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1
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Yang L, Zheng SG. Role of regulatory T cells in inflammatory liver diseases. Autoimmun Rev 2025; 24:103806. [PMID: 40139456 DOI: 10.1016/j.autrev.2025.103806] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2024] [Revised: 03/21/2025] [Accepted: 03/21/2025] [Indexed: 03/29/2025]
Abstract
The liver is the human body's largest digestive gland, which can participate in digestion, metabolism, excretion, detoxification and immunity. Chronic liver diseases such as metabolic dysfunction-associated fatty liver disease (MAFLD) or viral hepatitis involve ongoing inflammation and resulting liver fibrosis may ultimately lead to the development of hepatobiliary cancers (HCC). Inflammation is the coordinated reaction of different liver cell types to cell signals and death of inflammation, which are linked to injury pathways within the liver or external agents from the gut-liver axis and the circulation. Regulatory T (Treg) cells play a crucial role in controlling inflammation and are essential for maintaining immune tolerance and balance. In this review, we highlight the recent discoveries related to the function of immune systems in liver inflammation and discuss the role of Treg cells in the different liver diseases (including MAFLD, autoimmune hepatitis and others).
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Affiliation(s)
- Linjie Yang
- The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan 523808, China
| | - Song Guo Zheng
- The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan 523808, China; Department of Immunology, School of Cell and Gene Therapy, Songjiang Research Institute, Shanghai Songjiang District Central Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201600, China; State Key Laboratory of Innovative Immunotherapy, Shanghai Jiao Tong University, Shanghai, 201600, China.
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2
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Takahashi H, Matsuyama T, Kawabata-Iwakawa R, Kawamoto T, Chikamatsu K. Comprehensive profiling of the heterogeneity of molecular endotypic traits in chronic rhinosinusitis. Hum Immunol 2025; 86:111267. [PMID: 39986126 DOI: 10.1016/j.humimm.2025.111267] [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: 09/06/2024] [Revised: 01/26/2025] [Accepted: 02/17/2025] [Indexed: 02/24/2025]
Abstract
Chronic rhinosinusitis (CRS) is a common clinical disease with molecular endotypes. In the present study, we performed a comprehensive transcriptomic profiling to investigate the heterogeneity of endotypes in CRS with nasal polyps (CRSwNP). The GSE23552 dataset, which includes microarray, was acquired from the Gene Expression Omnibus database. Additionally, surgical specimens were collected at Gunma University Hospital, and reverse transcription-quantitative PCR was performed. We performed gene expression analysis, Gene Set Enrichment Analysis (GSEA), deconvolution analysis, and hierarchical clustering of samples. Gene expression analysis and GSEA revealed that type 1, type 2, and Treg-related responses, were upregulated in nasal polyp tissues when compared with those in controls. Deconvolution analysis indicated the enrichment of type 1-related cells and generation of memory T cells. Furthermore, nasal polyps exhibited higher expression of effector function- and immune checkpoint-related genes than controls. In addition, hierarchical clustering revealed the heterogeneity in patients with type 2-inflamed CRSwNP. Notably, type 1 and type 2 scores correlated with the duration from surgery to biopharmaceuticals initiation. In conclusion, our study demonstrated the heterogeneity of molecular endotypes in CRSwNP. Further characterisation and stratification are required to develop a new endotype-based precision medicine for patients with CRS.
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Affiliation(s)
- Hideyuki Takahashi
- Department of Otolaryngology-Head and Neck Surgery, Gunma University Graduate School of Medicine, 3-39-22, Showa-machi, Maebashi, Gunma 371-8511, Japan.
| | - Toshiyuki Matsuyama
- Department of Otolaryngology-Head and Neck Surgery, Gunma University Graduate School of Medicine, 3-39-22, Showa-machi, Maebashi, Gunma 371-8511, Japan
| | - Reika Kawabata-Iwakawa
- Division of Integrated Oncology Research, Gunma University, Initiative for Advanced Research, 3-39-22, Showa-machi, Maebashi, Gunma 371-8511, Japan
| | - Takayuki Kawamoto
- Department of Otolaryngology-Head and Neck Surgery, Gunma University Graduate School of Medicine, 3-39-22, Showa-machi, Maebashi, Gunma 371-8511, Japan
| | - Kazuaki Chikamatsu
- Department of Otolaryngology-Head and Neck Surgery, Gunma University Graduate School of Medicine, 3-39-22, Showa-machi, Maebashi, Gunma 371-8511, Japan
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Zhang M, Yang Y, Liu J, Guo L, Guo Q, Liu W. Bone marrow immune cells and drug resistance in acute myeloid leukemia. Exp Biol Med (Maywood) 2025; 250:10235. [PMID: 40008144 PMCID: PMC11851207 DOI: 10.3389/ebm.2025.10235] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2024] [Accepted: 01/23/2025] [Indexed: 02/27/2025] Open
Abstract
In recent years, the relationship between the immunosuppressive niche of the bone marrow and therapy resistance in acute myeloid leukemia (AML) has become a research focus. The abnormal number and function of immunosuppressive cells, including regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), along with the dysfunction and exhaustion of immunological effector cells, including cytotoxic T lymphocytes (CTLs), dendritic cells (DCs) and natural killer cells (NKs), can induce immune escape of leukemia cells and are closely linked to therapy resistance in leukemia. This article reviews the research progress on the relationship between immune cells in the marrow microenvironment and chemoresistance in AML, aiming to provide new ideas for the immunotherapy of AML.
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Affiliation(s)
- Miao Zhang
- Department of Pediatrics (Hematological Oncology), Children Hematological Oncology and Birth Defects Laboratory, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
- Sichuan Clinical Research Center for Birth Defects, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - You Yang
- Department of Pediatrics (Hematological Oncology), Children Hematological Oncology and Birth Defects Laboratory, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
- Sichuan Clinical Research Center for Birth Defects, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Jing Liu
- Department of Pediatrics (Hematological Oncology), Children Hematological Oncology and Birth Defects Laboratory, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
- Sichuan Clinical Research Center for Birth Defects, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Ling Guo
- Department of Pediatrics (Hematological Oncology), Children Hematological Oncology and Birth Defects Laboratory, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
- Sichuan Clinical Research Center for Birth Defects, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Qulian Guo
- Department of Pediatrics (Hematological Oncology), Children Hematological Oncology and Birth Defects Laboratory, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
- Sichuan Clinical Research Center for Birth Defects, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Wenjun Liu
- Department of Pediatrics (Hematological Oncology), Children Hematological Oncology and Birth Defects Laboratory, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
- Sichuan Clinical Research Center for Birth Defects, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
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Alvarez F, Acuff NV, La Muraglia GM, Sabri N, Milla ME, Mooney JM, Mackey MF, Peakman M, Piccirillo CA. The IL-2 SYNTHORIN molecule promotes functionally adapted Tregs in a preclinical model of type 1 diabetes. JCI Insight 2024; 9:e182064. [PMID: 39704171 DOI: 10.1172/jci.insight.182064] [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: 04/19/2024] [Accepted: 10/25/2024] [Indexed: 12/21/2024] Open
Abstract
Deficits in IL-2 signaling can precipitate autoimmunity by altering the function and survival of FoxP3+ regulatory T cells (Tregs) while high concentrations of IL-2 fuel inflammatory responses. Recently, we showed that the non-beta IL-2 SYNTHORIN molecule SAR444336 (SAR'336) can bypass the induction of autoimmune and inflammatory responses by increasing its reliance on IL-2 receptor α chain subunit (CD25) to provide a bona fide IL-2 signal selectively to Tregs, making it an attractive approach for the control of autoimmunity. In this report, we further demonstrate that SAR'336 can support non-beta IL-2 signaling in murine Tregs and limit NK and CD8+ T cells' proliferation and function. Using a murine model of spontaneous type 1 diabetes, we showed that the administration of SAR'336 slows the development of disease in mice by decreasing the degree of insulitis through the expansion of antigen-specific Tregs over Th1 cells in pancreatic islets. Specifically, SAR'336 promoted the differentiation of IL-33-responsive (ST2+), IL-10-producing GATA3+ Tregs over other Treg subsets in the pancreas, demonstrating the ability of this molecule to further orchestrate Treg adaptation. These results offer insight into the capacity of SAR'336 to generate highly specialized, tissue-localized Tregs that promote restoration of homeostasis during ongoing autoimmune disease.
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Affiliation(s)
- Fernando Alvarez
- Department of Microbiology and Immunology, McGill University, Montreal, Quebec, Canada
- Program in Infectious Diseases and Immunology in Global Health, the Research Institute of the McGill University Health Centre (RI-MUHC), Montreal, Quebec, Canada
- Centre of Excellence in Translational Immunology (CETI), RI-MUHC, Montreal, Quebec, Canada
| | | | | | - Nazila Sabri
- Synthorx, a Sanofi company, La Jolla, California, USA
| | | | - Jill M Mooney
- Synthorx, a Sanofi company, La Jolla, California, USA
| | | | | | - Ciriaco A Piccirillo
- Department of Microbiology and Immunology, McGill University, Montreal, Quebec, Canada
- Program in Infectious Diseases and Immunology in Global Health, the Research Institute of the McGill University Health Centre (RI-MUHC), Montreal, Quebec, Canada
- Centre of Excellence in Translational Immunology (CETI), RI-MUHC, Montreal, Quebec, Canada
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Kaptein P, Slingerland N, Metoikidou C, Prinz F, Brokamp S, Machuca-Ostos M, de Roo G, Schumacher TN, Yeung YA, Moynihan KD, Djuretic IM, Thommen DS. CD8-Targeted IL2 Unleashes Tumor-Specific Immunity in Human Cancer Tissue by Reviving the Dysfunctional T-cell Pool. Cancer Discov 2024; 14:1226-1251. [PMID: 38563969 PMCID: PMC11215409 DOI: 10.1158/2159-8290.cd-23-1263] [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: 10/25/2023] [Revised: 02/05/2024] [Accepted: 03/26/2024] [Indexed: 04/04/2024]
Abstract
Tumor-specific CD8+ T cells are key effectors of antitumor immunity but are often rendered dysfunctional in the tumor microenvironment. Immune-checkpoint blockade can restore antitumor T-cell function in some patients; however, most do not respond to this therapy, often despite T-cell infiltration in their tumors. We here explored a CD8-targeted IL2 fusion molecule (CD8-IL2) to selectively reactivate intratumoral CD8+ T cells in patient-derived tumor fragments. Treatment with CD8-IL2 broadly armed intratumoral CD8+ T cells with enhanced effector capacity, thereby specifically enabling reinvigoration of the dysfunctional T-cell pool to elicit potent immune activity. Notably, the revival of dysfunctional T cells to mediate effector activity by CD8-IL2 depended on simultaneous antigen recognition and was quantitatively and qualitatively superior to that achieved by PD-1 blockade. Finally, CD8-IL2 was able to functionally reinvigorate T cells in tumors resistant to anti-PD-1, underscoring its potential as a novel treatment strategy for patients with cancer. Significance: Reinvigorating T cells is crucial for response to checkpoint blockade therapy. However, emerging evidence suggests that the PD-1/PD-L1 axis is not the sole impediment for activating T cells within tumors. Selectively targeting cytokines toward specific T-cell subsets might overcome these barriers and stimulate T cells within resistant tumors. See related article by Moynihan et al., p. 1206 (32).
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Affiliation(s)
- Paulien Kaptein
- Division of Molecular Oncology and Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
| | - Nadine Slingerland
- Division of Molecular Oncology and Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
| | - Christina Metoikidou
- Division of Molecular Oncology and Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
| | - Felix Prinz
- Division of Molecular Oncology and Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
- Division of Oncology, Department of Internal Medicine, Medical University of Graz, Graz, Austria.
| | - Simone Brokamp
- Division of Molecular Oncology and Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
| | - Mercedes Machuca-Ostos
- Division of Molecular Oncology and Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
- Division of Tumor Biology and Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
| | - Guido de Roo
- Flow Cytometry Facility, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
| | - Ton N.M. Schumacher
- Division of Molecular Oncology and Immunology, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
- Department of Hematology, Leiden University Medical Center, Leiden, the Netherlands.
| | - Yik A. Yeung
- Asher Biotherapeutics, Inc., South San Francisco, California.
| | | | | | - Daniela S. Thommen
- Division of Molecular Oncology and Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
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Zwick D, Vo MT, Shim YJ, Reijonen H, Do JS. BACH2: The Future of Induced T-Regulatory Cell Therapies. Cells 2024; 13:891. [PMID: 38891024 PMCID: PMC11172166 DOI: 10.3390/cells13110891] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Revised: 05/17/2024] [Accepted: 05/20/2024] [Indexed: 06/20/2024] Open
Abstract
BACH2 (BTB Domain and CNC Homolog 2) is a transcription factor that serves as a central regulator of immune cell differentiation and function, particularly in T and B lymphocytes. A picture is emerging that BACH2 may function as a master regulator of cell fate that is exquisitely sensitive to cell activation status. In particular, BACH2 plays a key role in stabilizing the phenotype and suppressive function of transforming growth factor-beta (TGF-β)-derived human forkhead box protein P3 (FOXP3)+ inducible regulatory T cells (iTregs), a cell type that holds great clinical potential as a cell therapeutic for diverse inflammatory conditions. As such, BACH2 potentially could be targeted to overcome the instability of the iTreg phenotype and suppressive function that has hampered their clinical application. In this review, we focus on the role of BACH2 in T cell fate and iTreg function and stability. We suggest approaches to modulate BACH2 function that may lead to more stable and efficacious Treg cell therapies.
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Affiliation(s)
- Daniel Zwick
- Frederick National Laboratory, Frederick, MD 21701, USA
| | - Mai Tram Vo
- School of Medicine, Johns Hopkins University, Baltimore, MD 21287, USA
| | - Young Jun Shim
- Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA;
| | - Helena Reijonen
- Department of Immunology and Theranostics, City of Hope, Duarte, CA 91010, USA;
| | - Jeong-su Do
- Department of Immunology and Theranostics, City of Hope, Duarte, CA 91010, USA;
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7
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Ma Y, Jiang T, Zhu X, Xu Y, Wan K, Zhang T, Xie M. Efferocytosis in dendritic cells: an overlooked immunoregulatory process. Front Immunol 2024; 15:1415573. [PMID: 38835772 PMCID: PMC11148234 DOI: 10.3389/fimmu.2024.1415573] [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: 04/10/2024] [Accepted: 05/09/2024] [Indexed: 06/06/2024] Open
Abstract
Efferocytosis, the process of engulfing and removing apoptotic cells, plays an essential role in preserving tissue health and averting undue inflammation. While macrophages are primarily known for this task, dendritic cells (DCs) also play a significant role. This review delves into the unique contributions of various DC subsets to efferocytosis, highlighting the distinctions in how DCs and macrophages recognize and handle apoptotic cells. It further explores how efferocytosis influences DC maturation, thereby affecting immune tolerance. This underscores the pivotal role of DCs in orchestrating immune responses and sustaining immune equilibrium, providing new insights into their function in immune regulation.
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Affiliation(s)
- Yanyan Ma
- Department of Emergency and Critical Care Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Tangxing Jiang
- Department of Emergency Medicine, Qilu Hospital of Shandong University, Jinan, China
| | - Xun Zhu
- Department of Emergency and Critical Care Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Yizhou Xu
- Department of Emergency and Critical Care Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Ke Wan
- Department of Emergency and Critical Care Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Tingxuan Zhang
- Department of Emergency and Critical Care Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Miaorong Xie
- Department of Emergency and Critical Care Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
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8
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Deng Z, Fan T, Xiao C, Tian H, Zheng Y, Li C, He J. TGF-β signaling in health, disease, and therapeutics. Signal Transduct Target Ther 2024; 9:61. [PMID: 38514615 PMCID: PMC10958066 DOI: 10.1038/s41392-024-01764-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Revised: 08/31/2023] [Accepted: 01/31/2024] [Indexed: 03/23/2024] Open
Abstract
Transforming growth factor (TGF)-β is a multifunctional cytokine expressed by almost every tissue and cell type. The signal transduction of TGF-β can stimulate diverse cellular responses and is particularly critical to embryonic development, wound healing, tissue homeostasis, and immune homeostasis in health. The dysfunction of TGF-β can play key roles in many diseases, and numerous targeted therapies have been developed to rectify its pathogenic activity. In the past decades, a large number of studies on TGF-β signaling have been carried out, covering a broad spectrum of topics in health, disease, and therapeutics. Thus, a comprehensive overview of TGF-β signaling is required for a general picture of the studies in this field. In this review, we retrace the research history of TGF-β and introduce the molecular mechanisms regarding its biosynthesis, activation, and signal transduction. We also provide deep insights into the functions of TGF-β signaling in physiological conditions as well as in pathological processes. TGF-β-targeting therapies which have brought fresh hope to the treatment of relevant diseases are highlighted. Through the summary of previous knowledge and recent updates, this review aims to provide a systematic understanding of TGF-β signaling and to attract more attention and interest to this research area.
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Affiliation(s)
- Ziqin Deng
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Tao Fan
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Chu Xiao
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - He Tian
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Yujia Zheng
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Chunxiang Li
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
| | - Jie He
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
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Zhang W, Lee PL, Li J, Komatsu C, Wang Y, Sun H, DeSanto M, Washington K, Gorantla V, Kokai L, Solari MG. Local Delivery of Adipose Stem Cells Promotes Allograft Survival in a Rat Hind-Limb Model of Vascularized Composite Allotransplantation. Plast Reconstr Surg 2024; 153:79e-90e. [PMID: 37014960 DOI: 10.1097/prs.0000000000010510] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/06/2023]
Abstract
BACKGROUND Adipose stem cells (ASCs) are a promising cell-based immunotherapy because of their minimally invasive harvest, high yield, and immunomodulatory capacity. In this study, the authors investigated the effects of local versus systemic ASC delivery on vascularized composite allotransplant survival and alloimmune regulation. METHODS Lewis rats received hind-limb transplants from Brown Norway rats and were administered donor-derived ASCs (passage 3 or 4, 1 × 10 6 cells/rat) locally in the allograft, or contralateral limb, or systemically at postoperative day 1. Recipients were treated intraperitoneally with rabbit anti-rat lymphocyte serum on postoperative days 1 and 4 and daily tacrolimus for 21 days. Limb allografts were monitored for clinical signs of rejection. Donor cell chimerism, immune cell differentiation, and cytokine expression in recipient lymphoid organs were measured by flow cytometric analysis. The immunomodulation function of ASCs was tested by mixed lymphocyte reaction assay and ASC stimulation studies. RESULTS Local-ASC-treated recipients achieved significant prolonged allograft survival (85.7% survived >130 days; n = 6) compared with systemic-ASC and contralateral-ASC groups. Secondary donor skin allografts transplanted to the local-ASC long-term surviving recipients accepted permanently without additional immunosuppression. The increases in donor cell chimerism and regulatory T-cells were evident in blood and draining lymph nodes of the local-ASC group. Moreover, mixed lymphocyte reaction showed that ASCs inhibited donor-specific T-cell proliferation independent of direct ASC-T-cell contact. ASCs up-regulated antiinflammatory molecules in response to cytokine stimulation in vitro. CONCLUSION Local delivery of ASCs promoted long-term survival and modulated alloimmune responses in a full major histocompatibility complex-mismatched vascularized composite allotransplantation model and was more effective than systemic administration. CLINICAL RELEVANCE STATEMENT ASCs are a readily available and abundant source of therapeutic cells that could decrease the amount of systemic immunosuppression required to maintain limb and face allografts.
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Affiliation(s)
- Wensheng Zhang
- From the Department of Plastic Surgery
- McGowan Institute for Regenerative Medicine, University of Pittsburgh
- Wilford Hall Ambulatory Surgical Center, 59th Medical Wing Office of Science and Technology, Joint Base San Antonio
| | | | - Jingjing Li
- From the Department of Plastic Surgery
- Department of Burn and Plastic Surgery, Xiangya Hospital, Central South University
| | | | - Yong Wang
- Department of Surgery, Division of Plastic and Reconstructive Surgery, University of Colorado Anschutz Medical Campus
| | | | - Marisa DeSanto
- Ohio University Heritage College of Osteopathic Medicine
| | - Kia Washington
- Department of Surgery, Division of Plastic and Reconstructive Surgery, University of Colorado Anschutz Medical Campus
| | - Vijay Gorantla
- McGowan Institute for Regenerative Medicine, University of Pittsburgh
- Institute for Regenerative Medicine, Wake Forest School of Medicine
| | - Lauren Kokai
- From the Department of Plastic Surgery
- McGowan Institute for Regenerative Medicine, University of Pittsburgh
| | - Mario G Solari
- From the Department of Plastic Surgery
- McGowan Institute for Regenerative Medicine, University of Pittsburgh
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10
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Georgiev P, Benamar M, Han S, Haigis MC, Sharpe AH, Chatila TA. Regulatory T cells in dominant immunologic tolerance. J Allergy Clin Immunol 2024; 153:28-41. [PMID: 37778472 PMCID: PMC10842646 DOI: 10.1016/j.jaci.2023.09.025] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2023] [Revised: 09/18/2023] [Accepted: 09/22/2023] [Indexed: 10/03/2023]
Abstract
Regulatory T cells expressing the transcription factor forkhead box protein 3 mediate peripheral immune tolerance both to self-antigens and to the commensal flora. Their defective function due to inborn errors of immunity or acquired insults is associated with a broad range of autoimmune and immune dysregulatory diseases. Although their function in suppressing autoimmunity and enforcing commensalism is established, a broader role for regulatory T cells in tissue repair and metabolic regulation has emerged, enabled by unique programs of tissue adaptability and specialization. In this review, we focus on the myriad roles played by regulatory T cells in immunologic tolerance and host homeostasis and the potential to harness these cells in novel therapeutic approaches to human diseases.
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Affiliation(s)
- Peter Georgiev
- Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, Mass; Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, Mass
| | - Mehdi Benamar
- Division of Immunology, Boston Children's Hospital, Boston, Mass; Department of Pediatrics, Harvard Medical School, Boston, Mass
| | - SeongJun Han
- Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, Mass; Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, Mass
| | - Marcia C Haigis
- Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, Mass
| | - Arlene H Sharpe
- Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, Mass
| | - Talal A Chatila
- Division of Immunology, Boston Children's Hospital, Boston, Mass; Department of Pediatrics, Harvard Medical School, Boston, Mass.
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11
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Han SC, Kang JI, Choi YK, Boo HJ, Yoon WJ, Kang HK, Yoo ES. Intermittent Fasting Modulates Immune Response by Generating Tregs via TGF-β Dependent Mechanisms in Obese Mice with Allergic Contact Dermatitis. Biomol Ther (Seoul) 2024; 32:136-145. [PMID: 37424516 PMCID: PMC10762271 DOI: 10.4062/biomolther.2023.053] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Revised: 05/25/2023] [Accepted: 06/14/2023] [Indexed: 07/11/2023] Open
Abstract
People with obesity maintain low levels of inflammation; therefore, their exposure to foreign antigens can trigger an excessive immune response. In people with obesity or allergic contact dermatitis (ACD), symptoms are exacerbated by a reduction in the number of regulatory T cells (Tregs) and IL-10/TGF-β-modified macrophages (M2 macrophages) at the inflammatory site. Benefits of intermittent fasting (IF) have been demonstrated for many diseases; however, the immune responses regulated by macrophages and CD4+T cells in obese ACD animal models are poorly understood. Therefore, we investigated whether IF suppresses inflammatory responses and upregulates the generation of Tregs and M2 macrophages in experimental ACD animal models of obese mice. The IF regimen relieved various ACD symptoms in inflamed and adipose tissues. We showed that the IF regimen upregulates Treg generation in a TGF-β-dependent manner and induces CD4+T cell hypo-responsiveness. IF-M2 macrophages, which strongly express TGF-β and inhibit CD4+T cell proliferation, directly regulated Treg differentiation from CD4+T cells. These results indicate that the IF regimen enhances the TGF-β-producing ability of M2 macrophages and that the development of Tregs keeps mice healthy against ACD exacerbated by obesity. Therefore, the IF regimen may ameliorate inflammatory immune disorders caused by obesity.
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Affiliation(s)
- Sang-Chul Han
- Department of Medicine, College of Medicine, Jeju National University, Jeju 63243, Republic of Korea
| | - Jung-Il Kang
- Department of Medicine, College of Medicine, Jeju National University, Jeju 63243, Republic of Korea
| | - Youn Kyung Choi
- Department of Medicine, College of Medicine, Jeju National University, Jeju 63243, Republic of Korea
| | - Hye-Jin Boo
- Department of Medicine, College of Medicine, Jeju National University, Jeju 63243, Republic of Korea
| | - Weon-Jong Yoon
- Jeju Biodiversity Research Institute (JBRI), Jeju Technopark (JTP), Jeju 63208, Republic of Korea
| | - Hee-Kyoung Kang
- Department of Medicine, College of Medicine, Jeju National University, Jeju 63243, Republic of Korea
| | - Eun-Sook Yoo
- Department of Medicine, College of Medicine, Jeju National University, Jeju 63243, Republic of Korea
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Alaei A, Mahmoudi M, Sahebari M, Vahidi Z, Tabasi N, Rastin M. The effects of Lactobacillus delbrueckii and Lactobacillus rhamnosus on cytokines and their related molecules: An ex vivo study on patients with systemic lupus erythematosus. Arch Rheumatol 2023; 38:642-652. [PMID: 38125063 PMCID: PMC10728742 DOI: 10.46497/archrheumatol.2023.9941] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Accepted: 03/05/2023] [Indexed: 12/23/2023] Open
Abstract
Objectives This study aimed to assess the ex vivo impact of Lactobacillus delbrueckii (L. delbrueckii) and Lactobacillus rhamnosus (L. rhamnosus) on inflammatory and anti-inflammatory cytokines as well as their related molecules on the peripheral blood mononuclear cells (PBMCs) of systemic lupus erythematosus (SLE) patients. Patients and methods This study was conducted with 20 newly diagnosed SLE patients (18 females, 2 males; mean age: 33.3±12.4 years; range, 18 to 68 years) between September 2017 and September 2018. Extracted PBMCs from each patient were divided into 4 cell groups in our study. Three cell groups act as treatment groups receiving L. rhamnosus (107 CFU/mL), L. delbrueckii (105 CFU/mL) or a mixture of both, and one group act as our untreated control group in the absence of any probiotic agents. All cell groups were cultured in RPMI 1460 medium for 48 h. Then, total RNA was extracted, and cDNA was synthesized. Results The gene expression levels of forkhead box P3 (FOXP3), transforming growth factor beta (TGF-β), interleukin (IL)-6, IL-10, and IL-2 were evaluated by a quantitative real-time polymerase chain reaction. The results revealed that expression levels of FOXP3, TGF-β, IL-10, and IL-2 increased and the level of IL-6 decreased in probiotics-receiving groups compared to the control group. Lactobacillus delbrueckii and L. rhamnosus enhanced the expression of regulatory T cell-related molecules such as FOXP3 and IL-2 and also increased the expression of IL-10. These probiotics also reduced the expression of IL-6 as proinflammatory cytokines in the PBMCs of SLE patients. Conclusion The results of the present study show that these probiotics could be effective in regulating the balance of cytokine gene expression ex vivo , and due to their beneficial effects, they can be an intriguing option in the production of new complement drugs for SLE.
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Affiliation(s)
- Atefeh Alaei
- Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Immunology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Student Research Committee, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mahmoud Mahmoudi
- Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Immunology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Maryam Sahebari
- Rheumatic Disease Research Center, Ghaem Hospital, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Zohreh Vahidi
- Division of Inflammation and Inflammatory Diseases, Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Nafiseh Tabasi
- Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Maryam Rastin
- Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Immunology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
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13
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Benamar M, Chen Q, Martinez-Blanco M, Chatila TA. Regulatory T cells in allergic inflammation. Semin Immunol 2023; 70:101847. [PMID: 37837939 PMCID: PMC10842049 DOI: 10.1016/j.smim.2023.101847] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/16/2023]
Abstract
Regulatory T (Treg) cells maintain immune tolerance to allergens at the environmental interfaces in the airways, skin and gut, marshalling in the process distinct immune regulatory circuits operative in the respective tissues. Treg cells are coordinately mobilized with allergic effector mechanisms in the context of a tissue-protective allergic inflammatory response against parasites, toxins and potentially harmful allergens, serving to both limit the inflammation and promote local tissue repair. Allergic diseases are associated with subverted Treg cell responses whereby a chronic allergic inflammatory environment can skew Treg cells toward pathogenic phenotypes that both perpetuate and aggravate disease. Interruption of Treg cell subversion in chronic allergic inflammatory conditions may thus provide novel therapeutic strategies by re-establishing effective immune regulation.
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Affiliation(s)
- Mehdi Benamar
- Division of Immunology, Boston Children's Hospital, Boston, MA, USA; Department of Pediatrics, Harvard Medical School, Boston, MA, USA
| | - Qian Chen
- Division of Immunology, Boston Children's Hospital, Boston, MA, USA; Department of Pediatrics, Harvard Medical School, Boston, MA, USA
| | - Monica Martinez-Blanco
- Division of Immunology, Boston Children's Hospital, Boston, MA, USA; Department of Pediatrics, Harvard Medical School, Boston, MA, USA
| | - Talal A Chatila
- Division of Immunology, Boston Children's Hospital, Boston, MA, USA; Department of Pediatrics, Harvard Medical School, Boston, MA, USA; Lead Contact, USA.
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14
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Biswas M, So K, Bertolini TB, Krishnan P, Rana J, Muñoz-Melero M, Syed F, Kumar SRP, Gao H, Xuei X, Terhorst C, Daniell H, Cao S, Herzog RW. Distinct functions and transcriptional signatures in orally induced regulatory T cell populations. Front Immunol 2023; 14:1278184. [PMID: 37954612 PMCID: PMC10637621 DOI: 10.3389/fimmu.2023.1278184] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2023] [Accepted: 10/16/2023] [Indexed: 11/14/2023] Open
Abstract
Oral administration of antigen induces regulatory T cells (Treg) that can not only control local immune responses in the small intestine, but also traffic to the central immune system to deliver systemic suppression. Employing murine models of the inherited bleeding disorder hemophilia, we find that oral antigen administration induces three CD4+ Treg subsets, namely FoxP3+LAP-, FoxP3+LAP+, and FoxP3-LAP+. These T cells act in concert to suppress systemic antibody production induced by therapeutic protein administration. Whilst both FoxP3+LAP+ and FoxP3-LAP+ CD4+ T cells express membrane-bound TGF-β (latency associated peptide, LAP), phenotypic, functional, and single cell transcriptomic analyses reveal distinct characteristics in the two subsets. As judged by an increase in IL-2Rα and TCR signaling, elevated expression of co-inhibitory receptor molecules and upregulation of the TGFβ and IL-10 signaling pathways, FoxP3+LAP+ cells are an activated form of FoxP3+LAP- Treg. Whereas FoxP3-LAP+ cells express low levels of genes involved in TCR signaling or co-stimulation, engagement of the AP-1 complex members Jun/Fos and Atf3 is most prominent, consistent with potent IL-10 production. Single cell transcriptomic analysis further reveals that engagement of the Jun/Fos transcription factors is requisite for mediating TGFβ expression. This can occur via an Il2ra dependent or independent process in FoxP3+LAP+ or FoxP3-LAP+ cells respectively. Surprisingly, both FoxP3+LAP+ and FoxP3-LAP+ cells potently suppress and induce FoxP3 expression in CD4+ conventional T cells. In this process, FoxP3-LAP+ cells may themselves convert to FoxP3+ Treg. We conclude that orally induced suppression is dependent on multiple regulatory cell types with complementary and interconnected roles.
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Affiliation(s)
- Moanaro Biswas
- Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Kaman So
- Department of Biostatistics and Health Data Science and Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Thais B. Bertolini
- Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Preethi Krishnan
- Department of Chemical and Biological Engineering, University of British Columbia, Vancouver, BC, Canada
| | - Jyoti Rana
- Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Maite Muñoz-Melero
- Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Farooq Syed
- Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Sandeep R. P. Kumar
- Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Hongyu Gao
- Center for Medical Genomics, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Xiaoling Xuei
- Center for Medical Genomics, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Cox Terhorst
- Division of Immunology, Beth Israel Deaconess Medical Center (BIDMC), Harvard Medical School, Boston, MA, United States
| | - Henry Daniell
- Department of Basic and Translational Sciences, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, United States
| | - Sha Cao
- Department of Biostatistics and Health Data Science and Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Roland W. Herzog
- Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, United States
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15
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Li J, Chen Z, Kim G, Luo J, Hori S, Wu C. Cathepsin W restrains peripheral regulatory T cells for mucosal immune quiescence. SCIENCE ADVANCES 2023; 9:eadf3924. [PMID: 37436991 DOI: 10.1126/sciadv.adf3924] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Accepted: 06/08/2023] [Indexed: 07/14/2023]
Abstract
Peripheral regulatory T (pTreg) cells are a key T cell lineage for mucosal immune tolerance and anti-inflammatory responses, and interleukin-2 receptor (IL-2R) signaling is critical for Treg cell generation, expansion, and maintenance. The expression of IL-2R on pTreg cells is tightly regulated to ensure proper induction and function of pTreg cells without a clear molecular mechanism. We here demonstrate that Cathepsin W (CTSW), a cysteine proteinase highly induced in pTreg cells under transforming growth factor-β stimulation is essential for the restraint of pTreg cell differentiation in an intrinsic manner. Loss of CTSW results in elevated pTreg cell generation, protecting the animals from intestinal inflammation. Mechanistically, CTSW inhibits IL-2R signaling in pTreg cells by cytosolic interaction with and process of CD25, repressing signal transducer and activator of transcription 5 activation to restrain pTreg cell generation and maintenance. Hence, our data indicate that CTSW acts as a gatekeeper to calibrate pTreg cell differentiation and function for mucosal immune quiescence.
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Affiliation(s)
- Jian Li
- Experimental Immunology Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA
| | - Zuojia Chen
- Experimental Immunology Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA
| | - Girak Kim
- Experimental Immunology Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA
| | - Jialie Luo
- Experimental Immunology Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA
| | - Shohei Hori
- Laboratory of Immunology and Microbiology, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan
| | - Chuan Wu
- Experimental Immunology Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA
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16
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Mani N, Andrews D, Obeng RC. Modulation of T cell function and survival by the tumor microenvironment. Front Cell Dev Biol 2023; 11:1191774. [PMID: 37274739 PMCID: PMC10232912 DOI: 10.3389/fcell.2023.1191774] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Accepted: 05/02/2023] [Indexed: 06/06/2023] Open
Abstract
Cancer immunotherapy is shifting paradigms in cancer care. T cells are an indispensable component of an effective antitumor immunity and durable clinical responses. However, the complexity of the tumor microenvironment (TME), which consists of a wide range of cells that exert positive and negative effects on T cell function and survival, makes achieving robust and durable T cell responses difficult. Additionally, tumor biology, structural and architectural features, intratumoral nutrients and soluble factors, and metabolism impact the quality of the T cell response. We discuss the factors and interactions that modulate T cell function and survive in the TME that affect the overall quality of the antitumor immune response.
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Affiliation(s)
- Nikita Mani
- Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
| | - Dathan Andrews
- Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH, United States
| | - Rebecca C. Obeng
- Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH, United States
- Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH, United States
- University Hospitals Cleveland Medical Center, Cleveland, OH, United States
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17
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Ott N, Faletti L, Heeg M, Andreani V, Grimbacher B. JAKs and STATs from a Clinical Perspective: Loss-of-Function Mutations, Gain-of-Function Mutations, and Their Multidimensional Consequences. J Clin Immunol 2023:10.1007/s10875-023-01483-x. [PMID: 37140667 DOI: 10.1007/s10875-023-01483-x] [Citation(s) in RCA: 35] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2022] [Accepted: 04/01/2023] [Indexed: 05/05/2023]
Abstract
The JAK/STAT signaling pathway plays a key role in cytokine signaling and is involved in development, immunity, and tumorigenesis for nearly any cell. At first glance, the JAK/STAT signaling pathway appears to be straightforward. However, on closer examination, the factors influencing the JAK/STAT signaling activity, such as cytokine diversity, receptor profile, overlapping JAK and STAT specificity among non-redundant functions of the JAK/STAT complexes, positive regulators (e.g., cooperating transcription factors), and negative regulators (e.g., SOCS, PIAS, PTP), demonstrate the complexity of the pathway's architecture, which can be quickly disturbed by mutations. The JAK/STAT signaling pathway has been, and still is, subject of basic research and offers an enormous potential for the development of new methods of personalized medicine and thus the translation of basic molecular research into clinical practice beyond the use of JAK inhibitors. Gain-of-function and loss-of-function mutations in the three immunologically particularly relevant signal transducers STAT1, STAT3, and STAT6 as well as JAK1 and JAK3 present themselves through individual phenotypic clinical pictures. The established, traditional paradigm of loss-of-function mutations leading to immunodeficiency and gain-of-function mutation leading to autoimmunity breaks down and a more differentiated picture of disease patterns evolve. This review is intended to provide an overview of these specific syndromes from a clinical perspective and to summarize current findings on pathomechanism, symptoms, immunological features, and therapeutic options of STAT1, STAT3, STAT6, JAK1, and JAK3 loss-of-function and gain-of-function diseases.
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Affiliation(s)
- Nils Ott
- Institute for Immunodeficiency, Center for Chronic Immunodeficiency (CCI), Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
| | - Laura Faletti
- Institute for Immunodeficiency, Center for Chronic Immunodeficiency (CCI), Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Maximilian Heeg
- Institute for Immunodeficiency, Center for Chronic Immunodeficiency (CCI), Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Division of Biological Sciences, Department of Molecular Biology, University of California, La Jolla, San Diego, CA, USA
| | - Virginia Andreani
- Institute for Immunodeficiency, Center for Chronic Immunodeficiency (CCI), Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Bodo Grimbacher
- Institute for Immunodeficiency, Center for Chronic Immunodeficiency (CCI), Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Clinic of Rheumatology and Clinical Immunology, Center for Chronic Immunodeficiency (CCI), Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- DZIF - German Center for Infection Research, Satellite Center Freiburg, Freiburg, Germany
- CIBSS - Centre for Integrative Biological Signalling Studies, University of Freiburg, Freiburg, Germany
- RESIST - Cluster of Excellence 2155 to Hanover Medical School, Satellite Center Freiburg, Freiburg, Germany
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18
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Teghanemt A, Misel-Wuchter K, Heath J, Thurman A, Pulipati P, Dixit G, Geesala R, Meyerholz DK, Maretzky T, Pezzulo A, Issuree PD. DNA demethylation fine-tunes IL-2 production during thymic regulatory T cell differentiation. EMBO Rep 2023; 24:e55543. [PMID: 36880575 PMCID: PMC10157375 DOI: 10.15252/embr.202255543] [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: 06/06/2022] [Revised: 02/10/2023] [Accepted: 02/16/2023] [Indexed: 03/08/2023] Open
Abstract
Regulatory T (T reg) cells developing in the thymus are essential to maintain tolerance and prevent fatal autoimmunity in mice and humans. Expression of the T reg lineage-defining transcription factor FoxP3 is critically dependent upon T cell receptor (TCR) and interleukin-2 (IL-2) signaling. Here, we report that ten-eleven translocation (Tet) enzymes, which are DNA demethylases, are required early during double-positive (DP) thymic T cell differentiation and prior to the upregulation of FoxP3 in CD4 single-positive (SP) thymocytes, to promote Treg differentiation. We show that Tet3 selectively controls the development of CD25- FoxP3lo CD4SP Treg cell precursors in the thymus and is critical for TCR-dependent IL-2 production, which drive chromatin remodeling at the FoxP3 locus as well as other Treg-effector gene loci in an autocrine/paracrine manner. Together, our results demonstrate a novel role for DNA demethylation in regulating the TCR response and promoting Treg cell differentiation. These findings highlight a novel epigenetic pathway to promote the generation of endogenous Treg cells for mitigation of autoimmune responses.
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Affiliation(s)
- Athmane Teghanemt
- Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, USA.,Inflammation Program, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, USA
| | - Kara Misel-Wuchter
- Inflammation Program, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, USA.,Molecular Medicine Graduate Program, Iowa City, IA, USA
| | - Jace Heath
- Inflammation Program, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, USA.,Immunology Graduate Program, Iowa City, IA, USA
| | - Andrew Thurman
- Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, USA
| | - Priyanjali Pulipati
- Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, USA.,Inflammation Program, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, USA
| | - Garima Dixit
- Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, USA.,Inflammation Program, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, USA
| | - Ramasatya Geesala
- Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, USA.,Inflammation Program, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, USA
| | | | - Thorsten Maretzky
- Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, USA.,Inflammation Program, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, USA
| | - Alejandro Pezzulo
- Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, USA
| | - Priya D Issuree
- Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, USA.,Inflammation Program, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, USA.,Molecular Medicine Graduate Program, Iowa City, IA, USA.,Immunology Graduate Program, Iowa City, IA, USA
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19
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Gomez-Bris R, Saez A, Herrero-Fernandez B, Rius C, Sanchez-Martinez H, Gonzalez-Granado JM. CD4 T-Cell Subsets and the Pathophysiology of Inflammatory Bowel Disease. Int J Mol Sci 2023; 24:2696. [PMID: 36769019 PMCID: PMC9916759 DOI: 10.3390/ijms24032696] [Citation(s) in RCA: 91] [Impact Index Per Article: 45.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Revised: 01/24/2023] [Accepted: 01/28/2023] [Indexed: 02/04/2023] Open
Abstract
Inflammatory bowel disease (IBD) is an umbrella term for the chronic immune-mediated idiopathic inflammation of the gastrointestinal tract, manifesting as Crohn's disease (CD) or ulcerative colitis (UC). IBD is characterized by exacerbated innate and adaptive immunity in the gut in association with microbiota dysbiosis and the disruption of the intestinal barrier, resulting in increased bacterial exposure. In response to signals from microorganisms and damaged tissue, innate immune cells produce inflammatory cytokines and factors that stimulate T and B cells of the adaptive immune system, and a prominent characteristic of IBD patients is the accumulation of inflammatory T-cells and their proinflammatory-associated cytokines in intestinal tissue. Upon antigen recognition and activation, CD4 T-cells differentiate towards a range of distinct phenotypes: T helper(h)1, Th2, Th9, Th17, Th22, T follicular helper (Tfh), and several types of T-regulatory cells (Treg). T-cells are generated according to and adapt to microenvironmental conditions and participate in a complex network of interactions among other immune cells that modulate the further progression of IBD. This review examines the role of the CD4 T-cells most relevant to IBD, highlighting how these cells adapt to the environment and interact with other cell populations to promote or inhibit the development of IBD.
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Affiliation(s)
- Raquel Gomez-Bris
- LamImSys Lab, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), 28041 Madrid, Spain
- Departamento de Fisiología, Facultad de Medicina, Universidad Autónoma de Madrid (UAM), 28029 Madrid, Spain
| | - Angela Saez
- LamImSys Lab, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), 28041 Madrid, Spain
- Facultad de Ciencias Experimentales, Universidad Francisco de Vitoria (UFV), 28223 Pozuelo de Alarcón, Spain
| | - Beatriz Herrero-Fernandez
- LamImSys Lab, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), 28041 Madrid, Spain
- Departamento de Fisiología, Facultad de Medicina, Universidad Autónoma de Madrid (UAM), 28029 Madrid, Spain
| | - Cristina Rius
- Department of History of Science and Information Science, School of Medicine and Dentistry, University of Valencia, 46010 Valencia, Spain
- UISYS Research Unit, University of Valencia, 46010 Valencia, Spain
- CIBER de Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain
| | - Hector Sanchez-Martinez
- LamImSys Lab, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), 28041 Madrid, Spain
| | - Jose M. Gonzalez-Granado
- LamImSys Lab, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), 28041 Madrid, Spain
- CIBER de Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain
- Department of Immunology, Ophthalmology and ENT, School of Medicine, Universidad Complutense de Madrid, 28040 Madrid, Spain
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029 Madrid, Spain
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20
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Wan S, Xu W, Xie B, Guan C, Song X. The potential of regulatory T cell-based therapies for alopecia areata. Front Immunol 2023; 14:1111547. [PMID: 37205097 PMCID: PMC10186346 DOI: 10.3389/fimmu.2023.1111547] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Accepted: 04/07/2023] [Indexed: 05/21/2023] Open
Abstract
Cytotoxic T lymphocyte has been a concern for the etiopathogenesis of alopecia areata (AA), some recent evidence suggests that the regulatory T (Treg) cell deficiency is also a contributing factor. In the lesional scalp of AA, Treg cells residing in the follicles are impaired, leading to dysregulated local immunity and hair follicle (HF) regeneration disorders. New strategies are emerging to modulate Treg cells' number and function for autoimmune diseases. There is much interest to boost Treg cells in AA patients to suppress the abnormal autoimmunity of HF and stimulate hair regeneration. With few satisfactory therapeutic regimens available for AA, Treg cell-based therapies could be the way forward. Specifically, CAR-Treg cells and novel formulations of low-dose IL-2 are the alternatives.
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Affiliation(s)
- Sheng Wan
- Department of Dermatology, Hangzhou Third People’s Hospital, Hangzhou Third Hospital Affiliated to Zhejiang Chinese Medical University, Affiliated Hangzhou Dermatology Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Wen Xu
- School of Medicine, Zhejiang University, Yuhangtang, Hangzhou, China
| | - Bo Xie
- Department of Dermatology, Hangzhou Third People’s Hospital, Hangzhou Third Hospital Affiliated to Zhejiang Chinese Medical University, Affiliated Hangzhou Dermatology Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Cuiping Guan
- Department of Dermatology, Hangzhou Third People’s Hospital, Hangzhou Third Hospital Affiliated to Zhejiang Chinese Medical University, Affiliated Hangzhou Dermatology Hospital, Zhejiang University School of Medicine, Hangzhou, China
- *Correspondence: Xiuzu Song, ; Cuiping Guan,
| | - Xiuzu Song
- Department of Dermatology, Hangzhou Third People’s Hospital, Hangzhou Third Hospital Affiliated to Zhejiang Chinese Medical University, Affiliated Hangzhou Dermatology Hospital, Zhejiang University School of Medicine, Hangzhou, China
- *Correspondence: Xiuzu Song, ; Cuiping Guan,
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21
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Rana PS, Soler DC, Kort J, Driscoll JJ. Targeting TGF-β signaling in the multiple myeloma microenvironment: Steering CARs and T cells in the right direction. Front Cell Dev Biol 2022; 10:1059715. [PMID: 36578789 PMCID: PMC9790996 DOI: 10.3389/fcell.2022.1059715] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2022] [Accepted: 11/29/2022] [Indexed: 12/14/2022] Open
Abstract
Multiple myeloma (MM) remains a lethal hematologic cancer characterized by the expansion of transformed plasma cells within the permissive bone marrow (BM) milieu. The emergence of relapsed and/or refractory MM (RRMM) is provoked through clonal evolution of malignant plasma cells that harbor genomic, metabolic and proteomic perturbations. For most patients, relapsed disease remains a major cause of overall mortality. Transforming growth factors (TGFs) have pleiotropic effects that regulate myelomagenesis as well as the emergence of drug resistance. Moreover, TGF-β modulates numerous cell types present with the tumor microenvironment, including many immune cell types. While numerous agents have been FDA-approved over the past 2 decades and significantly expanded the treatment options available for MM patients, the molecular mechanisms responsible for drug resistance remain elusive. Multiple myeloma is uniformly preceded by a premalignant state, monoclonal gammopathy of unknown significance, and both conditions are associated with progressive deregulation in host immunity characterized by reduced T cell, natural killer (NK) cell and antigen-presenting dendritic cell (DC) activity. TGF-β promotes myelomagenesis as well as intrinsic drug resistance by repressing anti-myeloma immunity to promote tolerance, drug resistance and disease progression. Hence, repression of TGF-β signaling is a prerequisite to enhance the efficacy of current and future immunotherapeutics. Novel strategies that incorporate T cells that have been modified to express chimeric antigen receptor (CARs), T cell receptors (TCRs) and bispecific T cell engagers (BiTEs) offer promise to block TGF-β signaling, overcome chemoresistance and enhance anti-myeloma immunity. Here, we describe the effects of TGF-β signaling on immune cell effectors in the bone marrow and emerging strategies to overcome TGF-β-mediated myeloma growth, drug resistance and survival.
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Affiliation(s)
- Priyanka S. Rana
- Division of Hematology and Oncology, Department of Medicine, Case Western Reserve University, Cleveland, OH, United States,Case Comprehensive Cancer Center, Cleveland, OH, United States
| | - David C. Soler
- The Brain Tumor and Neuro-Oncology Center, The Center of Excellence for Translational Neuro-Oncology, Department of Neurosurgery, Case Western Reserve University, Cleveland, OH, United States
| | - Jeries Kort
- Division of Hematology and Oncology, Department of Medicine, Case Western Reserve University, Cleveland, OH, United States,Case Comprehensive Cancer Center, Cleveland, OH, United States,Adult Hematologic Malignancies and Stem Cell Transplant Section, Seidman Cancer Center, University Hospitals Cleveland Medical Center, Cleveland, OH, United States
| | - James J. Driscoll
- Division of Hematology and Oncology, Department of Medicine, Case Western Reserve University, Cleveland, OH, United States,Case Comprehensive Cancer Center, Cleveland, OH, United States,Adult Hematologic Malignancies and Stem Cell Transplant Section, Seidman Cancer Center, University Hospitals Cleveland Medical Center, Cleveland, OH, United States,*Correspondence: James J. Driscoll,
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22
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Benamar M, Chen Q, Wang M, Chan TMF, Chatila TA. CPHEN-016: Comprehensive phenotyping of human regulatory T cells. Cytometry A 2022; 101:1006-1011. [PMID: 36165514 PMCID: PMC10031414 DOI: 10.1002/cyto.a.24692] [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: 06/16/2022] [Revised: 08/12/2022] [Accepted: 09/13/2022] [Indexed: 01/27/2023]
Abstract
Peripheral immunological tolerance is mainly maintained by regulatory T (Treg) cells, a specific CD4 T cells subset that expresses the transcription factor Foxp3. Treg cells are crucial to control autoimmunity and inflammation and to limit tissue destruction arising from inflammatory responses. Loss of functions mutations in FOXP3 in humans induces a fatal autoimmune lymphoproliferative disorder, known as Immune dysregulation, Polyendocrinopathy, Enteropathy, X-linked (IPEX). Specific Treg cell differentiation and activation states have been linked to several human diseases. Indeed, Treg cells play a crucial role in different diseases including colitis, multiple sclerosis, autoimmunity, and infection. Characterization of Treg cell functions and understanding the role of different Treg cell subsets are crucial to the development of novel Treg cell-specific therapeutics for inflammatory diseases. In this phenotype report, we will describe laboratory methods to effectively study and characterize human Treg cells.
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Affiliation(s)
- Mehdi Benamar
- Division of Immunology, Boston Children’s Hospital, Boston, Massachusetts, USA
- Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA
- Correspondence to: Mehdi Benamar
| | - Qian Chen
- Division of Immunology, Boston Children’s Hospital, Boston, Massachusetts, USA
- Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA
| | - Muyun Wang
- Division of Immunology, Boston Children’s Hospital, Boston, Massachusetts, USA
- Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA
| | - Tsz Man Fion Chan
- Division of Immunology, Boston Children’s Hospital, Boston, Massachusetts, USA
- Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA
| | - Talal A. Chatila
- Division of Immunology, Boston Children’s Hospital, Boston, Massachusetts, USA
- Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA
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23
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Chen SS, Lee D, Zhang H, Cao XH, DuPrez K. Long-term IgE immunological tolerance to peanut allergens: An alternative to Noon's daily desensitization paradigm. Cell Immunol 2022; 381:104611. [PMID: 36194940 DOI: 10.1016/j.cellimm.2022.104611] [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: 04/14/2022] [Revised: 08/29/2022] [Accepted: 09/09/2022] [Indexed: 11/28/2022]
Abstract
Herein, we show that profound afferent long-term peanut-allergen-specific IgE immunological tolerance for 3 to 9 months induced sustained unresponsiveness (SU) in naïve or peanut-sensitized rodents after peanut allergen immunization. Rodents were vaccinated sublingually with a peanut allergen extract or recombinant peanut allergen in chenodeoxycholate (CDCA), a fanesoid X receptor (FXR, NR1H4) agonist that downregulates SREBP-1c (sterol regulatory element binding protein-1c) and upregulates SHP in bone marrow-derived tolerogenic dendritic cells (DCs). Approximately 90 ∼ 95 % of the total circulating PE-potentiated IgE and Ara h1, Ara h 2, and Ara h 6 peanut allergen-specific IgE responses were suppressed by recombinant peanut allergen-conjugated solid magnetic beads (sensitivity of 0.2 IU/ml). In contrast, peanut allergen-specific IgG production was not affected. Similarly, oleoylethanolamine (OEA), a peroxisome proliferator-activator receptor alpha (PPARα) agonist, and GW9662, a PPARγ antagonist, induced long-term peanut-specific IgE tolerance when administered via the sublingual, oral or i.p. route. Prophylactic Ara h2 DNA immunization with caNRF2 and IL-35 coexpression induced Ara h2 IgE tolerance. In summary, peanut allergen vaccination with select natural molecular ligands of nuclear receptors induced long-term peanut allergen-specific IgE tolerance via the afferent limb, which indicates that vaccination is an immune tolerance-promoting strategy that is effective at the DC level and that differs from Noon's daily desensitization program, which is effective at the mast cell level.
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Affiliation(s)
- Swey-Shen Chen
- Division of Vaccinology and Immunotherapy, IGE Therapeutics Inc., 10225 Barnes Canyon Road, Suite A106, San Diego, CA 92121, United States; Department of Immunology and Cell Biology, Institute of Genetics, 10225 Barnes Canyon Road, Suite A106, San Diego, CA 92121, United States; Department of Immunoregulation and Immunotherapy, AAIIT LLC, 12528 Kirkham Ct, STE 8, Poway, CA 92064, United States.
| | - David Lee
- Division of Vaccinology and Immunotherapy, IGE Therapeutics Inc., 10225 Barnes Canyon Road, Suite A106, San Diego, CA 92121, United States
| | - Hailan Zhang
- Division of Vaccinology and Immunotherapy, IGE Therapeutics Inc., 10225 Barnes Canyon Road, Suite A106, San Diego, CA 92121, United States; Department of Immunoregulation and Immunotherapy, AAIIT LLC, 12528 Kirkham Ct, STE 8, Poway, CA 92064, United States
| | - Xi-Hua Cao
- Division of Vaccinology and Immunotherapy, IGE Therapeutics Inc., 10225 Barnes Canyon Road, Suite A106, San Diego, CA 92121, United States
| | - Kevin DuPrez
- Division of Vaccinology and Immunotherapy, IGE Therapeutics Inc., 10225 Barnes Canyon Road, Suite A106, San Diego, CA 92121, United States
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24
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Abstract
Inflammation is a biological process that dynamically alters the surrounding microenvironment, including participating immune cells. As a well-protected organ surrounded by specialized barriers and with immune privilege properties, the central nervous system (CNS) tightly regulates immune responses. Yet in neuroinflammatory conditions, pathogenic immunity can disrupt CNS structure and function. T cells in particular play a key role in promoting and restricting neuroinflammatory responses, while the inflamed CNS microenvironment can influence and reshape T cell function and identity. Still, the contraction of aberrant T cell responses within the CNS is not well understood. Using autoimmunity as a model, here we address the contribution of CD4 T helper (Th) cell subsets in promoting neuropathology and disease. To address the mechanisms antagonizing neuroinflammation, we focus on the control of the immune response by regulatory T cells (Tregs) and describe the counteracting processes that preserve their identity under inflammatory challenges. Finally, given the influence of the local microenvironment on immune regulation, we address how CNS-intrinsic signals reshape T cell function to mitigate abnormal immune T cell responses.
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Affiliation(s)
- Nail Benallegue
- Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104
- Nantes Université, CHU Nantes, INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, F-44000, Nantes, France
| | - Hania Kebir
- Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104
| | - Jorge I. Alvarez
- Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104
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25
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Martínez-Méndez D, Huerta L, Villarreal C. Modeling the effect of environmental cytokines, nutrient conditions and hypoxia on CD4+ T cell differentiation. Front Immunol 2022; 13:962175. [PMID: 36211418 PMCID: PMC9539201 DOI: 10.3389/fimmu.2022.962175] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Accepted: 08/05/2022] [Indexed: 11/13/2022] Open
Abstract
Upon antigen stimulation and co-stimulation, CD4+ T lymphocytes produce soluble factors that promote the activity of other immune cells against pathogens or modified tissues; this task must be performed in presence of a variety of environmental cytokines, nutrient, and oxygen conditions, which necessarily impact T cell function. The complexity of the early intracellular processes taking place upon lymphocyte stimulation is addressed by means of a mathematical model based on a network that integrates variable microenvironmental conditions with intracellular activating, regulatory, and metabolic signals. Besides the phenotype subsets considered in previous works (Th1, Th2, Th17, and Treg) the model includes the main early events in differentiation to the TFH phenotype. The model describes how cytokines, nutrients and oxygen availability regulate the differentiation of naïve CD4+ T cells into distinct subsets. Particularly, it shows that elevated amounts of an all-type mixture of effector cytokines under optimal nutrient and oxygen availability conduces the system towards a highly-polarized Th1 or Th2 state, while reduced cytokine levels allow the expression of the Th17, Treg or TFH subsets, or even hybrid phenotypes. On the other hand, optimal levels of an all-type cytokine mixture in combination with glutamine or tryptophan restriction implies a shift from Th1 to Th2 expression, while decreased levels of the Th2-inducing cytokine IL-4 leads to the rupture of the Th1-Th2 axis, allowing the manifestation of different (or hybrid) subsets. Modeling proposes that, even under reduced levels of pro-inflammatory cytokines, the sole action of hypoxia boost Th17 expression.
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Affiliation(s)
| | - Leonor Huerta
- Instituto de Investigaciones Biomédicas, Departamento de Inmunología, Universidad Nacional Autónoma de México, Mexico City, Mexico
- *Correspondence: Carlos Villarreal, ; Leonor Huerta,
| | - Carlos Villarreal
- Instituto de Física, Universidad Nacional Autónoma de México, Mexico City, Mexico
- *Correspondence: Carlos Villarreal, ; Leonor Huerta,
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26
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Raugh A, Allard D, Bettini M. Nature vs. nurture: FOXP3, genetics, and tissue environment shape Treg function. Front Immunol 2022; 13:911151. [PMID: 36032083 PMCID: PMC9411801 DOI: 10.3389/fimmu.2022.911151] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2022] [Accepted: 07/11/2022] [Indexed: 12/11/2022] Open
Abstract
The importance of regulatory T cells (Tregs) in preventing autoimmunity has been well established; however, the precise alterations in Treg function in autoimmune individuals and how underlying genetic associations impact the development and function of Tregs is still not well understood. Polygenetic susceptibly is a key driving factor in the development of autoimmunity, and many of the pathways implicated in genetic association studies point to a potential alteration or defect in regulatory T cell function. In this review transcriptomic control of Treg development and function is highlighted with a focus on how these pathways are altered during autoimmunity. In combination, observations from autoimmune mouse models and human patients now provide insights into epigenetic control of Treg function and stability. How tissue microenvironment influences Treg function, lineage stability, and functional plasticity is also explored. In conclusion, the current efficacy and future direction of Treg-based therapies for Type 1 Diabetes and other autoimmune diseases is discussed. In total, this review examines Treg function with focuses on genetic, epigenetic, and environmental mechanisms and how Treg functions are altered within the context of autoimmunity.
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Affiliation(s)
- Arielle Raugh
- Department of Pathology, Microbiology and Immunology, University of Utah, Salt Lake City, UT, United States
- Translational Biology and Molecular Medicine Graduate Program, Baylor College of Medicine, Houston, TX, United States
| | - Denise Allard
- Department of Pathology, Microbiology and Immunology, University of Utah, Salt Lake City, UT, United States
| | - Maria Bettini
- Department of Pathology, Microbiology and Immunology, University of Utah, Salt Lake City, UT, United States
- *Correspondence: Maria Bettini,
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27
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Bellini R, Bonacina F, Norata GD. Crosstalk between dendritic cells and T lymphocytes during atherogenesis: Focus on antigen presentation and break of tolerance. Front Cardiovasc Med 2022; 9:934314. [PMID: 35966516 PMCID: PMC9365967 DOI: 10.3389/fcvm.2022.934314] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Accepted: 07/05/2022] [Indexed: 12/14/2022] Open
Abstract
Atherosclerosis is a chronic disease resulting from an impaired lipid and immune homeostasis, where the interaction between innate and adaptive immune cells leads to the promotion of atherosclerosis-associated immune-inflammatory response. Emerging evidence has suggested that this response presents similarities to the reactivity of effector immune cells toward self-epitopes, often as a consequence of a break of tolerance. In this context, dendritic cells, a heterogeneous population of antigen presenting cells, play a key role in instructing effector T cells to react against foreign antigens and T regulatory cells to maintain tolerance against self-antigens and/or to patrol for self-reactive effector T cells. Alterations in this delicate balance appears to contribute to atherogenesis. The aim of this review is to discuss different DC subsets, and their role in atherosclerosis as well as in T cell polarization. Moreover, we will discuss how loss of T cell tolerogenic phenotype participates to the immune-inflammatory response associated to atherosclerosis and how a better understanding of these mechanisms might result in designing immunomodulatory therapies targeting DC-T cell crosstalk for the treatment of atherosclerosis-related inflammation.
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Affiliation(s)
- Rossella Bellini
- Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy
| | - Fabrizia Bonacina
- Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy
- *Correspondence: Fabrizia Bonacina,
| | - Giuseppe Danilo Norata
- Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy
- Center for the Study of Atherosclerosis, E. Bassini Hospital, Cinisello Balsamo, Milan, Italy
- Giuseppe Danilo Norata,
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28
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Malko D, Elmzzahi T, Beyer M. Implications of regulatory T cells in non-lymphoid tissue physiology and pathophysiology. Front Immunol 2022; 13:954798. [PMID: 35936011 PMCID: PMC9354719 DOI: 10.3389/fimmu.2022.954798] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Accepted: 06/29/2022] [Indexed: 11/26/2022] Open
Abstract
Treg cells have been initially described as gatekeepers for the control of autoimmunity, as they can actively suppress the activity of other immune cells. However, their role goes beyond this as Treg cells further control immune responses during infections and tumor development. Furthermore, Treg cells can acquire additional properties for e.g., the control of tissue homeostasis. This is instructed by a specific differentiation program and the acquisition of effector properties unique to Treg cells in non-lymphoid tissues. These tissue Treg cells can further adapt to their tissue environment and acquire distinct functional properties through specific transcription factors activated by a combination of tissue derived factors, including tissue-specific antigens and cytokines. In this review, we will focus on recent findings extending our current understanding of the role and differentiation of these tissue Treg cells. As such we will highlight the importance of tissue Treg cells for tissue maintenance, regeneration, and repair in adipose tissue, muscle, CNS, liver, kidney, reproductive organs, and the lung.
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Affiliation(s)
- Darya Malko
- Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC, Australia
- Immunogenomics and Neurodegeneration, Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Bonn, Germany
| | - Tarek Elmzzahi
- Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC, Australia
- Immunogenomics and Neurodegeneration, Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Bonn, Germany
| | - Marc Beyer
- Immunogenomics and Neurodegeneration, Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Bonn, Germany
- Platform foR SinglE Cell GenomIcS and Epigenomics (PRECISE), Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE) and University of Bonn, Bonn, Germany
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29
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Bednar KJ, Lee JH, Ort T. Tregs in Autoimmunity: Insights Into Intrinsic Brake Mechanism Driving Pathogenesis and Immune Homeostasis. Front Immunol 2022; 13:932485. [PMID: 35844555 PMCID: PMC9280893 DOI: 10.3389/fimmu.2022.932485] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Accepted: 05/16/2022] [Indexed: 11/16/2022] Open
Abstract
CD4+CD25highFoxp3+ regulatory T-cells (Tregs) are functionally characterized for their ability to suppress the activation of multiple immune cell types and are indispensable for maintaining immune homeostasis and tolerance. Disruption of this intrinsic brake system assessed by loss of suppressive capacity, cell numbers, and Foxp3 expression, leads to uncontrolled immune responses and tissue damage. The conversion of Tregs to a pathogenic pro-inflammatory phenotype is widely observed in immune mediated diseases. However, the molecular mechanisms that underpin the control of Treg stability and suppressive capacity are incompletely understood. This review summarizes the concepts of Treg cell stability and Treg cell plasticity highlighting underlying mechanisms including translational and epigenetic regulators that may enable translation to new therapeutic strategies. Our enhanced understanding of molecular mechanism controlling Tregs will have important implications into immune homeostasis and therapeutic potential for the treatment of immune-mediated diseases.
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30
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Liu W, Fan M, Lu W, Zhu W, Meng L, Lu S. Emerging Roles of T Helper Cells in Non-Infectious Neuroinflammation: Savior or Sinner. Front Immunol 2022; 13:872167. [PMID: 35844577 PMCID: PMC9280647 DOI: 10.3389/fimmu.2022.872167] [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: 02/09/2022] [Accepted: 05/30/2022] [Indexed: 12/03/2022] Open
Abstract
CD4+ T cells, also known as T helper (Th) cells, contribute to the adaptive immunity both in the periphery and in the central nervous system (CNS). At least seven subsets of Th cells along with their signature cytokines have been identified nowadays. Neuroinflammation denotes the brain’s immune response to inflammatory conditions. In recent years, various CNS disorders have been related to the dysregulation of adaptive immunity, especially the process concerning Th cells and their cytokines. However, as the functions of Th cells are being discovered, it’s also found that their roles in different neuroinflammatory conditions, or even the participation of a specific Th subset in one CNS disorder may differ, and sometimes contrast. Based on those recent and contradictory evidence, the conflicting roles of Th cells in multiple sclerosis, Alzheimer’s disease, Parkinson’s disease, epilepsy, traumatic brain injury as well as some typical mental disorders will be reviewed herein. Research progress, limitations and novel approaches concerning different neuroinflammatory conditions will also be mentioned and compared.
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Affiliation(s)
- Wenbin Liu
- Institute of Molecular and Translational Medicine, and Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, Xi’an, China
- Department of Neurosurgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Meiyang Fan
- Institute of Molecular and Translational Medicine, and Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, Xi’an, China
| | - Wen Lu
- Department of Psychiatry, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Wenhua Zhu
- Institute of Molecular and Translational Medicine, and Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, Xi’an, China
- National Joint Engineering Research Center of Biodiagnostics and Biotherapy, Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, China
- *Correspondence: Wenhua Zhu, ; Liesu Meng,
| | - Liesu Meng
- Institute of Molecular and Translational Medicine, and Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, Xi’an, China
- National Joint Engineering Research Center of Biodiagnostics and Biotherapy, Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, China
- Key Laboratory of Environment and Genes Related to Diseases (Xi’an Jiaotong University), Ministry of Education, Xi’an, China
- *Correspondence: Wenhua Zhu, ; Liesu Meng,
| | - Shemin Lu
- Institute of Molecular and Translational Medicine, and Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, Xi’an, China
- National Joint Engineering Research Center of Biodiagnostics and Biotherapy, Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, China
- Key Laboratory of Environment and Genes Related to Diseases (Xi’an Jiaotong University), Ministry of Education, Xi’an, China
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31
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Radovani B, Gudelj I. N-Glycosylation and Inflammation; the Not-So-Sweet Relation. Front Immunol 2022; 13:893365. [PMID: 35833138 PMCID: PMC9272703 DOI: 10.3389/fimmu.2022.893365] [Citation(s) in RCA: 61] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Accepted: 05/30/2022] [Indexed: 12/28/2022] Open
Abstract
Chronic inflammation is the main feature of many long-term inflammatory diseases such as autoimmune diseases, metabolic disorders, and cancer. There is a growing number of studies in which alterations of N-glycosylation have been observed in many pathophysiological conditions, yet studies of the underlying mechanisms that precede N-glycome changes are still sparse. Proinflammatory cytokines have been shown to alter the substrate synthesis pathways as well as the expression of glycosyltransferases required for the biosynthesis of N-glycans. The resulting N-glycosylation changes can further contribute to disease pathogenesis through modulation of various aspects of immune cell processes, including those relevant to pathogen recognition and fine-tuning the inflammatory response. This review summarizes our current knowledge of inflammation-induced N-glycosylation changes, with a particular focus on specific subsets of immune cells of innate and adaptive immunity and how these changes affect their effector functions, cell interactions, and signal transduction.
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Affiliation(s)
- Barbara Radovani
- Department of Biotechnology, University of Rijeka, Rijeka, Croatia
| | - Ivan Gudelj
- Department of Biotechnology, University of Rijeka, Rijeka, Croatia
- Genos Glycoscience Research Laboratory, Zagreb, Croatia
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32
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Small extracellular vesicles derived from PD-L1-modified mesenchymal stem cell promote Tregs differentiation and prolong allograft survival. Cell Tissue Res 2022; 389:465-481. [PMID: 35688948 DOI: 10.1007/s00441-022-03650-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Accepted: 06/02/2022] [Indexed: 11/02/2022]
Abstract
We aimed to explore whether programmed cell death protein-1 ligand (PD-L1) modification on small extracellular vesicles (sEVs) could promote T regulatory cells (Tregs) differentiation. In this study, it was confirmed that under physiological conditions, PD-L1 expression was minimal in the MSCs and absent in the MSC-sEVs. A vector harboring the PD-L1 gene was constructed and transfected into bone marrow mesenchymal stem cells (BM-MSCs). By extracting the sEVs of these modified BM-MSCs and monitoring the expression of the PD-L1 protein, however, PD-L1 expression was substantially increased in the MSCs and concentrated in the sEVs. Then, the rat naïve CD4 + T cells were cocultured with the sEVs derived from the PD-L1-modified MSCs (sEVsPD-L1). By flow cytometry, a higher percentage of Tregs and anti-inflammatory downstream cytokines (including IL-2, IFN-γ, TGF-β, IL-10) was detected in the sEVsPD-L1 group than that in the control group treated by either sEVs in wild type, modified by empty vector, or blank control. Suppressive effect on CD4 + T cell proliferation serves as additional evidence to support the immunoregulation capacity of sEVsPD-L1. The animal model of vascularized composite allograft further confirmed that PD-L1-modified sEVs induce an immune tolerance, by clinically observation, histopathology, T cell fate and cell product. In conclusion, sEVsPD-L1 efficiently promotes Treg cell differentiation in vitro and in vivo, which suggests their therapeutic potential in the treatment of allograft rejection.
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33
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Jung K, Pawluk MA, Lane M, Nabai L, Granville DJ. Granzyme B in Epithelial Barrier Dysfunction and Related Skin Diseases. Am J Physiol Cell Physiol 2022; 323:C170-C189. [PMID: 35442832 DOI: 10.1152/ajpcell.00052.2022] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
The predominant function of the skin is to serve as a barrier - to protect against external insults and to prevent water loss. Junctional and structural proteins in the stratum corneum, the outermost layer of the epidermis, are critical to the integrity of the epidermal barrier as it balances ongoing outward migration, differentiation, and desquamation of keratinocytes in the epidermis. As such, epidermal barrier function is highly susceptible to upsurges of proteolytic activity in the stratum corneum and epidermis. Granzyme B is a serine protease scarce in healthy tissues but present at high levels in tissues encumbered by chronic inflammation. Discovered in the 1980s, Granzyme B is currently recognized for its intracellular roles in immune cell-mediated targeted apoptosis as well as extracellular roles in inflammation, chronic injuries, tissue remodeling, and processing of cytokines, matrix proteins, and autoantigens. Increasing evidence has emerged in recent years supporting a role for Granzyme B in promoting barrier dysfunction in the epidermis by direct cleavage of barrier proteins and eliciting immunoreactivity. Likewise, Granzyme B contributes to impaired epithelial function of the airways, retina, gut and vessels. In the present review, the role of Granzyme B in cutaneous epithelial dysfunction is discussed in the context of specific conditions with an overview of underlying mechanisms as well as utility of current experimental and therapeutic inhibitors.
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Affiliation(s)
- Karen Jung
- International Collaboration on Repair Discoveries (ICORD), Vancouver Coastal Health Research Institute (VCHRI), University of British Columbia (UBC), Vancouver, BC, Canada.,Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada.,British Columbia Professional Firefighters' Wound Healing Laboratory, VCHRI, Vancouver, British Columbia, Canada
| | - Megan A Pawluk
- International Collaboration on Repair Discoveries (ICORD), Vancouver Coastal Health Research Institute (VCHRI), University of British Columbia (UBC), Vancouver, BC, Canada.,Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada.,British Columbia Professional Firefighters' Wound Healing Laboratory, VCHRI, Vancouver, British Columbia, Canada
| | - Michael Lane
- International Collaboration on Repair Discoveries (ICORD), Vancouver Coastal Health Research Institute (VCHRI), University of British Columbia (UBC), Vancouver, BC, Canada.,Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada.,British Columbia Professional Firefighters' Wound Healing Laboratory, VCHRI, Vancouver, British Columbia, Canada
| | - Layla Nabai
- International Collaboration on Repair Discoveries (ICORD), Vancouver Coastal Health Research Institute (VCHRI), University of British Columbia (UBC), Vancouver, BC, Canada.,Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada.,British Columbia Professional Firefighters' Wound Healing Laboratory, VCHRI, Vancouver, British Columbia, Canada
| | - David J Granville
- International Collaboration on Repair Discoveries (ICORD), Vancouver Coastal Health Research Institute (VCHRI), University of British Columbia (UBC), Vancouver, BC, Canada.,Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada.,British Columbia Professional Firefighters' Wound Healing Laboratory, VCHRI, Vancouver, British Columbia, Canada
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34
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Abstract
The transforming growth factor-β (TGF-β) family includes cytokines controlling cell behavior, differentiation and homeostasis of various tissues including components of the immune system. Despite well recognized importance of TGF-β in controlling T cell functions, the immunomodulatory roles of many other members of the TGF-β cytokine family, especially bone morphogenetic proteins (BMPs), start to emerge. Bone Morphogenic Protein Receptor 1α (BMPR1α) is upregulated by activated effector and Foxp3+ regulatory CD4+ T cells (Treg cells) and modulates functions of both of these cell types. BMPR1α inhibits generation of proinflammatory Th17 cells and sustains peripheral Treg cells. This finding underscores the importance of the BMPs in controlling Treg cell plasticity and transition between Treg and Th cells. BMPR1α deficiency in in vitro induced and peripheral Treg cells led to upregulation of Kdm6b (Jmjd3) demethylase, an antagonist of polycomb repressive complex 2 (PRC2), and cell cycle inhibitor Cdkn1a (p21Cip1) promoting cell senescence. This indicates that BMPs and BMPR1α may represent regulatory modules shaping epigenetic landscape and controlling proinflammatory reprogramming of Th and Treg cells. Revealing functions of other BMP receptors and their crosstalk with receptors for TGF-β will contribute to our understanding of peripheral immunoregulation.
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Affiliation(s)
- Piotr Kraj
- Department of Biological Sciences, Old Dominion University, Norfolk, VA, United States
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35
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Reduced vitamin D receptor (VDR) and cathelicidin antimicrobial peptide (CAMP) gene expression contribute to the maintenance of inflammatory immune response in leprosy patients. Microbes Infect 2022; 24:104981. [DOI: 10.1016/j.micinf.2022.104981] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Revised: 03/17/2022] [Accepted: 04/11/2022] [Indexed: 11/18/2022]
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Qin Y, Gao C, Luo J. Metabolism Characteristics of Th17 and Regulatory T Cells in Autoimmune Diseases. Front Immunol 2022; 13:828191. [PMID: 35281063 PMCID: PMC8913504 DOI: 10.3389/fimmu.2022.828191] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Accepted: 02/07/2022] [Indexed: 12/12/2022] Open
Abstract
The abnormal number and functional deficiency of immune cells are the pathological basis of various diseases. Recent years, the imbalance of Th17/regulatory T (Treg) cell underlies the occurrence and development of inflammation in autoimmune diseases (AID). Currently, studies have shown that material and energy metabolism is essential for maintaining cell survival and normal functions and the altered metabolic state of immune cells exists in a variety of AID. This review summarizes the biology and functions of Th17 and Treg cells in AID, with emphasis on the advances of the roles and regulatory mechanisms of energy metabolism in activation, differentiation and physiological function of Th17 and Treg cells, which will facilitate to provide targets for the treatment of immune-mediated diseases.
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Affiliation(s)
- Yan Qin
- Department of Rheumatology, The Second Hospital of Shanxi Medical University, Taiyuan, China
| | - Chong Gao
- Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
| | - Jing Luo
- Department of Rheumatology, The Second Hospital of Shanxi Medical University, Taiyuan, China
- *Correspondence: Jing Luo,
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Wang WL, Ouyang C, Graham NM, Zhang Y, Cassady K, Reyes EY, Xiong M, Davis AM, Tang K, Zeng D, Boldin MP. microRNA-142 guards against autoimmunity by controlling Treg cell homeostasis and function. PLoS Biol 2022; 20:e3001552. [PMID: 35180231 PMCID: PMC8893712 DOI: 10.1371/journal.pbio.3001552] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Revised: 03/03/2022] [Accepted: 01/21/2022] [Indexed: 01/10/2023] Open
Abstract
Regulatory T (Treg) cells are critical in preventing aberrant immune responses. Posttranscriptional control of gene expression by microRNA (miRNA) has recently emerged as an essential genetic element for Treg cell function. Here, we report that mice with Treg cell-specific ablation of miR-142 (hereafter Foxp3CremiR-142fl/fl mice) developed a fatal systemic autoimmune disorder due to a breakdown in peripheral T-cell tolerance. Foxp3CremiR-142fl/fl mice displayed a significant decrease in the abundance and suppressive capacity of Treg cells. Expression profiling of miR-142-deficient Treg cells revealed an up-regulation of multiple genes in the interferon gamma (IFNγ) signaling network. We identified several of these IFNγ-associated genes as direct miR-142-3p targets and observed excessive IFNγ production and signaling in miR-142-deficient Treg cells. Ifng ablation rescued the Treg cell homeostatic defect and alleviated development of autoimmunity in Foxp3CremiR-142fl/fl mice. Thus, our findings implicate miR-142 as an indispensable regulator of Treg cell homeostasis that exerts its function by attenuating IFNγ responses.
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Affiliation(s)
- Wei-Le Wang
- Irell and Manella Graduate School of Biological Sciences, Beckman Research Institute, City of Hope, Duarte, California, United States of America
- Department of Systems Biology, Beckman Research Institute, City of Hope, Duarte, California, United States of America
| | - Ching Ouyang
- Center for Informatics, Beckman Research Institute, City of Hope, Duarte, California, United States of America
- Department of Computational and Quantitative Medicine, Beckman Research Institute, City of Hope, Duarte, California, United States of America
| | - Natalie M. Graham
- Irell and Manella Graduate School of Biological Sciences, Beckman Research Institute, City of Hope, Duarte, California, United States of America
- Department of Systems Biology, Beckman Research Institute, City of Hope, Duarte, California, United States of America
| | - Yuankun Zhang
- Department of Diabetes Research, Beckman Research Institute, City of Hope, Duarte, California, United States of America
| | - Kaniel Cassady
- Irell and Manella Graduate School of Biological Sciences, Beckman Research Institute, City of Hope, Duarte, California, United States of America
- Department of Diabetes Research, Beckman Research Institute, City of Hope, Duarte, California, United States of America
| | - Estefany Y. Reyes
- Department of Systems Biology, Beckman Research Institute, City of Hope, Duarte, California, United States of America
| | - Min Xiong
- Irell and Manella Graduate School of Biological Sciences, Beckman Research Institute, City of Hope, Duarte, California, United States of America
- Department of Systems Biology, Beckman Research Institute, City of Hope, Duarte, California, United States of America
| | - Alicia M. Davis
- Irell and Manella Graduate School of Biological Sciences, Beckman Research Institute, City of Hope, Duarte, California, United States of America
| | - Kathie Tang
- Department of Systems Biology, Beckman Research Institute, City of Hope, Duarte, California, United States of America
| | - Defu Zeng
- Irell and Manella Graduate School of Biological Sciences, Beckman Research Institute, City of Hope, Duarte, California, United States of America
- Department of Diabetes Research, Beckman Research Institute, City of Hope, Duarte, California, United States of America
| | - Mark P. Boldin
- Irell and Manella Graduate School of Biological Sciences, Beckman Research Institute, City of Hope, Duarte, California, United States of America
- Department of Systems Biology, Beckman Research Institute, City of Hope, Duarte, California, United States of America
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Dai C, Zhou X, Wang L, Tan R, Wang W, Yang B, Zhang Y, Shi H, Chen D, Wei L, Chen Z. Rocaglamide Prolonged Allograft Survival by Inhibiting Differentiation of Th1/Th17 Cells in Cardiac Transplantation. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:2048095. [PMID: 35087613 PMCID: PMC8787457 DOI: 10.1155/2022/2048095] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Accepted: 10/13/2021] [Indexed: 11/17/2022]
Abstract
BACKGROUND Aglaia (Meliaceae) species are used for treating autoimmune disorders and allergic diseases in Asian countries. Rocaglamide, an extract obtained from Aglaia species, exhibits suppressive effect by regulating the T cell subset balance and cytokine network in cancer. However, whether it can be used in organ transplantation is unknown. In this study, we investigated the antirejection effect and mechanism of action of rocaglamide in a mouse cardiac allograft model. METHODS Survival studies were performed by administering mice with phosphate-buffered saline (PBS) (n = 6) and rocaglamide (n = 8). Heart grafts were monitored until they stopped beating. After grafting, the mice were sacrificed on day 7 for histological, mixed lymphocyte reaction (MLR), enzyme-linked immunosorbent assay (ELISA), and flow cytometric analyses. RESULTS Rocaglamide administration significantly prolonged the median survival of the grafts from 7 to 25 days compared with PBS treatment (P < 0.001). On posttransplantation day 7, the rocaglamide-treated group showed a significant decrease in the percentage of Th1 cells (7.9 ± 0.9% vs. 1.58 ± 0.5%, P < 0.001) in the lymph nodes and spleen (8.0 ± 2.5% vs. 2.4 ± 1.3%, P < 0.05). Rocaglamide treatment also significantly inhibited the production of Th17 cells (6.4 ± 1.0% vs. 1.8 ± 0.4%, P < 0.01) in the lymph nodes and spleen (5.9 ± 0.3% vs. 2.9 ± 0.8%, P < 0.01). Furthermore, the prolonged survival of the grafts was associated with a significant decrease in IFN-γ and IL-17 levels. Our results also showed that NF-AT activation was inhibited by rocaglamide, which also induced p38 and Jun N-terminal kinase (JNK) phosphorylation in Jurkat T cells. Furthermore, by using inhibitors that suppressed p38 and JNK phosphorylation, rocaglamide-mediated reduction in NF-AT protein levels was prevented. CONCLUSION We identified a new immunoregulatory property of rocaglamide, wherein it was found to regulate oxidative stress response and reduce inflammatory cell infiltration and organ injury, which have been associated with the inhibition of NF-AT activation in T cells.
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Affiliation(s)
- Chen Dai
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology; Key Laboratory of Organ Transplantation, Ministry of Education; NHC Key Laboratory of Organ Transplantation; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China 430030
| | - Xi Zhou
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology; Key Laboratory of Organ Transplantation, Ministry of Education; NHC Key Laboratory of Organ Transplantation; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China 430030
| | - Lu Wang
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology; Key Laboratory of Organ Transplantation, Ministry of Education; NHC Key Laboratory of Organ Transplantation; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China 430030
| | - Rumeng Tan
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology; Key Laboratory of Organ Transplantation, Ministry of Education; NHC Key Laboratory of Organ Transplantation; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China 430030
| | - Wei Wang
- Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China 430030
| | - Bo Yang
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology; Key Laboratory of Organ Transplantation, Ministry of Education; NHC Key Laboratory of Organ Transplantation; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China 430030
| | - Yucong Zhang
- Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China 430030
| | - Huibo Shi
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology; Key Laboratory of Organ Transplantation, Ministry of Education; NHC Key Laboratory of Organ Transplantation; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China 430030
| | - Dong Chen
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology; Key Laboratory of Organ Transplantation, Ministry of Education; NHC Key Laboratory of Organ Transplantation; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China 430030
| | - Lai Wei
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology; Key Laboratory of Organ Transplantation, Ministry of Education; NHC Key Laboratory of Organ Transplantation; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China 430030
| | - Zhishui Chen
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology; Key Laboratory of Organ Transplantation, Ministry of Education; NHC Key Laboratory of Organ Transplantation; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China 430030
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Goepp M, Crittenden S, Zhou Y, Rossi AG, Narumiya S, Yao C. Prostaglandin E 2 directly inhibits the conversion of inducible regulatory T cells through EP2 and EP4 receptors via antagonizing TGF-β signalling. Immunology 2021; 164:777-791. [PMID: 34529833 PMCID: PMC8561111 DOI: 10.1111/imm.13417] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Revised: 07/28/2021] [Accepted: 08/31/2021] [Indexed: 12/27/2022] Open
Abstract
Regulatory T (Treg) cells are essential for control of inflammatory processes by suppressing effector T-cell functions. The actions of PGE2 on the development and function of Treg cells, particularly under inflammatory conditions, are debated. In this study, we employed pharmacological and genetic approaches to examine whether PGE2 had a direct action on T cells to modulate de novo differentiation of Treg cells. We found that TGF-β-induced Foxp3 expression and iTreg cell differentiation in vitro is markedly inhibited by PGE2 , which was mediated by the receptors EP2 and EP4. Mechanistically, PGE2 -EP2/EP4 signalling interrupts TGF-β signalling during iTreg differentiation. Moreover, EP4 deficiency in T cells impaired iTreg cell differentiation in vivo. Thus, our results demonstrate that PGE2 negatively regulates iTreg cell differentiation through a direct action on T cells, highlighting the potential for selectively targeting the PGE2 -EP2/EP4 pathway to control T cell-mediated inflammation.
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Affiliation(s)
- Marie Goepp
- Centre for Inflammation Research, Queen’s Medical Research Institute,The University of EdinburghEdinburghUK
| | - Siobhan Crittenden
- Centre for Inflammation Research, Queen’s Medical Research Institute,The University of EdinburghEdinburghUK
| | - You Zhou
- Systems Immunity University Research Institute, and Division of Infection and ImmunityCardiff UniversityCardiffUK
| | - Adriano G Rossi
- Centre for Inflammation Research, Queen’s Medical Research Institute,The University of EdinburghEdinburghUK
| | - Shuh Narumiya
- Alliance Laboratory for Advanced Medical Research and Department of Drug Discovery Medicine, Medical Innovation CenterKyoto University Graduate School of MedicineKyotoJapan
| | - Chengcan Yao
- Centre for Inflammation Research, Queen’s Medical Research Institute,The University of EdinburghEdinburghUK
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Ding M, Malhotra R, Ottosson T, Lundqvist M, Mebrahtu A, Brengdahl J, Gehrmann U, Bäck E, Ross-Thriepland D, Isaksson I, Magnusson B, Sachsenmeier KF, Tegel H, Hober S, Uhlén M, Mayr LM, Davies R, Rockberg J, Schiavone LH. Secretome screening reveals immunomodulating functions of IFNα-7, PAP and GDF-7 on regulatory T-cells. Sci Rep 2021; 11:16767. [PMID: 34408239 PMCID: PMC8373891 DOI: 10.1038/s41598-021-96184-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Accepted: 08/05/2021] [Indexed: 02/07/2023] Open
Abstract
Regulatory T cells (Tregs) are the key cells regulating peripheral autoreactive T lymphocytes. Tregs exert their function by suppressing effector T cells. Tregs have been shown to play essential roles in the control of a variety of physiological and pathological immune responses. However, Tregs are unstable and can lose the expression of FOXP3 and suppressive functions as a consequence of outer stimuli. Available literature suggests that secreted proteins regulate Treg functional states, such as differentiation, proliferation and suppressive function. Identification of secreted proteins that affect Treg cell function are highly interesting for both therapeutic and diagnostic purposes in either hyperactive or immunosuppressed populations. Here, we report a phenotypic screening of a human secretome library in human Treg cells utilising a high throughput flow cytometry technology. Screening a library of 575 secreted proteins allowed us to identify proteins stabilising or destabilising the Treg phenotype as suggested by changes in expression of Treg marker proteins FOXP3 and/or CTLA4. Four proteins including GDF-7, IL-10, PAP and IFNα-7 were identified as positive regulators that increased FOXP3 and/or CTLA4 expression. PAP is a phosphatase. A catalytic-dead version of the protein did not induce an increase in FOXP3 expression. Ten interferon proteins were identified as negative regulators that reduced the expression of both CTLA4 and FOXP3, without affecting cell viability. A transcriptomics analysis supported the differential effect on Tregs of IFNα-7 versus other IFNα proteins, indicating differences in JAK/STAT signaling. A conformational model experiment confirmed a tenfold reduction in IFNAR-mediated ISG transcription for IFNα-7 compared to IFNα-10. This further strengthened the theory of a shift in downstream messaging upon external stimulation. As a summary, we have identified four positive regulators of FOXP3 and/or CTLA4 expression. Further exploration of these Treg modulators and their method of action has the potential to aid the discovery of novel therapies for both autoimmune and infectious diseases as well as for cancer.
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Affiliation(s)
- Mei Ding
- grid.418151.80000 0001 1519 6403Discovery Biology, Discovery Sciences, R&D, AstraZeneca, Gothenburg, Sweden
| | - Rajneesh Malhotra
- grid.418151.80000 0001 1519 6403Translational Science and Experimental Medicine, Research and Early Development, Respiratory and Immunology (R&I), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Tomas Ottosson
- grid.418151.80000 0001 1519 6403Translational Science and Experimental Medicine, Research and Early Development, Respiratory and Immunology (R&I), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Magnus Lundqvist
- grid.5037.10000000121581746Department of Protein Science, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH - Royal Institute of Technology, Stockholm, Sweden
| | - Aman Mebrahtu
- grid.5037.10000000121581746Department of Protein Science, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH - Royal Institute of Technology, Stockholm, Sweden
| | - Johan Brengdahl
- grid.418151.80000 0001 1519 6403Discovery Biology, Discovery Sciences, R&D, AstraZeneca, Gothenburg, Sweden
| | - Ulf Gehrmann
- grid.418151.80000 0001 1519 6403Translational Science and Experimental Medicine, Research and Early Development, Respiratory and Immunology (R&I), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Elisabeth Bäck
- grid.418151.80000 0001 1519 6403Mechanistic Biology and Profiling, Discovery Sciences, R&D, AstraZeneca, Gothenburg, Sweden
| | - Douglas Ross-Thriepland
- grid.417815.e0000 0004 5929 4381Discovery Biology, Discovery Sciences, R&D, AstraZeneca, Cambridge, UK
| | - Ida Isaksson
- grid.418151.80000 0001 1519 6403Sample Management, Discovery Sciences, R&D, AstraZeneca, Gothenburg, Sweden
| | - Björn Magnusson
- grid.418151.80000 0001 1519 6403Discovery Biology, Discovery Sciences, R&D, AstraZeneca, Gothenburg, Sweden
| | | | - Hanna Tegel
- grid.5037.10000000121581746Department of Protein Science, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH - Royal Institute of Technology, Stockholm, Sweden
| | - Sophia Hober
- grid.5037.10000000121581746Department of Protein Science, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH - Royal Institute of Technology, Stockholm, Sweden
| | - Mathias Uhlén
- grid.5037.10000000121581746Department of Protein Science, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH - Royal Institute of Technology, Stockholm, Sweden
| | - Lorenz M. Mayr
- grid.417815.e0000 0004 5929 4381Discovery Biology, Discovery Sciences, R&D, AstraZeneca, Cambridge, UK
| | - Rick Davies
- grid.417815.e0000 0004 5929 4381Discovery Biology, Discovery Sciences, R&D, AstraZeneca, Cambridge, UK
| | - Johan Rockberg
- grid.5037.10000000121581746Department of Protein Science, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH - Royal Institute of Technology, Stockholm, Sweden
| | - Lovisa Holmberg Schiavone
- grid.418151.80000 0001 1519 6403Discovery Biology, Discovery Sciences, R&D, AstraZeneca, Gothenburg, Sweden
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Mesenchymal stromal cell mitochondrial transfer to human induced T-regulatory cells mediates FOXP3 stability. Sci Rep 2021; 11:10676. [PMID: 34021231 PMCID: PMC8140113 DOI: 10.1038/s41598-021-90115-8] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Accepted: 05/06/2021] [Indexed: 01/14/2023] Open
Abstract
The key obstacle to clinical application of human inducible regulatory T cells (iTreg) as an adoptive cell therapy in autoimmune disorders is loss of FOXP3 expression in an inflammatory milieu. Here we report human iTreg co-cultured with bone marrow-derived mesenchymal stromal cells (MSCs) during short-term ex vivo expansion enhances the stability of iTreg FOXP3 expression and suppressive function in vitro and in vivo, and further that a key mechanism of action is MSC mitochondrial (mt) transfer via tunneling nanotubules (TNT). MSC mt transfer is driven by mitochondrial metabolic function (CD39/CD73 signaling) in proliferating iTreg and promotes iTreg expression of FOXP3 stabilizing factors BACH2 and SENP3. These results elucidate cellular and molecular mechanisms underlying human MSC mt transfer to proliferating cells. MSC mt transfer stabilizes FOXP3 expression in iTregs, thereby enhancing and sustaining their suppressive function in inflammatory conditions in vitro and in vivo.
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Dong Y, Yang C, Pan F. Post-Translational Regulations of Foxp3 in Treg Cells and Their Therapeutic Applications. Front Immunol 2021; 12:626172. [PMID: 33912156 PMCID: PMC8071870 DOI: 10.3389/fimmu.2021.626172] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Accepted: 03/17/2021] [Indexed: 12/15/2022] Open
Abstract
Regulatory T (Treg) cells are indispensable for immune homeostasis due to their roles in peripheral tolerance. As the master transcription factor of Treg cells, Forkhead box P3 (Foxp3) strongly regulates Treg function and plasticity. Because of this, considerable research efforts have been directed at elucidating the mechanisms controlling Foxp3 and its co-regulators. Such work is not only advancing our understanding on Treg cell biology, but also uncovering novel targets for clinical manipulation in autoimmune diseases, organ transplantation, and tumor therapies. Recently, many studies have explored the post-translational regulation of Foxp3, which have shown that acetylation, phosphorylation, glycosylation, methylation, and ubiquitination are important for determining Foxp3 function and plasticity. Additionally, some of these targets have been implicated to have great therapeutic values. In this review, we will discuss emerging evidence of post-translational regulations on Foxp3 in Treg cells and their exciting therapeutic applications.
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Affiliation(s)
- Yi Dong
- Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Cuiping Yang
- Department of Gastroenterology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Fan Pan
- Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Science, Shenzhen, China
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Dong Y, Pan F. Ubiquitin-Dependent Regulation of Treg Function and Plasticity. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1278:63-80. [PMID: 33523443 DOI: 10.1007/978-981-15-6407-9_4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/08/2023]
Abstract
As an indispensable part of peripheral tolerance, regulatory T (Treg) cells play an important role in immune homeostasis by suppressing other immune cells. Behind this function is a complex network of transcription factors and signaling cascades that regulates the function and plasticity of regulatory T cells. Among these, Forkhead box P3 (Foxp3) is considered as the master transcription factor, and its stability will influence the function and viability of Treg cells. Because of this, understanding the mechanisms that regulate Foxp3 and its co-regulators will provide more understanding to Treg cells and uncover more targets to manipulate Treg cells in treating autoimmune diseases, organ transplantation, and tumor. Interestingly, several recent studies show that ubiquitin-dependent pathways are important regulators of Foxp3, which suggest both great scientific and therapeutic values. In this chapter, we cover emerging evidence of ubiquitin-dependent, posttranslational regulation of Treg function and plasticity.
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Affiliation(s)
- Yi Dong
- Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Fan Pan
- Center for Cancer Immunology Research, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong, China.
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Abstract
To antagonize tumor-derived TGFβ contemporaneously to anticancer immunotherapy, we genetically engineered a fusion protein coupling IL-2 and the ectodomain of TGFβ receptor II (Fusion of Interleukin-2 and Soluble TGFβ receptor – a.k.a. FIST). FIST possesses intriguing gain-of-function properties and induces potent activation of IL2-receptor expressing cells and inhibits tumor-derived angiogenesis. Thus FIST constitutes a first-in-class biological that couples anti-angiogenesis to an immune antitumor response.
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Affiliation(s)
- Claudia Penafuerte
- The Rosalind & Morris Goodman Cancer Research Centre; McGill University; Montreal, QC Canada
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Schreiber TH, Wolf D, Bodero M, Podack E. Tumor antigen specific iTreg accumulate in the tumor microenvironment and suppress therapeutic vaccination. Oncoimmunology 2021; 1:642-648. [PMID: 22934256 PMCID: PMC3429568 DOI: 10.4161/onci.20298] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Tumor specific antigens (TSA) provide an opportunity to mobilize therapeutic immune responses against cancer. To evade such responses, tumor development in immunocompetent hosts is accompanied by acquisition of both active and passive mechanisms of immune suppression, including recruitment of CD4+FoxP3+ regulatory T cells (Treg). Thymic derived Treg (nTreg) may recognize self-antigens in the tumor microenvironment, while peripherally induced Treg (iTreg) may preferentially recognize the same TSA which provide an opportunity for therapeutic immunity from peripheral T cells. In this study we provide a systematic analysis of nTreg and iTreg accumulation in the tumor microenvironment (TME) at the cellular level. iTreg accumulation to the TME was influenced by the abundance of a known TSA, and in the absence of a known TSA intratumoral Treg displayed a unique TCR repertoire from peripheral Treg. In vivo suppression assays demonstrate that cognate-antigen matched iTreg are more potent suppressors of CD4+ than are polyclonal iTreg or nTreg, but were unable to suppress CD8+ T cell proliferation. Suppression occurred only locally at the site of immunization, and correlated with decreased expression of CD80 and CD86 on CD11c positive cells. Although established tumors facilitated the induction of TSA-specific iTreg, these iTreg suppressed CD4+ T cell accumulation only locally to the TME. Tumor mediated suppression of CD8+ T cell immunity appeared independent of TSA-specific iTreg.
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Affiliation(s)
- Taylor H Schreiber
- Department of Microbiology and Immunology; University of Miami Miller School of Medicine; Miami, FL USA
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46
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Soskic B, Jeffery LE, Kennedy A, Gardner DH, Hou TZ, Halliday N, Williams C, Janman D, Rowshanravan B, Hirschfield GM, Sansom DM. CD80 on Human T Cells Is Associated With FoxP3 Expression and Supports Treg Homeostasis. Front Immunol 2021; 11:577655. [PMID: 33488578 PMCID: PMC7820758 DOI: 10.3389/fimmu.2020.577655] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Accepted: 11/25/2020] [Indexed: 11/24/2022] Open
Abstract
CD80 and CD86 are expressed on antigen presenting cells (APCs) and their role in providing costimulation to T cells is well established. However, it has been shown that these molecules can also be expressed by T cells, but the significance of this observation remains unknown. We have investigated stimuli that control CD80 and CD86 expression on T cells and show that in APC-free conditions around 40% of activated, proliferating CD4+ T cells express either CD80, CD86 or both. Expression of CD80 and CD86 was strongly dependent upon provision of CD28 costimulation as ligands were not expressed following TCR stimulation alone. Furthermore, we observed that CD80+ T cells possessed the hallmarks of induced regulatory T cells (iTreg), expressing Foxp3 and high levels of CTLA-4 whilst proliferating less extensively. In contrast, CD86 was preferentially expressed on INF-γ producing cells, which proliferated more extensively and had characteristics of effector T cells. Finally, we demonstrated that CD80 expressed on T cells inhibits CTLA-4 function and facilitates the growth of iTreg. Together these data establish endogenous expression of CD80 and CD86 by activated T cells is not due to ligand capture by transendocytosis and highlight clear differences in their expression patterns and associated functions.
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Affiliation(s)
- Blagoje Soskic
- Institute of Immunity and Transplantation, Division of Infection & Immunity, University College London, Royal Free Hospital, London, United Kingdom
| | - Louisa E Jeffery
- Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, United Kingdom
| | - Alan Kennedy
- Institute of Immunity and Transplantation, Division of Infection & Immunity, University College London, Royal Free Hospital, London, United Kingdom
| | - David H Gardner
- School of Immunity and Infection, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, United Kingdom
| | - Tie Zheng Hou
- Institute of Immunity and Transplantation, Division of Infection & Immunity, University College London, Royal Free Hospital, London, United Kingdom
| | - Neil Halliday
- Institute of Immunity and Transplantation, Division of Infection & Immunity, University College London, Royal Free Hospital, London, United Kingdom
| | - Cayman Williams
- Institute of Immunity and Transplantation, Division of Infection & Immunity, University College London, Royal Free Hospital, London, United Kingdom
| | - Daniel Janman
- Institute of Immunity and Transplantation, Division of Infection & Immunity, University College London, Royal Free Hospital, London, United Kingdom
| | - Behzad Rowshanravan
- Institute of Immunity and Transplantation, Division of Infection & Immunity, University College London, Royal Free Hospital, London, United Kingdom
| | | | - David M Sansom
- Institute of Immunity and Transplantation, Division of Infection & Immunity, University College London, Royal Free Hospital, London, United Kingdom
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Huang Z, Li W, Su W. Tregs in Autoimmune Uveitis. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1278:205-227. [PMID: 33523450 DOI: 10.1007/978-981-15-6407-9_11] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Uveitis is a chronic disease with relapsing and remitting ocular attack, which requires corticosteroids and systemic immunosuppression to prevent severe vision loss. Classically, uveitis is referred to an autoimmune disease, mediated by pro-inflammatory Th17 cells and immunosuppressive CD4+CD25+FoxP3+ T-regulatory cells (Tregs). More and more evidence indicates that Tregs are involved in development, resolution, and remission of uveitis. Clinically, many researchers have conducted quantitative and functional analyses of peripheral blood from patients with different subtypes of uveitis, in an attempt to find the changing rules of Tregs. Consistently, using the experimental autoimmune uveitis (EAU) model, researchers have explored the development and resolution mechanism of uveitis in many aspects. In addition, many drug and Tregs therapy investigations have yielded encouraging results. In this chapter, we introduced the current understanding of Tregs, summarized the clinical changes in the number and function of patients with uveitis and the immune mechanism of Tregs involved in EAU model, as well as discussed the progress and shortcomings of Tregs-related drug therapy and Tregs therapy. Although the exact mechanism of Tregs-mediated uveitis protection remains to be elucidated, the strategy of Tregs regulation may provide a specific and meaningful way for the prevention and treatment of uveitis.
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Affiliation(s)
- Zhaohao Huang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Wenli Li
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Wenru Su
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China.
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Mohammadi S, Abdollahi E, Nezamnia M, Esmaeili SA, Tavasolian F, Sathyapalan T, Sahebkar A. Adoptive transfer of Tregs: A novel strategy for cell-based immunotherapy in spontaneous abortion: Lessons from experimental models. Int Immunopharmacol 2021; 90:107195. [PMID: 33278746 DOI: 10.1016/j.intimp.2020.107195] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2020] [Revised: 11/06/2020] [Accepted: 11/07/2020] [Indexed: 01/05/2023]
Abstract
Since half of the genes are inherited from the paternal side, the maternal immune system has to tolerate the presence of foreign paternal antigens. Regulatory T cells facilitate the development and maintenance of peripheral tissue tolerance of the fetus during pregnancy. Reduction in regulatory T cells is associated with complications of pregnancy, including spontaneous abortion. Recent studies in mouse models have shown that the adoptive transfer of Tregs can prevent spontaneous abortion in mouse models through improving maternal tolerance. Thus, adoptive cell therapy using autologous Tregs could potentially be a novel therapeutic approach for cell-based immunotherapy in women with unexplained spontaneous abortion. Besides, strategies for activating and expanding antigen-specific Tregs ex vivo and in vivo based on pharmacological agents can pave the foundation for an approach incorporating immunotherapy and pharmacotherapy. This review aims to elaborate on the current understanding of the therapeutic potential of the adoptive transfer of Tregs in the treatment of spontaneous abortion disease.
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Affiliation(s)
- Sasan Mohammadi
- Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Elham Abdollahi
- Department of Medical Immunology and Allergy, Student Research Committee, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; Mater Research Institute-University of Queensland, Translational Research Institute, South Brisbane, Australia.
| | - Maria Nezamnia
- Department of Obstetrics and Gynecology, School of Medicine, Bam University of Medical Sciences, Bam, Iran
| | - Seyed-Alireza Esmaeili
- Immunology Research Center, Bu-Ali Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Fataneh Tavasolian
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Thozhukat Sathyapalan
- Academic Diabetes, Endocrinology and Metabolism, Hull York Medical School, University of Hull, United Kingdom
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Halal Research Center of IRI, FDA, Tehran, Iran; Polish Mother's Memorial Hospital Research Institute (PMMHRI), Lodz, Poland.
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Kolb HR, Borcherding N, Zhang W. Understanding and Targeting Human Cancer Regulatory T Cells to Improve Therapy. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1278:229-256. [PMID: 33523451 DOI: 10.1007/978-981-15-6407-9_12] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Regulatory T cells (Tregs) are critical in maintaining immune homeostasis under various pathophysiological conditions. A growing body of evidence demonstrates that Tregs play an important role in cancer progression and that they do so by suppressing cancer-directed immune responses. Tregs have been targeted for destruction by exploiting antibodies against and small-molecule inhibitors of several molecules that are highly expressed in Tregs-including immune checkpoint molecules, chemokine receptors, and metabolites. To date, these strategies have had only limited antitumor efficacy, yet they have also created significant risk of autoimmunity because most of them do not differentiate Tregs in tumors from those in normal tissues. Currently, immune checkpoint inhibitor (ICI)-based cancer immunotherapies have revolutionized cancer treatment, but the resistance to ICI is common and the elevation of Tregs is one of the most important mechanisms. Therapeutic strategies that can selectively eliminate Tregs in the tumor (i.e. therapies that do not run the risk of causing autoimmunity by affecting normal tissue), are urgently needed for the development of cancer immunotherapies. This chapter discusses specific properties of human Tregs under the context of cancer and the various ways to target Treg for cancer immunotherapy.
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Affiliation(s)
- H Ryan Kolb
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL, USA
| | - Nicholas Borcherding
- Department of Pathology and Immunology, Washington University, St. Louis, MO, USA
| | - Weizhou Zhang
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL, USA.
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Abstract
Mucosal surfaces are distinctive sites exposed to environmental, dietary, and microbial antigens. Particularly in the gut, the host continuously actively adapts via complex interactions between the microbiota and dietary compounds and immune and other tissue cells. Regulatory T cells (Tregs) are critical for tuning the intestinal immune response to self- and non-self-antigens in the intestine. Its importance in intestinal homeostasis is illustrated by the onset of overt inflammation caused by deficiency in Treg generation, function, or stability in the gut. A substantial imbalance in Tregs has been observed in intestinal tissue during pathogenic conditions, when a tightly regulated and equilibrated system becomes dysregulated and leads to unimpeded and chronic immune responses. In this chapter, we compile and critically discuss the current knowledge on the key factors that promote Treg-mediated tolerance in the gut, such as those involved in intestinal Treg differentiation, specificity and suppressive function, and their immunophenotype during health and disease. We also discuss the current state of knowledge on Treg dysregulation in human intestine during pathological states such as inflammatory bowel disease (IBD), necrotizing enterocolitis (NEC), graft-versus-host disease (GVHD), and colorectal cancer (CRC), and how that knowledge is guiding development of Treg-targeted therapies to treat or prevent intestinal disorders.
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