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      High salt promotes autoimmunity by TET2-induced DNA demethylation and driving the differentiation of Tfh cells

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          Abstract

          Follicular helper T cells (Tfh) have been well documented to play a critical role in autoimmunity, such as systemic lupus erythematosus (SLE), by helping B cells. In this study, high salt (sodium chloride, NaCl), under physiological conditions, was demonstrated to increase the differentiation of Tfh. A high-salt diet markedly increased lupus features in MRL/lpr mice. The mechanism is NaCl-induced DNA demethylation via the recruitment of the hydroxytransferase Ten-Eleven Translocation 2 (TET2). Gene silencing of TET2 obviously diminished NaCl-induced Tfh cell polarization in vitro. In addition, the gene expression of sh2d1a, map3k1, spn and stat5b was enhanced after NaCl treatment, consistent with the findings in lupus CD4 +T cells. However, only spn was directly regulated by TET2, and spn was not the sole target for NaCl. Our findings not only explain the epigenetic mechanisms of high-salt induced autoimmunity but also provide an attractive molecular target for intervention strategies of patients.

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          The origins, function, and regulation of T follicular helper cells

          Cindy Ma, Elissa K. Deenick, Marcel Batten … (2012)
          The generation of high-affinity antibodies (Abs) plays a critical role in the neutralization and clearance of pathogens and subsequent host survival after natural infection with a variety of microorganisms. Most currently available vaccines rely on the induction of long-lived protective humoral immune responses by memory B cells and plasma cells, underscoring the importance of Abs in host protection. Ab responses against most antigens (Ags) require interactions between B cells and CD4+ T helper cells, and it is now well recognized that T follicular helper cells (Tfh) specialize in providing cognate help to B cells and are fundamentally required for the generation of T cell–dependent B cell responses. Perturbations in the development and/or function of Tfh cells can manifest as immunopathologies, such as immunodeficiency, autoimmunity, and malignancy. Unraveling the cellular and molecular requirements underlying Tfh cell formation and maintenance will help to identify molecules that could be targeted for the treatment of immunological diseases that are characterized by insufficient or excessive Ab responses.
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            TGF-β co-opts STAT3-STAT4 signaling to promote human T follicular helper cell differentiation

            Nathalie Schmitt, Yang Liu, Salah-Eddine Bentebibel … (2014)
            Understanding the developmental mechanisms of T follicular helper (TFH) cells in humans is a highly relevant topic to clinic. However, factors that drive human CD4+ helper T (TH) cell differentiation program towards TFH cells remain largely undefined. Here we show that TGF-β provides critical additional signals for the transcription factors STAT3 and STAT4 to promote the initial TFH differentiation programs in humans. This mechanism does not appear to be shared with mouse TH cells. The developing human Bcl-6+ TFH cells also expressed RORγt, a transcription factor typically expressed by TH17 cells. Our study documents a mechanism by which TFH and TH17 cells co-emerge in inflammatory environments in humans, as often observed in many human autoimmune diseases.
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              NFAT5/TonEBP mutant mice define osmotic stress as a critical feature of the lymphoid microenvironment.

              William Y Go, Megan F. Liu, Michelle Roti … (2004)
              Osmotic stress responses are critical not only to the survival of unicellular organisms but also to the normal function of the mammalian kidney. However, the extent to which cells outside the kidney rely on osmotic stress responses in vivo remains unknown. Nuclear factor of activated T cells 5 (NFAT5)/tonicity enhancer binding protein (TonEBP), the only known osmosensitive mammalian transcription factor, is expressed most abundantly in the thymus and is induced upon lymphocyte activation. Here we report that NFAT5/TonEBP is not only essential for normal cell proliferation under hyperosmotic conditions but also necessary for optimal adaptive immunity. Targeted deletion of exons 6 and 7 of the Nfat5 gene, which encode a critical region of the DNA-binding domain, gave rise to a complete loss of function in the homozygous state and a partial loss of function in the heterozygous state. Complete loss of function resulted in late gestational lethality. Furthermore, hypertonicity-induced NFAT5/TonEBP transcriptional activity and hsp70.1 promoter function were completely eliminated, and cell proliferation under hyperosmotic culture conditions was markedly impaired. Partial loss of NFAT5/TonEBP function resulted in lymphoid hypocellularity and impaired antigen-specific antibody responses in viable heterozygous animals. In addition, lymphocyte proliferation ex vivo was reduced under hypertonic, but not isotonic, culture conditions. Direct measurement of tissue osmolality further revealed lymphoid tissues to be hyperosmolar. These results indicate that lymphocyte-mediated immunity is contingent on adaptation to physiologic osmotic stress, thus providing insight into the lymphoid microenvironment and the importance of the NFAT5/TonEBP osmotic stress response pathway in vivo.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Sci Rep
                Journal ID (iso-abbrev): Sci Rep
                Title: Scientific Reports
                Publisher: Nature Publishing Group
                ISSN (Electronic): 2045-2322
                Publication date (Electronic): 21 June 2016
                Publication date Collection: 2016
                Volume: 6
                Electronic Location Identifier: 28065
                Affiliations
                [1 ]Department of Dermatology, Hunan Key Laboratory of Medical Epigenomics, Second Xiangya Hospital, Central South University , Changsha, Hunan, China
                [2 ]Department of Nephrology, Second Xiangya Hospital, Central South University , Changsha, Hunan, China
                [3 ]Changsha Blood Center , Changsha, Hunan, China
                [4 ]Clinical medical research center, the Second Clinical medical college of Jinan University (Shenzhen People’s Hospital) , Shenzhen, Guangdong, China
                [5 ]Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis , Davis , USA
                [6 ]Department of Microbiology and Immunology, Keio University School of Medicine , Tokyo, Japan
                Author notes
                [*]

                These authors contributed equally to this work.

                Article
                Publisher Item ID: srep28065
                DOI: 10.1038/srep28065
                PMC ID: 4914849
                PubMed ID: 27325182
                SO-VID: a1833985-d69f-4e10-93bc-6b363cda1436
                Copyright © Copyright © 2016, Macmillan Publishers Limited
                License:

                This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

                History
                Date received : 04 April 2016
                Date accepted : 31 May 2016
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