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      HIF1α–dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of T H17 and T reg cells

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          Abstract

          HIF1α induction by mTOR represents a metabolic checkpoint for the differentiation of T H17 and T reg cells.

          Abstract

          Upon antigen stimulation, the bioenergetic demands of T cells increase dramatically over the resting state. Although a role for the metabolic switch to glycolysis has been suggested to support increased anabolic activities and facilitate T cell growth and proliferation, whether cellular metabolism controls T cell lineage choices remains poorly understood. We report that the glycolytic pathway is actively regulated during the differentiation of inflammatory T H17 and Foxp3-expressing regulatory T cells (T reg cells) and controls cell fate determination. T H17 but not T reg cell–inducing conditions resulted in strong up-regulation of the glycolytic activity and induction of glycolytic enzymes. Blocking glycolysis inhibited T H17 development while promoting T reg cell generation. Moreover, the transcription factor hypoxia-inducible factor 1α (HIF1α) was selectively expressed in T H17 cells and its induction required signaling through mTOR, a central regulator of cellular metabolism. HIF1α–dependent transcriptional program was important for mediating glycolytic activity, thereby contributing to the lineage choices between T H17 and T reg cells. Lack of HIF1α resulted in diminished T H17 development but enhanced T reg cell differentiation and protected mice from autoimmune neuroinflammation. Our studies demonstrate that HIF1α–dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of T H17 and T reg cells.

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          Most cited references18

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          On the origin of cancer cells.

          O WARBURG (1956)
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            The interleukin 23 receptor is essential for the terminal differentiation of interleukin 17-producing effector T helper cells in vivo.

            Interleukin 23 (IL-23) is required for autoimmune inflammation mediated by IL-17-producing helper T cells (T(H)-17 cells) and has been linked to many human immune disorders. Here we restricted deficiency in the IL-23 receptor to defined cell populations in vivo to investigate the requirement for IL-23 signaling in the development and function of T(H)-17 cells in autoimmunity, inflammation and infection. In the absence of IL-23, T(H)-17 development was stalled at the early activation stage. T(H)-17 cells failed to downregulate IL-2 and also failed to maintain IL-17 production or upregulate expression of the IL-7 receptor alpha-chain. These defects were associated with less proliferation; consequently, fewer effector T(H)-17 cells were produced in the lymph nodes and hence available to emigrate to the bloodstream and tissues.
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              T cell receptor signaling controls Foxp3 expression via PI3K, Akt, and mTOR.

              Regulatory T (Treg) cells safeguard against autoimmunity and immune pathology. Because determinants of the Treg cell fate are not completely understood, we have delineated signaling events that control the de novo expression of Foxp3 in naive peripheral CD4 T cells and in thymocytes. We report that premature termination of TCR signaling and inibition of phosphatidyl inositol 3-kinase (PI3K) p110alpha, p110delta, protein kinase B (Akt), or mammalian target of rapamycin (mTOR) conferred Foxp3 expression and Treg-like gene expression profiles. Conversely, continued TCR signaling and constitutive PI3K/Akt/mTOR activity antagonised Foxp3 induction. At the chromatin level, di- and trimethylation of lysine 4 of histone H3 (H3K4me2 and -3) near the Foxp3 transcription start site (TSS) and within the 5' untranslated region (UTR) preceded active Foxp3 expression and, like Foxp3 inducibility, was lost upon continued TCR stimulation. These data demonstrate that the PI3K/Akt/mTOR signaling network regulates Foxp3 expression.
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                Author and article information

                Journal
                J Exp Med
                J. Exp. Med
                jem
                The Journal of Experimental Medicine
                The Rockefeller University Press
                0022-1007
                1540-9538
                4 July 2011
                : 208
                : 7
                : 1367-1376
                Affiliations
                [1 ]Department of Immunology , [2 ]Department of Pathology , and [3 ]Hartwell Center for Bioinformatics and Biotechnology, St. Jude Children’s Research Hospital, Memphis, TN 38105
                Author notes
                CORRESPONDENCE Douglas R. Green: douglas.green@ 123456stjude.org OR Hongbo Chi: chi@ 123456stjude.org

                L.Z. Shi and R. Wang contributed equally to this paper.

                Article
                20110278
                10.1084/jem.20110278
                3135370
                21708926
                ff5ae6f5-7a0b-4aca-af14-31caf8aeda57
                © 2011 Shi et al.

                This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

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