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      NFAT control of immune function: New Frontiers for an Abiding Trooper

      review-article
      1 , a , 1
      F1000Research
      F1000 Research Limited
      NFAT, CRAC, Calcium, STIM, T cell, metabolism, anergy, exhaustion

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          Abstract

          Nuclear factor of activated T cells (NFAT) was first described almost three decades ago as a Ca 2+/calcineurin-regulated transcription factor in T cells. Since then, a large body of research uncovered the regulation and physiological function of different NFAT homologues in the immune system and many other tissues. In this review, we will discuss novel roles of NFAT in T cells, focusing mainly on its function in humoral immune responses, immunological tolerance, and the regulation of immune metabolism.

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          Most cited references86

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          LDHA-Associated Lactic Acid Production Blunts Tumor Immunosurveillance by T and NK Cells.

          Elevated lactate dehydrogenase A (LDHA) expression is associated with poor outcome in tumor patients. Here we show that LDHA-associated lactic acid accumulation in melanomas inhibits tumor surveillance by T and NK cells. In immunocompetent C57BL/6 mice, tumors with reduced lactic acid production (Ldha(low)) developed significantly slower than control tumors and showed increased infiltration with IFN-γ-producing T and NK cells. However, in Rag2(-/-)γc(-/-) mice, lacking lymphocytes and NK cells, and in Ifng(-/-) mice, Ldha(low) and control cells formed tumors at similar rates. Pathophysiological concentrations of lactic acid prevented upregulation of nuclear factor of activated T cells (NFAT) in T and NK cells, resulting in diminished IFN-γ production. Database analyses revealed negative correlations between LDHA expression and T cell activation markers in human melanoma patients. Our results demonstrate that lactic acid is a potent inhibitor of function and survival of T and NK cells leading to tumor immune escape.
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            Fueling immunity: insights into metabolism and lymphocyte function.

            Lymphocytes face major metabolic challenges upon activation. They must meet the bioenergetic and biosynthetic demands of increased cell proliferation and also adapt to changing environmental conditions, in which nutrients and oxygen may be limiting. An emerging theme in immunology is that metabolic reprogramming and lymphocyte activation are intricately linked. However, why T cells adopt specific metabolic programs and the impact that these programs have on T cell function and, ultimately, immunological outcome remain unclear. Research on tumor cell metabolism has provided valuable insight into metabolic pathways important for cell proliferation and the influence of metabolites themselves on signal transduction and epigenetic programming. In this Review, we highlight emerging concepts regarding metabolic reprogramming in proliferating cells and discuss their potential impact on T cell fate and function.
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              T cell metabolism drives immunity

              Buck et al. discuss the role of lymphocyte metabolism on immune cell development and function.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: VisualizationRole: Writing – Original Draft PreparationRole: Writing – Review & Editing
                Role: ConceptualizationRole: Funding AcquisitionRole: SupervisionRole: VisualizationRole: Writing – Original Draft PreparationRole: Writing – Review & Editing
                Journal
                F1000Res
                F1000Res
                F1000Research
                F1000Research
                F1000 Research Limited (London, UK )
                2046-1402
                2 March 2018
                2018
                : 7
                : 260
                Affiliations
                [1 ]Department of Pathology, New York University School of Medicine, New York, NY, 10016, USA
                Author notes

                Competing interests: SF is a co-founder of CalciMedica. MV declares that he has no competing interests.

                Author information
                https://orcid.org/0000-0001-5431-8178
                Article
                10.12688/f1000research.13426.1
                5840618
                29568499
                9bf6b8cf-7d25-4753-a771-b27e97514e50
                Copyright: © 2018 Vaeth M and Feske S

                This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 16 February 2018
                Funding
                Funded by: National Institutes of Health
                Award ID: AI097302
                Award ID: AI130143
                This work was funded by National Institutes of Health grants AI097302 and AI130143 (to SF).
                The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Review
                Articles

                nfat,crac,calcium,stim,t cell,metabolism,anergy,exhaustion
                nfat, crac, calcium, stim, t cell, metabolism, anergy, exhaustion

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