lab of Pharmaceutical Biotechnology, College of Life Sciences, Nanjing University, Nanjing, China.
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34
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Shen Y, Zhang J. Tight Regulation of Major Histocompatibility Complex I for the Spatial and Temporal Expression in the Hippocampal Neurons. Front Cell Neurosci 2021; 15:739136. [PMID: 34658795 PMCID: PMC8517433 DOI: 10.3389/fncel.2021.739136] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2021] [Accepted: 09/06/2021] [Indexed: 11/16/2022] Open
Abstract
The expression and function of immune molecules, such as major histocompatibility complex (MHC), within the developing and adult brain have been discovered over the past few years. Studies utilizing classical class I MHC knockout animals suggest that these molecules, in fact, play essential roles in the establishment, function, and modification of synapses in the CNS. Altered neuronal expression of class I MHC, as has been reported in pathological conditions, leads to aberrations in neuronal development and repair. In the hippocampus, cellular and molecular mechanisms that regulate synaptic plasticity have heretofore been extensively studied. It is for this reason that multiple studies directed at better understanding the expression, regulation, and function of class I MHC within the hippocampus have been undertaken. Since several previous reviews have addressed the roles of class I MHC in the formation and function of hippocampal connections, the present review will focus on describing the spatial and temporal expression of class I MHC in developing, healthy adult, and aging hippocampus. Herein, we also review current literatures exploring mechanisms that regulate class I MHC expression in murine hippocampus. With this review, we aim to facilitate a deeper mechanistic understanding into the complex tight regulation of MHC I expression in hippocampus, which are needed as we explore the potential for targeting MHC I for therapeutic intervention in normal aging and in neurodegenerative diseases in the future.
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Affiliation(s)
- Yuqing Shen
- Department of Microbiology and Immunology, Medical School, Southeast University, Nanjing, China.,Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, School of Medicine, Zhongda Hospital, Southeast University, Nanjing, China
| | - Jianqiong Zhang
- Department of Microbiology and Immunology, Medical School, Southeast University, Nanjing, China.,Key Laboratory of Developmental Genes and Human Disease, Ministry of Education, Southeast University, Nanjing, China.,Jiangsu Key Laboratory of Molecular and Functional Imaging, Medical School, Zhongda Hospital, Southeast University, Nanjing, China
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35
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Prampolini C, Almadori G, Bonvissuto D, Barba M, Giraldi L, Boccia S, Paludetti G, Galli J, Parolini O, Settimi S, Cadoni G. Immunohistochemical detection of "ex novo" HLA-DR in tumor cells determines clinical outcome in laryngeal cancer patients. HLA 2021; 98:517-524. [PMID: 34605215 DOI: 10.1111/tan.14441] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2021] [Revised: 09/27/2021] [Accepted: 09/30/2021] [Indexed: 12/09/2022]
Abstract
There are controversial results about the role of "ex novo" HLA-DR expression by tumor cells and its correlation with the oncological outcomes. Unfortunately, little is known about HLA-DR expression in laryngeal cancer tumor cells. The main purpose of this retrospective study is to strengthen the usefulness of studying "ex novo" HLA-DR expression on tumor cells from primary laryngeal squamous cell carcinoma (LSCC) patients and investigate its correlation with clinical outcome. We analyzed HLA-DR expression by immunohistochemical analysis in 56 patients with LSCC. The "ex novo" HLA-DR expression on laryngeal cancer tumor cells, assessing non-neoplastic LSCC - adjacent tissue, and the association of HLA-DR expression (HLA-DR+) with clinical outcomes were investigated. HLA-DR+ tumor cells were detected in 18/56 LSCC patients (32.1%). All specimens of non-neoplastic laryngeal carcinoma-adjacent tissue resulted HLA-DR negative (HLA-DR-). A statistically significant association was observed between HLA-DR + and well differentiated tumors (G1) (p<0.001). The Kaplan-Meier method showed how HLA-DR+ is significantly associated with both a better disease specific survival (HLA-DR+=100% vs. HLA-DR-=77.4%; p=0.047) and a better relapse free survival (HLA-DR+=100% vs. HLA-DR-=72.3%; p=0.021). Cox regression univariate analysis for death of disease confirmed a higher HR for HLA-DR absence on the surface of epithelial tumor cell [HR:37.489; 95% CI:0.750-18730.776; p=0.253] and for high-grade (G3) tumors [HR:18.601; 95% CI:3.613-95.764; p<0.0001]. Our results confirm that MHC class II HLA-DR expression is activated in a sub-set of LSCC patients. Evaluation of HLA-DR expression in LSCC could be useful for prognosis and future approaches towards personalized therapy.
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Affiliation(s)
- Chiara Prampolini
- Department of Head-Neck and Sensory Organs, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Giovanni Almadori
- Department of Head-Neck and Sensory Organs, Università Cattolica del Sacro Cuore, Rome, Italy.,Department of Aging, Neurologic, Orthopedic and Head-Neck Sciences, Otorhinolaryngology Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
| | - Davide Bonvissuto
- Department of Neurosciences, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Marta Barba
- Department of Life Science and Public Health, Università Cattolica del Sacro Cuore, Rome, Italy.,Biobank for Personalized Medicine, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Luca Giraldi
- Department of Life Science and Public Health, Section of Hygiene and Public Health, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Stefania Boccia
- Department of Life Science and Public Health, Section of Hygiene and Public Health, Università Cattolica del Sacro Cuore, Rome, Italy.,Department of Woman and Child Health and Public Health, Public Health Area, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
| | - Gaetano Paludetti
- Department of Head-Neck and Sensory Organs, Università Cattolica del Sacro Cuore, Rome, Italy.,Department of Aging, Neurologic, Orthopedic and Head-Neck Sciences, Otorhinolaryngology Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
| | - Jacopo Galli
- Department of Head-Neck and Sensory Organs, Università Cattolica del Sacro Cuore, Rome, Italy.,Department of Aging, Neurologic, Orthopedic and Head-Neck Sciences, Otorhinolaryngology Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
| | - Ornella Parolini
- Department of Life Science and Public Health, Università Cattolica del Sacro Cuore, Rome, Italy.,Biobank for Personalized Medicine, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Stefano Settimi
- Department of Aging, Neurologic, Orthopedic and Head-Neck Sciences, Otorhinolaryngology Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
| | - Gabriella Cadoni
- Department of Head-Neck and Sensory Organs, Università Cattolica del Sacro Cuore, Rome, Italy.,Department of Aging, Neurologic, Orthopedic and Head-Neck Sciences, Otorhinolaryngology Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
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Meyer S, Handke D, Mueller A, Biehl K, Kreuz M, Bukur J, Koehl U, Lazaridou MF, Berneburg M, Steven A, Massa C, Seliger B. Distinct Molecular Mechanisms of Altered HLA Class II Expression in Malignant Melanoma. Cancers (Basel) 2021; 13:cancers13153907. [PMID: 34359808 PMCID: PMC8345549 DOI: 10.3390/cancers13153907] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Accepted: 07/29/2021] [Indexed: 01/10/2023] Open
Abstract
BACKGROUND The human leukocyte antigen (HLA) class II molecules are constitutively expressed in some melanoma, but the underlying molecular mechanisms have not yet been characterized. METHODS The expression of HLA class II antigen processing machinery (APM) components was determined in melanoma samples by qPCR, Western blot, flow cytometry and immunohistochemistry. Immunohistochemical and TCGA datasets were used for correlation of HLA class II expression to tumor grading, T-cell infiltration and patients' survival. RESULTS The heterogeneous HLA class II expression in melanoma samples allowed us to characterize four distinct phenotypes. Phenotype I totally lacks constitutive HLA class II surface expression, which is inducible by interferon-gamma (IFN-γ); phenotype II expresses low basal surface HLA class II that is further upregulated by IFN-γ; phenotype III lacks constitutive and IFN-γ controlled HLA class II expression, but could be induced by epigenetic drugs; and in phenotype IV, lack of HLA class II expression is not recovered by any drug tested. High levels of HLA class II APM component expression were associated with an increased intra-tumoral CD4+ T-cell density and increased patients' survival. CONCLUSIONS The heterogeneous basal expression of HLA class II antigens and/or APM components in melanoma cells is caused by distinct molecular mechanisms and has clinical relevance.
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Affiliation(s)
- Stefanie Meyer
- Department of Dermatology, University Hospital of Regensburg, Franz-Josef-Strauss-Allee 11, 93053 Regensburg, Germany; (S.M.); (M.B.)
| | - Diana Handke
- Institute of Medical Immunology, Martin Luther University Halle-Wittenberg, Magdeburger Str. 2, 06112 Halle (Saale), Germany; (D.H.); (A.M.); (K.B.); (J.B.); (M.-F.L.); (A.S.); (C.M.)
| | - Anja Mueller
- Institute of Medical Immunology, Martin Luther University Halle-Wittenberg, Magdeburger Str. 2, 06112 Halle (Saale), Germany; (D.H.); (A.M.); (K.B.); (J.B.); (M.-F.L.); (A.S.); (C.M.)
| | - Katharina Biehl
- Institute of Medical Immunology, Martin Luther University Halle-Wittenberg, Magdeburger Str. 2, 06112 Halle (Saale), Germany; (D.H.); (A.M.); (K.B.); (J.B.); (M.-F.L.); (A.S.); (C.M.)
| | - Markus Kreuz
- Fraunhofer Institute for Cell Therapy and Immunology, Perlickstr. 1, 04103 Leipzig, Germany; (M.K.); (U.K.)
| | - Jürgen Bukur
- Institute of Medical Immunology, Martin Luther University Halle-Wittenberg, Magdeburger Str. 2, 06112 Halle (Saale), Germany; (D.H.); (A.M.); (K.B.); (J.B.); (M.-F.L.); (A.S.); (C.M.)
| | - Ulrike Koehl
- Fraunhofer Institute for Cell Therapy and Immunology, Perlickstr. 1, 04103 Leipzig, Germany; (M.K.); (U.K.)
| | - Maria-Filothei Lazaridou
- Institute of Medical Immunology, Martin Luther University Halle-Wittenberg, Magdeburger Str. 2, 06112 Halle (Saale), Germany; (D.H.); (A.M.); (K.B.); (J.B.); (M.-F.L.); (A.S.); (C.M.)
| | - Mark Berneburg
- Department of Dermatology, University Hospital of Regensburg, Franz-Josef-Strauss-Allee 11, 93053 Regensburg, Germany; (S.M.); (M.B.)
| | - André Steven
- Institute of Medical Immunology, Martin Luther University Halle-Wittenberg, Magdeburger Str. 2, 06112 Halle (Saale), Germany; (D.H.); (A.M.); (K.B.); (J.B.); (M.-F.L.); (A.S.); (C.M.)
| | - Chiara Massa
- Institute of Medical Immunology, Martin Luther University Halle-Wittenberg, Magdeburger Str. 2, 06112 Halle (Saale), Germany; (D.H.); (A.M.); (K.B.); (J.B.); (M.-F.L.); (A.S.); (C.M.)
| | - Barbara Seliger
- Institute of Medical Immunology, Martin Luther University Halle-Wittenberg, Magdeburger Str. 2, 06112 Halle (Saale), Germany; (D.H.); (A.M.); (K.B.); (J.B.); (M.-F.L.); (A.S.); (C.M.)
- Fraunhofer Institute for Cell Therapy and Immunology, Perlickstr. 1, 04103 Leipzig, Germany; (M.K.); (U.K.)
- Correspondence: ; Tel.: +49-(0)-345-557-4054
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Chinniah R, Sevak V, Pandi S, Ravi PM, Vijayan M, Kannan A, Karuppiah B. HLA-DRB1 genes and the expression dynamics of HLA CIITA determine the susceptibility to T2DM. Immunogenetics 2021; 73:291-305. [PMID: 33754173 DOI: 10.1007/s00251-021-01212-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Accepted: 03/01/2021] [Indexed: 12/18/2022]
Abstract
Type 2 diabetes mellitus (T2DM) is a disease with polygenic inheritance. The expression of major histocompatibility complex class II genes are regulated by several trans-activators. We have studied the expression of HLA-DRB1, RFX, CIITA-P1, PIV transactivators, immunophenotyping of cells, SNPs in CIITA-168 (A/G) and IFN-γ + 874 (T/A) in T2DM patients and controls (n = 201 each). We observed increased frequencies of DRB1*03, DRB1*04 and DRB1*07 and decreased frequencies of DRB1*10, DRB1*14, and DRB1*15 alleles among patients. Significant up-regulations of HLA-DRB1 genes were observed in patients (p < 0.0001). Down-regulated expressions were documented in DRB1*03-homo (p < 0.002) and DRB1*04-homo (p < 0.009) patients. No significant differences were observed for CIITA-P1 expression except DRB1*04-pooled (p < 0.0113). The CIITA-PIV was up-regulated in overall (p < 0.0001), DRB1*03-pooled (p < 0.0006), DRB1*03-hetero (p < 0.0006) and DRB1*03-homo (p < 0.001) T2DM patients. However, significant down-regulations were documented for DRB1*04-pooled (p < 0.040), DRB1*04-hetero (p < 0.060), and DRB1*04-homo (p < 0.027) combinations. Further, significant down-regulations of RFX5 were observed in overall (p < 0.0006), DRB1*04-pooled (p < 0.0022), and DRB1*04-hetero (p < 0.0004) combinations. Immunophenotyping studies revealed significant increase of CD45+ CD14-, CD19+, CD14- and CD8 cells and elevated level of expression of IFN-γ (p < 0.0001) in patients. A significant increase of TT (p < 3.35 × 10-6) and decrease of TA (p < 4.57 × 10-4) genotypes of IFN-γ + 874 (T/A) and an increase of GG (p < 0.001) and decrease of AG (p < 8.24 × 10-5) genotypes of CIITA-168 A/G SNPs were observed. The combinatorial analysis revealed susceptible associations for DRB1*03 + AA, *03 + AG, *03 + GG and *04 + GG and protective associations for DRB1*10 + AG, *10 + GG, *15 + AG, and *14 + GG combinations. Thus, the present study corroborated the effect of differential expressions of promoters of risk alleles in the pathogenesis of T2DM.
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Affiliation(s)
- Rathika Chinniah
- Department of Immunology, School of Biological Sciences, Madurai, Tamil Nadu, 625021, India
| | - Vandit Sevak
- Department of Immunology, School of Biological Sciences, Madurai, Tamil Nadu, 625021, India
| | - Sasiharan Pandi
- Department of Immunology, School of Biological Sciences, Madurai, Tamil Nadu, 625021, India
| | - Padma Malini Ravi
- Department of Immunology, School of Biological Sciences, Madurai, Tamil Nadu, 625021, India
| | - Murali Vijayan
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, 79430, USA
| | - Arun Kannan
- The Madurai Institute of Diabetes and Endocrine Practice Research, Madurai, Tamil Nadu, 625 001, India
| | - Balakrishnan Karuppiah
- Department of Immunology, School of Biological Sciences, Madurai, Tamil Nadu, 625021, India.
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Wang HY, Sokol ES, Goodman AM, Feldman AL, Mulroney CM. Case Report: Multiple Chromosomal Translocations Including Novel CIITA-CREBBP Fusion and Mutations in a Follicular Lymphoma. Front Oncol 2021; 11:620435. [PMID: 33777766 PMCID: PMC7988195 DOI: 10.3389/fonc.2021.620435] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Accepted: 02/15/2021] [Indexed: 11/13/2022] Open
Abstract
The pathogenesis of follicular lymphoma is a multi-step process, in which chromosomal translocation between immunoglobulin heavy chain (IgH) and anti-apoptotic B-cell lymphoma 2 (BCL2), namely IgH-BCL2, is an earliest step, followed by other genetic/genomic alterations including but not limited to mutation of CREB binding protein (CREBBP). MHC class II transactivator (CIITA) is a transcription regulator responsible for expression of MHC class II molecules including HLA-DR in human. We report herein a novel fusion gene involving CIITA and CREBBP in a patient with a low-grade follicular lymphoma (FL) but with high Ki-67 proliferation index. In addition, our patient also harbors CREBBP mutation. Together, we postulate that total loss of CREBBP function may contribute, in part, to the lymphoma genesis. Furthermore, this patient has addition rare (TBL1XR1-TP63) and common (IgH-BCL2) chromosomal translocations and multiple mutations including BCL2, BRAF, MUTYH, and STAT6.
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Affiliation(s)
- Huan-You Wang
- Division of Laboratory and Genomic Medicine, Department of Pathology, University of California San Diego Health System, La Jolla, CA, United States
| | | | - Aaron M Goodman
- Division of Blood and Bone Marrow Transplant, Department of Medicine, University of California San Diego Health System, La Jolla, CA, United States
| | - Andrew L Feldman
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, United States
| | - Carolyn M Mulroney
- Division of Blood and Bone Marrow Transplant, Department of Medicine, University of California San Diego Health System, La Jolla, CA, United States
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Shukla A, Cloutier M, Appiya Santharam M, Ramanathan S, Ilangumaran S. The MHC Class-I Transactivator NLRC5: Implications to Cancer Immunology and Potential Applications to Cancer Immunotherapy. Int J Mol Sci 2021; 22:ijms22041964. [PMID: 33671123 PMCID: PMC7922096 DOI: 10.3390/ijms22041964] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Revised: 02/03/2021] [Accepted: 02/08/2021] [Indexed: 12/13/2022] Open
Abstract
The immune system constantly monitors the emergence of cancerous cells and eliminates them. CD8+ cytotoxic T lymphocytes (CTLs), which kill tumor cells and provide antitumor immunity, select their targets by recognizing tumor antigenic peptides presented by MHC class-I (MHC-I) molecules. Cancer cells circumvent immune surveillance using diverse strategies. A key mechanism of cancer immune evasion is downregulation of MHC-I and key proteins of the antigen processing and presentation machinery (APM). Even though impaired MHC-I expression in cancers is well-known, reversing the MHC-I defects remains the least advanced area of tumor immunology. The discoveries that NLRC5 is the key transcriptional activator of MHC-I and APM genes, and genetic lesions and epigenetic modifications of NLRC5 are the most common cause of MHC-I defects in cancers, have raised the hopes for restoring MHC-I expression. Here, we provide an overview of cancer immunity mediated by CD8+ T cells and the functions of NLRC5 in MHC-I antigen presentation pathways. We describe the impressive advances made in understanding the regulation of NLRC5 expression, the data supporting the antitumor functions of NLRC5 and a few reports that argue for a pro-tumorigenic role. Finally, we explore the possible avenues of exploiting NLRC5 for cancer immunotherapy.
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Affiliation(s)
- Akhil Shukla
- Department of Immunology and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada; (A.S.); (M.C.); (M.A.S.); (S.R.)
| | - Maryse Cloutier
- Department of Immunology and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada; (A.S.); (M.C.); (M.A.S.); (S.R.)
| | - Madanraj Appiya Santharam
- Department of Immunology and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada; (A.S.); (M.C.); (M.A.S.); (S.R.)
| | - Sheela Ramanathan
- Department of Immunology and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada; (A.S.); (M.C.); (M.A.S.); (S.R.)
- CRCHUS, Centre Hospitalier de l’Université de Sherbrooke, Sherbrooke, QC J1H5N4, Canada
| | - Subburaj Ilangumaran
- Department of Immunology and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada; (A.S.); (M.C.); (M.A.S.); (S.R.)
- CRCHUS, Centre Hospitalier de l’Université de Sherbrooke, Sherbrooke, QC J1H5N4, Canada
- Correspondence: ; Tel.: +1-819-346-1110 (ext. 14834)
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León Machado JA, Steimle V. The MHC Class II Transactivator CIITA: Not (Quite) the Odd-One-Out Anymore among NLR Proteins. Int J Mol Sci 2021; 22:1074. [PMID: 33499042 PMCID: PMC7866136 DOI: 10.3390/ijms22031074] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 01/15/2021] [Accepted: 01/19/2021] [Indexed: 12/14/2022] Open
Abstract
In this review, we discuss the major histocompatibility complex (MHC) class II transactivator (CIITA), which is the master regulator of MHC class II gene expression. CIITA is the founding member of the mammalian nucleotide-binding and leucine-rich-repeat (NLR) protein family but stood apart for a long time as the only transcriptional regulator. More recently, it was found that its closest homolog, NLRC5 (NLR protein caspase activation and recruitment domain (CARD)-containing 5), is a regulator of MHC-I gene expression. Both act as non-DNA-binding activators through multiple protein-protein interactions with an MHC enhanceosome complex that binds cooperatively to a highly conserved combinatorial cis-acting module. Thus, the regulation of MHC-II expression is regulated largely through the differential expression of CIITA. In addition to the well-defined role of CIITA in MHC-II GENE regulation, we will discuss several other aspects of CIITA functions, such as its role in cancer, its role as a viral restriction element contributing to intrinsic immunity, and lastly, its very recently discovered role as an inhibitor of Ebola and SARS-Cov-2 virus replication. We will briefly touch upon the recently discovered role of NLRP3 as a transcriptional regulator, which suggests that transcriptional regulation is, after all, not such an unusual feature for NLR proteins.
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Affiliation(s)
| | - Viktor Steimle
- Département de Biologie, Université de Sherbrooke, 2500 Boul., Sherbrooke, QC J1K 2R1, Canada;
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Doshi J, Willis K, Madurga A, Stelzer C, Benenson Y. Multiple Alternative Promoters and Alternative Splicing Enable Universal Transcription-Based Logic Computation in Mammalian Cells. Cell Rep 2020; 33:108437. [PMID: 33264624 DOI: 10.1016/j.celrep.2020.108437] [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: 02/28/2020] [Revised: 09/04/2020] [Accepted: 11/05/2020] [Indexed: 10/22/2022] Open
Abstract
Multi-input logic gene circuits can enable sophisticated control of cell function, yet large-scale synthetic circuitry in mammalian cells has relied on post-transcriptional regulation or recombinase-triggered state transitions. Large-scale transcriptional logic, on the other hand, has been challenging to implement. Inspired by a naturally found regulatory strategy of using multiple alternative promoters, followed by alternative splicing, we developed a scalable and compact platform for transcriptional OR logic using inputs to those promoters. The platform is extended to implement disjunctive normal form (DNF) computations capable of implementing arbitrary logic rules. Specifically, AND logic is implemented at individual promoters using synergistic transcriptional inputs, and NOT logic via microRNA inputs targeting unique exon sequences driven by those promoters. Together, these regulatory programs result in DNF-like logic control of output gene expression. The approach offers flexibility for building complex logic programs in mammalian cells.
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Affiliation(s)
- Jiten Doshi
- Department of Biosystems Science and Engineering, ETH Zurich, Mattenstrasse 26, 4058 Basel, Switzerland
| | - Katie Willis
- Department of Biosystems Science and Engineering, ETH Zurich, Mattenstrasse 26, 4058 Basel, Switzerland
| | - Angela Madurga
- Department of Biosystems Science and Engineering, ETH Zurich, Mattenstrasse 26, 4058 Basel, Switzerland
| | - Christoph Stelzer
- Department of Biosystems Science and Engineering, ETH Zurich, Mattenstrasse 26, 4058 Basel, Switzerland
| | - Yaakov Benenson
- Department of Biosystems Science and Engineering, ETH Zurich, Mattenstrasse 26, 4058 Basel, Switzerland.
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Brouwer MAE, Jones-Warner W, Rahman S, Kerstholt M, Ferreira AV, Oosting M, Hooiveld GJ, Netea MG, Joosten LAB. B. burgdorferi sensu lato-induced inhibition of antigen presentation is mediated by RIP1 signaling resulting in impaired functional T cell responses towards Candida albicans. Ticks Tick Borne Dis 2020; 12:101611. [PMID: 33360386 DOI: 10.1016/j.ttbdis.2020.101611] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Revised: 10/22/2020] [Accepted: 11/06/2020] [Indexed: 02/06/2023]
Abstract
Antigen presentation is a crucial innate immune cell function that instructs adaptive immune cells. Loss of this pathway severely impairs the development of adaptive immune responses. To investigate whether B. burgdorferi sensu lato. spirochetes modulate the induction of an effective immune response, primary human PBMCs were isolated from healthy volunteers and stimulated with B. burgdorferi s.l. Through cell entry, TNF receptor I, and RIP1 signaling cascades, B. burgdorferi s.l. strongly downregulated genes and proteins involved in antigen presentation, specifically HLA-DM, MHC class II and CD74. Antigen presentation proteins were distinctively inhibited in monocyte subsets, monocyte-derived macrophages, and dendritic cells. When compared to a range of other pathogens, B. burgdorferi s.l.-induced suppression of antigen presentation appears to be specific. Inhibition of antigen presentation interfered with T-cell recognition of B. burgdorferi s.l., and memory T-cell responses against Candidaalbicans. Re-stimulation of PBMCs with the commensal microbe C.albicans following B. burgdorferi s.l. exposure resulted in significantly reduced IFN-γ, IL-17 and IL-22 production. These findings may explain why patients with Lyme borreliosis develop delayed adaptive immune responses. Unravelling the mechanism of B. burgdorferi s.l.-induced inhibition of antigen presentation, via cell entry, TNF receptor I, and RIP1 signaling cascades, explains the difficulty to diagnose the disease based on serology and to obtain an effective vaccine against Lyme borreliosis.
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Affiliation(s)
- Michelle A E Brouwer
- Department of Internal Medicine, Radboud Center for Infectious Diseases (RCI), Radboud Institute of Molecular Life Sciences (RIMLS), Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands
| | - William Jones-Warner
- Department of Internal Medicine, Radboud Center for Infectious Diseases (RCI), Radboud Institute of Molecular Life Sciences (RIMLS), Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands
| | - Shafaque Rahman
- Department of Internal Medicine, Radboud Center for Infectious Diseases (RCI), Radboud Institute of Molecular Life Sciences (RIMLS), Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands
| | - Mariska Kerstholt
- Department of Internal Medicine, Radboud Center for Infectious Diseases (RCI), Radboud Institute of Molecular Life Sciences (RIMLS), Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands
| | - Anaísa V Ferreira
- Department of Internal Medicine, Radboud Center for Infectious Diseases (RCI), Radboud Institute of Molecular Life Sciences (RIMLS), Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands; Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto, Porto, Portugal
| | - Marije Oosting
- Department of Internal Medicine, Radboud Center for Infectious Diseases (RCI), Radboud Institute of Molecular Life Sciences (RIMLS), Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands
| | - Guido J Hooiveld
- Nutrition, Metabolism and Genomics Group, Division of Human Nutrition and Health, Wageningen University, Wageningen, the Netherlands
| | - Mihai G Netea
- Department of Internal Medicine, Radboud Center for Infectious Diseases (RCI), Radboud Institute of Molecular Life Sciences (RIMLS), Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands; Department for Genomics & Immunoregulation, Life and Medical Sciences Institute (LIMES), University of Bonn, Bonn, Germany
| | - Leo A B Joosten
- Department of Internal Medicine, Radboud Center for Infectious Diseases (RCI), Radboud Institute of Molecular Life Sciences (RIMLS), Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands.
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Dufva O, Pölönen P, Brück O, Keränen MAI, Klievink J, Mehtonen J, Huuhtanen J, Kumar A, Malani D, Siitonen S, Kankainen M, Ghimire B, Lahtela J, Mattila P, Vähä-Koskela M, Wennerberg K, Granberg K, Leivonen SK, Meriranta L, Heckman C, Leppä S, Nykter M, Lohi O, Heinäniemi M, Mustjoki S. Immunogenomic Landscape of Hematological Malignancies. Cancer Cell 2020; 38:380-399.e13. [PMID: 32649887 DOI: 10.1016/j.ccell.2020.06.002] [Citation(s) in RCA: 112] [Impact Index Per Article: 22.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2019] [Revised: 03/27/2020] [Accepted: 05/29/2020] [Indexed: 12/15/2022]
Abstract
Understanding factors that shape the immune landscape across hematological malignancies is essential for immunotherapy development. We integrated over 8,000 transcriptomes and 2,000 samples with multilevel genomics of hematological cancers to investigate how immunological features are linked to cancer subtypes, genetic and epigenetic alterations, and patient survival, and validated key findings experimentally. Infiltration of cytotoxic lymphocytes was associated with TP53 and myelodysplasia-related changes in acute myeloid leukemia, and activated B cell-like phenotype and interferon-γ response in lymphoma. CIITA methylation regulating antigen presentation, cancer type-specific immune checkpoints, such as VISTA in myeloid malignancies, and variation in cancer antigen expression further contributed to immune heterogeneity and predicted survival. Our study provides a resource linking immunology with cancer subtypes and genomics in hematological malignancies.
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MESH Headings
- Acute Disease
- Epigenesis, Genetic
- Gene Expression Profiling/methods
- Gene Expression Regulation, Neoplastic
- Genomics/methods
- HLA Antigens/genetics
- Humans
- Immunotherapy/methods
- Leukemia, Myeloid/genetics
- Leukemia, Myeloid/immunology
- Leukemia, Myeloid/therapy
- Lymphocytes, Tumor-Infiltrating/immunology
- Lymphocytes, Tumor-Infiltrating/metabolism
- Lymphoma, Large B-Cell, Diffuse/genetics
- Lymphoma, Large B-Cell, Diffuse/immunology
- Lymphoma, Large B-Cell, Diffuse/therapy
- Multiple Myeloma/genetics
- Multiple Myeloma/immunology
- Multiple Myeloma/therapy
- Mutation
- Tumor Suppressor Protein p53/genetics
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Affiliation(s)
- Olli Dufva
- Hematology Research Unit Helsinki, Helsinki University Hospital Comprehensive Cancer Center (HUH CCC), 00029 Helsinki, Finland; Translational Immunology Research Program and Department of Clinical Chemistry and Hematology, University of Helsinki (UH), 00029 Helsinki, Finland; iCAN Digital Precision Cancer Medicine Flagship, Helsinki, Finland
| | - Petri Pölönen
- Institute of Biomedicine, School of Medicine, University of Eastern Finland, 70211 Kuopio, Finland
| | - Oscar Brück
- Hematology Research Unit Helsinki, Helsinki University Hospital Comprehensive Cancer Center (HUH CCC), 00029 Helsinki, Finland; Translational Immunology Research Program and Department of Clinical Chemistry and Hematology, University of Helsinki (UH), 00029 Helsinki, Finland; iCAN Digital Precision Cancer Medicine Flagship, Helsinki, Finland
| | - Mikko A I Keränen
- Hematology Research Unit Helsinki, Helsinki University Hospital Comprehensive Cancer Center (HUH CCC), 00029 Helsinki, Finland; Translational Immunology Research Program and Department of Clinical Chemistry and Hematology, University of Helsinki (UH), 00029 Helsinki, Finland
| | - Jay Klievink
- Hematology Research Unit Helsinki, Helsinki University Hospital Comprehensive Cancer Center (HUH CCC), 00029 Helsinki, Finland; Translational Immunology Research Program and Department of Clinical Chemistry and Hematology, University of Helsinki (UH), 00029 Helsinki, Finland
| | - Juha Mehtonen
- Institute of Biomedicine, School of Medicine, University of Eastern Finland, 70211 Kuopio, Finland
| | - Jani Huuhtanen
- Hematology Research Unit Helsinki, Helsinki University Hospital Comprehensive Cancer Center (HUH CCC), 00029 Helsinki, Finland; Translational Immunology Research Program and Department of Clinical Chemistry and Hematology, University of Helsinki (UH), 00029 Helsinki, Finland
| | - Ashwini Kumar
- Institute for Molecular Medicine Finland, UH, 00014 Helsinki, Finland
| | - Disha Malani
- Institute for Molecular Medicine Finland, UH, 00014 Helsinki, Finland
| | - Sanna Siitonen
- Department of Clinical Chemistry, UH and HUSLAB, HUH, 00029 Helsinki, Finland
| | - Matti Kankainen
- Hematology Research Unit Helsinki, Helsinki University Hospital Comprehensive Cancer Center (HUH CCC), 00029 Helsinki, Finland; Translational Immunology Research Program and Department of Clinical Chemistry and Hematology, University of Helsinki (UH), 00029 Helsinki, Finland; iCAN Digital Precision Cancer Medicine Flagship, Helsinki, Finland
| | - Bishwa Ghimire
- Institute for Molecular Medicine Finland, UH, 00014 Helsinki, Finland
| | - Jenni Lahtela
- Institute for Molecular Medicine Finland, UH, 00014 Helsinki, Finland
| | - Pirkko Mattila
- Institute for Molecular Medicine Finland, UH, 00014 Helsinki, Finland
| | | | | | - Kirsi Granberg
- Laboratory of Computational Biology, Faculty of Medicine and Health Technology, Tampere University (TU), 33014 Tampere, Finland
| | - Suvi-Katri Leivonen
- Department of Oncology, HUH CCC, 00029 Helsinki, Finland; Applied Tumor Genomics Research Program, Faculty of Medicine, UH, 00014 Helsinki, Finland
| | - Leo Meriranta
- Department of Oncology, HUH CCC, 00029 Helsinki, Finland; Applied Tumor Genomics Research Program, Faculty of Medicine, UH, 00014 Helsinki, Finland
| | - Caroline Heckman
- iCAN Digital Precision Cancer Medicine Flagship, Helsinki, Finland; Institute for Molecular Medicine Finland, UH, 00014 Helsinki, Finland
| | - Sirpa Leppä
- iCAN Digital Precision Cancer Medicine Flagship, Helsinki, Finland; Department of Oncology, HUH CCC, 00029 Helsinki, Finland; Applied Tumor Genomics Research Program, Faculty of Medicine, UH, 00014 Helsinki, Finland
| | - Matti Nykter
- Laboratory of Computational Biology, Faculty of Medicine and Health Technology, Tampere University (TU), 33014 Tampere, Finland
| | - Olli Lohi
- Tampere Center for Child Health Research, TU and Tays Cancer Center, Tampere University Hospital, 33521 Tampere, Finland
| | - Merja Heinäniemi
- Institute of Biomedicine, School of Medicine, University of Eastern Finland, 70211 Kuopio, Finland.
| | - Satu Mustjoki
- Hematology Research Unit Helsinki, Helsinki University Hospital Comprehensive Cancer Center (HUH CCC), 00029 Helsinki, Finland; Translational Immunology Research Program and Department of Clinical Chemistry and Hematology, University of Helsinki (UH), 00029 Helsinki, Finland; iCAN Digital Precision Cancer Medicine Flagship, Helsinki, Finland.
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Matsubara Y, Kiwan G, Fereydooni A, Langford J, Dardik A. Distinct subsets of T cells and macrophages impact venous remodeling during arteriovenous fistula maturation. JVS Vasc Sci 2020; 1:207-218. [PMID: 33748787 PMCID: PMC7971420 DOI: 10.1016/j.jvssci.2020.07.005] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Patients with end-stage renal failure depend on hemodialysis indefinitely without renal transplantation, requiring a long-term patent vascular access. While the arteriovenous fistula (AVF) remains the preferred vascular access for hemodialysis because of its longer patency and fewer complications compared with other vascular accesses, the primary patency of AVF is only 50-60%, presenting a clinical need for improvement. AVF mature by developing a thickened vascular wall and increased diameter to adapt to arterial blood pressure and flow volume. Inflammation plays a critical role during vascular remodeling and fistula maturation; increased shear stress triggers infiltration of T-cells and macrophages that initiate inflammation, with involvement of several different subsets of T-cells and macrophages. We review the literature describing distinct roles of the various subsets of T-cells and macrophages during vascular remodeling. Immunosuppression with sirolimus or prednisolone reduces neointimal hyperplasia during AVF maturation, suggesting novel approaches to enhance vascular remodeling. However, M2 macrophages and CD4+ T-cells play essential roles during AVF maturation, suggesting that total immunosuppression may suppress adaptive vascular remodeling. Therefore it is likely that regulation of inflammation during fistula maturation will require a balanced approach to coordinate the various inflammatory cell subsets. Advances in immunosuppressive drug development and delivery systems may allow for more targeted regulation of inflammation to improve vascular remodeling and enhance AVF maturation.
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Affiliation(s)
- Yutaka Matsubara
- Vascular Biology and Therapeutics Program, Yale School of Medicine, New Haven, CT.,Department of Surgery and Sciences, Kyushu University, Fukuoka, Japan
| | - Gathe Kiwan
- Vascular Biology and Therapeutics Program, Yale School of Medicine, New Haven, CT
| | - Arash Fereydooni
- Vascular Biology and Therapeutics Program, Yale School of Medicine, New Haven, CT
| | - John Langford
- Vascular Biology and Therapeutics Program, Yale School of Medicine, New Haven, CT
| | - Alan Dardik
- Vascular Biology and Therapeutics Program, Yale School of Medicine, New Haven, CT.,Division of Vascular and Endovascular Surgery, Department of Surgery, Yale School of Medicine, New Haven, CT.,Department of Surgery, VA Connecticut Healthcare Systems, West Haven, CT
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45
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Elad O, Uribe-Diaz S, Losada-Medina D, Yitbarek A, Sharif S, Rodriguez-Lecompte JC. Epigenetic effect of folic acid (FA) on the gene proximal promoter area and mRNA expression of chicken B cell as antigen presenting cells. Br Poult Sci 2020; 61:725-733. [PMID: 32705890 DOI: 10.1080/00071668.2020.1799332] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
1. This study evaluated and characterised the effect of folic acid (FA) on chromosomal DNA methylation and the epigenetic result on gene expression control mechanisms in chicken B cells as a model of antigen presenting cells. 2. After FA supplementation, the methylation pattern on the proximal promoter area and mRNA expression of toll-like receptor (TLR) 2b, TLR4, B cell receptor (BCR) immunoglobulin (Ig) β and major histocompatibility complex (MHC) II β chain genes in chicken B cells was observed 3. Chicken B cell line (DT40) cultures were incubated with 0, 1.72 or 3.96 mM of FA for 4 and 8 h and samples were taken at specific time points. After 4 h of incubation, cells were challenged with 0, 1 or 10 µg/ml of lipopolysaccharide (LPS) and samples were collected 4 h post-challenge. 4. FA supplementation modified the methylation patterns of the proximal promoter regions of TLR4, Igß, and MHCII ß chain at 4 and 8 hours of incubation; however, the single CpG dinucleotide of TLR2b remained methylated regardless of the treatment. 5. A positive association was found between FA concentration and percentage DNA methylation on the promoter area of Igβ and TLR2b. However, there was a negative association between FA and MHCII β chain. 6. There were downregulatory effects in TLR4, Igß and MHCII ß chain gene expression after 8 h of incubation, nut not at 4 h. Although incubation time did not affect TLR2b gene expression, FA concentration did, whereby it increased TLR2b expression at 1.72 mM FA (P < 0.05). 7. LPS significant downregulated TLR2b expression, while an interaction between FA and LPS concentration affected TLR4 and Igβ gene expression. 8. In conclusion, the results showed that FA can have an immunomodulatory effect on chicken B cells, possibly affecting their ability to both recognise antigens through the TLR and BCR pathways, and to present it via the MHCII presentation pathway.
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Affiliation(s)
- O Elad
- Department of Pathology and Microbiology, Atlantic Veterinary College , Charlottetown, Canada
| | - S Uribe-Diaz
- Department of Pathology and Microbiology, Atlantic Veterinary College , Charlottetown, Canada.,Department of Chemistry, University of Prince Edward Island , Charlottetown, Prince Edward Island, Canada
| | - D Losada-Medina
- Department of Pathology and Microbiology, Atlantic Veterinary College , Charlottetown, Canada.,Department of Chemistry, University of Prince Edward Island , Charlottetown, Prince Edward Island, Canada
| | - A Yitbarek
- Department of Pathobiology, Ontario Veterinary College, University of Guelph , Guelph, Ontario, Canada
| | - S Sharif
- Department of Pathobiology, Ontario Veterinary College, University of Guelph , Guelph, Ontario, Canada
| | - J C Rodriguez-Lecompte
- Department of Pathology and Microbiology, Atlantic Veterinary College , Charlottetown, Canada
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Huber A, Killy B, Grummel N, Bodendorfer B, Paul S, Wiesmann V, Naschberger E, Zimmer J, Wirtz S, Schleicher U, Vera J, Ekici AB, Dalpke A, Lang R. Mycobacterial Cord Factor Reprograms the Macrophage Response to IFN-γ towards Enhanced Inflammation yet Impaired Antigen Presentation and Expression of GBP1. THE JOURNAL OF IMMUNOLOGY 2020; 205:1580-1592. [PMID: 32796022 DOI: 10.4049/jimmunol.2000337] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Accepted: 07/09/2020] [Indexed: 12/12/2022]
Abstract
Mycobacteria survive in macrophages despite triggering pattern recognition receptors and T cell-derived IFN-γ production. Mycobacterial cord factor trehalose-6,6-dimycolate (TDM) binds the C-type lectin receptor MINCLE and induces inflammatory gene expression. However, the impact of TDM on IFN-γ-induced macrophage activation is not known. In this study, we have investigated the cross-regulation of the mouse macrophage transcriptome by IFN-γ and by TDM or its synthetic analogue trehalose-6,6-dibehenate (TDB). As expected, IFN-γ induced genes involved in Ag presentation and antimicrobial defense. Transcriptional programs induced by TDM and TDB were highly similar but clearly distinct from the response to IFN-γ. The glycolipids enhanced expression of a subset of IFN-γ-induced genes associated with inflammation. In contrast, TDM/TDB exerted delayed inhibition of IFN-γ-induced genes, including pattern recognition receptors, MHC class II genes, and IFN-γ-induced GTPases, with antimicrobial function. TDM downregulated MHC class II cell surface expression and impaired T cell activation by peptide-pulsed macrophages. Inhibition of the IFN-γ-induced GTPase GBP1 occurred at the level of transcription by a partially MINCLE-dependent mechanism that may target IRF1 activity. Although activation of STAT1 was unaltered, deletion of Socs1 relieved inhibition of GBP1 expression by TDM. Nonnuclear Socs1 was sufficient for inhibition, suggesting a noncanonical, cytoplasmic mechanism. Taken together, unbiased analysis of transcriptional reprogramming revealed a significant degree of negative regulation of IFN-γ-induced Ag presentation and antimicrobial gene expression by the mycobacterial cord factor that may contribute to mycobacterial persistence.
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Affiliation(s)
- Alexandra Huber
- Institut für Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg, D-91054 Erlangen, Germany
| | - Barbara Killy
- Institut für Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg, D-91054 Erlangen, Germany
| | - Nadine Grummel
- Institut für Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg, D-91054 Erlangen, Germany
| | - Barbara Bodendorfer
- Institut für Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg, D-91054 Erlangen, Germany
| | - Sushmita Paul
- Laboratory of Systems Tumor Immunology, University Hospital Erlangen and Friedrich-Alexander University Erlangen-Nürnberg, D-91054 Erlangen, Germany
| | - Veit Wiesmann
- Fraunhofer-Institut für Integrierte Schaltungen, D-91058 Erlangen, Germany
| | - Elisabeth Naschberger
- Molekulare und Experimentelle Chirurgie, Universitätsklinikum Erlangen, Friedrich-Alexander Universität Erlangen-Nuremberg, D-91054 Erlangen, Germany
| | - Jana Zimmer
- Department of Infectious Diseases, University Hospital Heidelberg, D-69120 Heidelberg, Germany
| | - Stefan Wirtz
- Medizinische Klinik 1, Universitätsklinikum Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg, D-91054 Erlangen, Germany
| | - Ulrike Schleicher
- Institut für Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg, D-91054 Erlangen, Germany
| | - Julio Vera
- Laboratory of Systems Tumor Immunology, University Hospital Erlangen and Friedrich-Alexander University Erlangen-Nürnberg, D-91054 Erlangen, Germany
| | - Arif Bülent Ekici
- Institut für Humangenetik, Universitätsklinikum Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg, D-91054 Erlangen, Germany; and
| | - Alexander Dalpke
- Department of Infectious Diseases, University Hospital Heidelberg, D-69120 Heidelberg, Germany.,Institut für Medizinische Mikrobiologie und Hygiene, Technische Universität Dresden, 01307 Dresden, Germany
| | - Roland Lang
- Institut für Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg, D-91054 Erlangen, Germany;
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47
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Erokhina SA, Streltsova MA, Kanevskiy LM, Grechikhina MV, Sapozhnikov AM, Kovalenko EI. HLA-DR-expressing NK cells: Effective killers suspected for antigen presentation. J Leukoc Biol 2020; 109:327-337. [PMID: 32421903 DOI: 10.1002/jlb.3ru0420-668rr] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2019] [Revised: 04/12/2020] [Accepted: 04/14/2020] [Indexed: 12/15/2022] Open
Abstract
HLA-DR-expressing cells comprise an intriguing group of NK cells, which combine phenotypic characteristics of both NK cells and dendritic cells. These cells can be found in humans and mice; they are present in blood and tissues in healthy conditions and can expand in a spectrum of pathologies. HLA-DR+ NK cells are functionally active: they produce proinflammatory cytokines, degranulate, and easily proliferate in response to stimuli. Additionally, HLA-DR+ NK cells seem able to take in and then present certain antigens to CD4+ and CD8+ T cells, inducing their activation and proliferation, which puts them closer to professional antigen-presenting cells. It appears that these NK cells should be considerable players of the innate immune system, both due to their functional activity and regulation of the innate and adaptive immune responses. In this review, for the first time, we provide a detailed description and analysis of the available data characterizing phenotypic, developmental, and functional features of the HLA-DR+ NK cells in a healthy condition and a disease.
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Affiliation(s)
- Sofya A Erokhina
- Laboratory of Cell Interactions, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia
| | - Maria A Streltsova
- Laboratory of Cell Interactions, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia
| | - Leonid M Kanevskiy
- Laboratory of Cell Interactions, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia
| | - Maria V Grechikhina
- Laboratory of Cell Interactions, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia
| | - Alexander M Sapozhnikov
- Laboratory of Cell Interactions, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia
| | - Elena I Kovalenko
- Laboratory of Cell Interactions, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia
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48
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Maenaka A, Kenta I, Ota A, Miwa Y, Ohashi W, Horimi K, Matsuoka Y, Ohnishi M, Uchida K, Kobayashi T. Interferon-γ-induced HLA Class II expression on endothelial cells is decreased by inhibition of mTOR and HMG-CoA reductase. FEBS Open Bio 2020; 10:927-936. [PMID: 32237049 PMCID: PMC7193171 DOI: 10.1002/2211-5463.12854] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Revised: 03/10/2020] [Accepted: 03/26/2020] [Indexed: 12/15/2022] Open
Abstract
In organ transplantation, donor‐specific HLA antibody (DSA) is considered a major cause of graft rejection. Because DSA targets primarily donor‐specific human leukocyte antigen (HLA) expressed on graft endothelial cells, the prevention of its expression is a possible strategy for avoiding or salvaging DSA‐mediated graft rejection. We examined the effect of various clinically used drugs on HLA class II expression on endothelial cells. Interferon‐γ (IFN‐γ)‐induced HLA class II DR (HLA‐DR) was downregulated by everolimus (EVR, 49.1% ± 0.8%; P < 0.01) and fluvastatin (FLU, 33.8% ± 0.6%; P < 0.01). Moreover, the combination of EVR and FLU showed a greater suppressive effect on HLA‐DR expression. In contrast, cyclosporine, tacrolimus, mycophenolic acid, and prednisolone did not exhibit any significant suppressive effect. FLU, but not EVR, suppressed mRNA of HLA‐DR. Imaging analysis revealed that HLA‐DR expressed in cytosol or on the cell surface was repressed by EVR (cytosol: 58.6% ± 4.9%, P < 0.01; cell surface: 80.9% ± 4.0%, P < 0.01) and FLU (cytosol: 19.0% ± 3.4%, P < 0.01; cell surface: 48.3% ± 4.8%, P < 0.01). These data indicated that FLU and EVR suppressed IFN‐γ‐induced HLA‐DR expression at the transcriptional and post‐translational level, respectively, suggesting a potential approach for alleviating DSA‐related issues in organ transplantation.
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Affiliation(s)
- Akihiro Maenaka
- Department of Pharmacy, Aichi Medical University School of Medicine, Nagakute, Japan.,Department of Renal Transplant Surgery, Aichi Medical University School of Medicine, Nagakute, Japan
| | - Iwasaki Kenta
- Department of Kidney Disease and Transplant Immunology, Aichi Medical University School of Medicine, Nagakute, Japan
| | - Akinobu Ota
- Department of Biochemistry, Aichi Medical University School of Medicine, Nagakute, Japan
| | - Yuko Miwa
- Department of Kidney Disease and Transplant Immunology, Aichi Medical University School of Medicine, Nagakute, Japan
| | - Wataru Ohashi
- Division of Biostatistics, Clinical Research Center, Aichi Medical University School of Medicine, Nagakute, Japan
| | - Kosei Horimi
- Department of Renal Transplant Surgery, Aichi Medical University School of Medicine, Nagakute, Japan
| | - Yutaka Matsuoka
- Department of Renal Transplant Surgery, Aichi Medical University School of Medicine, Nagakute, Japan
| | - Masafumi Ohnishi
- Department of Pharmacy, Aichi Medical University School of Medicine, Nagakute, Japan
| | - Kazuharu Uchida
- Department of Kidney Disease and Transplant Immunology, Aichi Medical University School of Medicine, Nagakute, Japan
| | - Takaaki Kobayashi
- Department of Renal Transplant Surgery, Aichi Medical University School of Medicine, Nagakute, Japan
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Hou J, Chen SN, Gan Z, Li N, Huang L, Huo HJ, Yang YC, Lu Y, Yin Z, Nie P. In Primitive Zebrafish, MHC Class II Expression Is Regulated by IFN-γ, IRF1, and Two Forms of CIITA. THE JOURNAL OF IMMUNOLOGY 2020; 204:2401-2415. [DOI: 10.4049/jimmunol.1801480] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/05/2018] [Accepted: 02/13/2020] [Indexed: 12/21/2022]
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50
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Human Cytomegalovirus Decreases Major Histocompatibility Complex Class II by Regulating Class II Transactivator Transcript Levels in a Myeloid Cell Line. J Virol 2020; 94:JVI.01901-19. [PMID: 31915281 DOI: 10.1128/jvi.01901-19] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2019] [Accepted: 01/02/2020] [Indexed: 12/17/2022] Open
Abstract
Human cytomegalovirus (HCMV) is a ubiquitous pathogen that encodes many proteins to modulate the host immune response. Extensive efforts have led to the elucidation of multiple strategies employed by HCMV to effectively block NK cell targeting of virus-infected cells and the major histocompatibility complex (MHC) class I-primed CD8+ T cell response. However, viral regulation of the MHC class II-mediated CD4+ T cell response is understudied in endogenous MHC class II-expressing cells, largely because the popular cell culture systems utilized for studying HCMV do not endogenously express MHC class II. Of the many cell types infected by HCMV in the host, myeloid cells, such as monocytes, are of particular importance due to their role in latency and subsequent dissemination throughout the host. We investigated the impact of HCMV infection on MHC class II in Kasumi-3 cells, a myeloid-progenitor cell line that endogenously expresses the MHC class II gene, HLA-DR. We observed a significant reduction in the expression of surface and total HLA-DR at 72 h postinfection (hpi) and 120 hpi in infected cells. The decrease in HLA-DR expression was independent of the expression of previously described viral genes that regulate the MHC class II complex or the unique short (US) region of HCMV, a region expressing many immunomodulatory genes. The altered surface level of HLA-DR was not a result of increased endocytosis and degradation but was a result of a reduction in HLA-DR transcripts due to a decrease in the expression of the class II transactivator (CIITA).IMPORTANCE Human cytomegalovirus (HCMV) is an opportunistic herpesvirus that is asymptomatic for healthy individuals but that can lead to severe pathology in patients with congenital infections and immunosuppressed patients. Thus, it is important to understand the modulation of the immune response by HCMV, which is understudied in the context of endogenous MHC class II regulation. Using Kasumi-3 cells as a myeloid progenitor cell model endogenously expressing MHC class II (HLA-DR), this study shows that HCMV decreases the expression of HLA-DR in infected cells by reducing the transcription of HLA-DR transcripts early during infection independently of the expression of previously implicated genes. This is an important finding, as it highlights a mechanism of immune evasion utilized by HCMV to decrease the expression of MHC class II in a relevant cell system that endogenously expresses the MHC class II complex.
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