Glutamine-dependent α-ketoglutarate production regulates the balance between T helper 1 cell and regulatory T cell generation.
Identifieur interne : 002D36 ( Main/Exploration ); précédent : 002D35; suivant : 002D37Glutamine-dependent α-ketoglutarate production regulates the balance between T helper 1 cell and regulatory T cell generation.
Auteurs : Dorota Klysz [France] ; Xuguang Tai [États-Unis] ; Philippe A. Robert [Allemagne] ; Marco Craveiro [France] ; Gaspard Cretenet [France] ; Leal Oburoglu [France] ; Cédric Mongellaz [France] ; Stefan Floess [Allemagne] ; Vanessa Fritz [France] ; Maria I. Matias [France] ; Carmen Yong [Australie] ; Natalie Surh [France] ; Julien C. Marie [Allemagne] ; Jochen Huehn [Allemagne] ; Valérie Zimmermann [France] ; Sandrina Kinet [France] ; Valérie Dardalhon [France] ; Naomi Taylor [France]Source :
- Science signaling [ 1937-9145 ] ; 2015.
Descripteurs français
- KwdFr :
- Acides cétoglutariques (immunologie), Acides cétoglutariques (métabolisme), Animaux, Complexes multiprotéiques (immunologie), Complexes multiprotéiques (métabolisme), Différenciation cellulaire (immunologie), Glutamine (immunologie), Glutamine (métabolisme), Lymphocytes T régulateurs (immunologie), Lymphocytes T régulateurs (métabolisme), Lymphocytes auxiliaires Th1 (immunologie), Lymphocytes auxiliaires Th1 (métabolisme), Souris, Sérine-thréonine kinases TOR (immunologie), Sérine-thréonine kinases TOR (métabolisme).
- MESH :
- immunologie : Acides cétoglutariques, Complexes multiprotéiques, Différenciation cellulaire, Glutamine, Lymphocytes T régulateurs, Lymphocytes auxiliaires Th1, Sérine-thréonine kinases TOR.
- métabolisme : Acides cétoglutariques, Complexes multiprotéiques, Glutamine, Lymphocytes T régulateurs, Lymphocytes auxiliaires Th1, Sérine-thréonine kinases TOR.
- Animaux, Souris.
English descriptors
- KwdEn :
- Animals, Cell Differentiation (immunology), Glutamine (immunology), Glutamine (metabolism), Ketoglutaric Acids (immunology), Ketoglutaric Acids (metabolism), Mice, Multiprotein Complexes (immunology), Multiprotein Complexes (metabolism), T-Lymphocytes, Regulatory (immunology), T-Lymphocytes, Regulatory (metabolism), TOR Serine-Threonine Kinases (immunology), TOR Serine-Threonine Kinases (metabolism), Th1 Cells (immunology), Th1 Cells (metabolism).
- MESH :
- chemical , immunology : Glutamine, Ketoglutaric Acids, Multiprotein Complexes, TOR Serine-Threonine Kinases.
- immunology : Cell Differentiation, T-Lymphocytes, Regulatory, Th1 Cells.
- chemical , metabolism : Glutamine, Ketoglutaric Acids, Multiprotein Complexes, T-Lymphocytes, Regulatory, TOR Serine-Threonine Kinases, Th1 Cells.
- Animals, Mice.
Abstract
T cell activation requires that the cell meet increased energetic and biosynthetic demands. We showed that exogenous nutrient availability regulated the differentiation of naïve CD4(+) T cells into distinct subsets. Activation of naïve CD4(+) T cells under conditions of glutamine deprivation resulted in their differentiation into Foxp3(+) (forkhead box P3-positive) regulatory T (Treg) cells, which had suppressor function in vivo. Moreover, glutamine-deprived CD4(+) T cells that were activated in the presence of cytokines that normally induce the generation of T helper 1 (TH1) cells instead differentiated into Foxp3(+) Treg cells. We found that α-ketoglutarate (αKG), the glutamine-derived metabolite that enters into the mitochondrial citric acid cycle, acted as a metabolic regulator of CD4(+) T cell differentiation. Activation of glutamine-deprived naïve CD4(+) T cells in the presence of a cell-permeable αKG analog increased the expression of the gene encoding the TH1 cell-associated transcription factor Tbet and resulted in their differentiation into TH1 cells, concomitant with stimulation of mammalian target of rapamycin complex 1 (mTORC1) signaling. Together, these data suggest that a decrease in the intracellular amount of αKG, caused by the limited availability of extracellular glutamine, shifts the balance between the generation of TH1 and Treg cells toward that of a Treg phenotype.
DOI: 10.1126/scisignal.aab2610
PubMed: 26420908
Affiliations:
- Allemagne, Australie, France, États-Unis
- Bade-Wurtemberg, District de Karlsruhe, Languedoc-Roussillon, Maryland, Occitanie (région administrative)
- Heidelberg, Montpellier
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Le document en format XML
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Department of Systems Immunology, Braunschweig Integrated Centre of Systems Biology, 38124 Braunschweig</wicri:regionArea><wicri:noRegion>38124 Braunschweig</wicri:noRegion><wicri:noRegion>38124 Braunschweig</wicri:noRegion><wicri:noRegion>38124 Braunschweig</wicri:noRegion></affiliation></author><author><name sortKey="Craveiro, Marco" sort="Craveiro, Marco" uniqKey="Craveiro M" first="Marco" last="Craveiro">Marco Craveiro</name><affiliation wicri:level="1"><nlm:affiliation>Institut de Génétique Moléculaire de Montpellier, CNRS, UMR 5535, Université de Montpellier, F-34293 Montpellier, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Institut de Génétique Moléculaire de Montpellier, CNRS, UMR 5535, Université de Montpellier, F-34293 Montpellier</wicri:regionArea><wicri:noRegion>34293 Montpellier</wicri:noRegion><wicri:noRegion>34293 Montpellier</wicri:noRegion></affiliation></author><author><name sortKey="Cretenet, Gaspard" sort="Cretenet, Gaspard" uniqKey="Cretenet G" first="Gaspard" last="Cretenet">Gaspard Cretenet</name><affiliation wicri:level="1"><nlm:affiliation>Institut de Génétique Moléculaire de Montpellier, CNRS, UMR 5535, Université de Montpellier, F-34293 Montpellier, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Institut de Génétique Moléculaire de Montpellier, CNRS, UMR 5535, Université de Montpellier, F-34293 Montpellier</wicri:regionArea><wicri:noRegion>34293 Montpellier</wicri:noRegion><wicri:noRegion>34293 Montpellier</wicri:noRegion></affiliation></author><author><name sortKey="Oburoglu, Leal" sort="Oburoglu, Leal" uniqKey="Oburoglu L" first="Leal" last="Oburoglu">Leal Oburoglu</name><affiliation wicri:level="1"><nlm:affiliation>Institut de Génétique Moléculaire de Montpellier, CNRS, UMR 5535, Université de Montpellier, F-34293 Montpellier, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Institut de Génétique Moléculaire de Montpellier, CNRS, UMR 5535, Université de Montpellier, F-34293 Montpellier</wicri:regionArea><wicri:noRegion>34293 Montpellier</wicri:noRegion><wicri:noRegion>34293 Montpellier</wicri:noRegion></affiliation></author><author><name sortKey="Mongellaz, Cedric" sort="Mongellaz, Cedric" uniqKey="Mongellaz C" first="Cédric" last="Mongellaz">Cédric Mongellaz</name><affiliation wicri:level="1"><nlm:affiliation>Institut de Génétique Moléculaire de Montpellier, CNRS, UMR 5535, Université de Montpellier, F-34293 Montpellier, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Institut de Génétique Moléculaire de Montpellier, CNRS, UMR 5535, Université de Montpellier, F-34293 Montpellier</wicri:regionArea><wicri:noRegion>34293 Montpellier</wicri:noRegion><wicri:noRegion>34293 Montpellier</wicri:noRegion></affiliation></author><author><name sortKey="Floess, Stefan" sort="Floess, Stefan" uniqKey="Floess S" first="Stefan" last="Floess">Stefan Floess</name><affiliation wicri:level="1"><nlm:affiliation>Department of Experimental Immunology, Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Experimental Immunology, Helmholtz Centre for Infection Research, 38124 Braunschweig</wicri:regionArea><wicri:noRegion>38124 Braunschweig</wicri:noRegion><wicri:noRegion>38124 Braunschweig</wicri:noRegion><wicri:noRegion>38124 Braunschweig</wicri:noRegion></affiliation></author><author><name sortKey="Fritz, Vanessa" sort="Fritz, Vanessa" uniqKey="Fritz V" first="Vanessa" last="Fritz">Vanessa Fritz</name><affiliation wicri:level="1"><nlm:affiliation>Institut de Génétique Moléculaire de Montpellier, CNRS, UMR 5535, Université de Montpellier, F-34293 Montpellier, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Institut de Génétique Moléculaire de Montpellier, CNRS, UMR 5535, Université de Montpellier, F-34293 Montpellier</wicri:regionArea><wicri:noRegion>34293 Montpellier</wicri:noRegion><wicri:noRegion>34293 Montpellier</wicri:noRegion></affiliation></author><author><name sortKey="Matias, Maria I" sort="Matias, Maria I" uniqKey="Matias M" first="Maria I" last="Matias">Maria I. Matias</name><affiliation wicri:level="1"><nlm:affiliation>Institut de Génétique Moléculaire de Montpellier, CNRS, UMR 5535, Université de Montpellier, F-34293 Montpellier, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Institut de Génétique Moléculaire de Montpellier, CNRS, UMR 5535, Université de Montpellier, F-34293 Montpellier</wicri:regionArea><wicri:noRegion>34293 Montpellier</wicri:noRegion><wicri:noRegion>34293 Montpellier</wicri:noRegion></affiliation></author><author><name sortKey="Yong, Carmen" sort="Yong, Carmen" uniqKey="Yong C" first="Carmen" last="Yong">Carmen Yong</name><affiliation wicri:level="1"><nlm:affiliation>Institut de Génétique Moléculaire de Montpellier, CNRS, UMR 5535, Université de Montpellier, F-34293 Montpellier, France. Cancer Immunology Research Program, Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria 3010, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Institut de Génétique Moléculaire de Montpellier, CNRS, UMR 5535, Université de Montpellier, F-34293 Montpellier, France. Cancer Immunology Research Program, Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria 3010</wicri:regionArea><wicri:noRegion>Victoria 3010</wicri:noRegion></affiliation></author><author><name sortKey="Surh, Natalie" sort="Surh, Natalie" uniqKey="Surh N" first="Natalie" last="Surh">Natalie Surh</name><affiliation wicri:level="1"><nlm:affiliation>Institut de Génétique Moléculaire de Montpellier, CNRS, UMR 5535, Université de Montpellier, F-34293 Montpellier, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Institut de Génétique Moléculaire de Montpellier, CNRS, UMR 5535, Université de Montpellier, F-34293 Montpellier</wicri:regionArea><wicri:noRegion>34293 Montpellier</wicri:noRegion><wicri:noRegion>34293 Montpellier</wicri:noRegion></affiliation></author><author><name sortKey="Marie, Julien C" sort="Marie, Julien C" uniqKey="Marie J" first="Julien C" last="Marie">Julien C. Marie</name><affiliation wicri:level="3"><nlm:affiliation>Cancer Research Center of Lyon, INSERM U1052, CNRS 5286, Université Lyon 1, 69373 Lyon cedex 03, France. DKFZ German Cancer Research Center, 69121 Heidelberg, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Cancer Research Center of Lyon, INSERM U1052, CNRS 5286, Université Lyon 1, 69373 Lyon cedex 03, France. DKFZ German Cancer Research Center, 69121 Heidelberg</wicri:regionArea><placeName><region type="land" nuts="1">Bade-Wurtemberg</region><region type="district" nuts="2">District de Karlsruhe</region><settlement type="city">Heidelberg</settlement></placeName></affiliation></author><author><name sortKey="Huehn, Jochen" sort="Huehn, Jochen" uniqKey="Huehn J" first="Jochen" last="Huehn">Jochen Huehn</name><affiliation wicri:level="1"><nlm:affiliation>Department of Experimental Immunology, Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Experimental Immunology, Helmholtz Centre for Infection Research, 38124 Braunschweig</wicri:regionArea><wicri:noRegion>38124 Braunschweig</wicri:noRegion><wicri:noRegion>38124 Braunschweig</wicri:noRegion><wicri:noRegion>38124 Braunschweig</wicri:noRegion></affiliation></author><author><name sortKey="Zimmermann, Valerie" sort="Zimmermann, Valerie" uniqKey="Zimmermann V" first="Valérie" last="Zimmermann">Valérie Zimmermann</name><affiliation wicri:level="1"><nlm:affiliation>Institut de Génétique Moléculaire de Montpellier, CNRS, UMR 5535, Université de Montpellier, F-34293 Montpellier, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Institut de Génétique Moléculaire de Montpellier, CNRS, UMR 5535, Université de Montpellier, F-34293 Montpellier</wicri:regionArea><wicri:noRegion>34293 Montpellier</wicri:noRegion><wicri:noRegion>34293 Montpellier</wicri:noRegion></affiliation></author><author><name sortKey="Kinet, Sandrina" sort="Kinet, Sandrina" uniqKey="Kinet S" first="Sandrina" last="Kinet">Sandrina Kinet</name><affiliation wicri:level="1"><nlm:affiliation>Institut de Génétique Moléculaire de Montpellier, CNRS, UMR 5535, Université de Montpellier, F-34293 Montpellier, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Institut de Génétique Moléculaire de Montpellier, CNRS, UMR 5535, Université de Montpellier, F-34293 Montpellier</wicri:regionArea><wicri:noRegion>34293 Montpellier</wicri:noRegion><wicri:noRegion>34293 Montpellier</wicri:noRegion></affiliation></author><author><name sortKey="Dardalhon, Valerie" sort="Dardalhon, Valerie" uniqKey="Dardalhon V" first="Valérie" last="Dardalhon">Valérie Dardalhon</name><affiliation wicri:level="1"><nlm:affiliation>Institut de Génétique Moléculaire de Montpellier, CNRS, UMR 5535, Université de Montpellier, F-34293 Montpellier, France. valerie.dardalhon@igmm.cnrs.fr taylor@igmm.cnrs.fr.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Institut de Génétique Moléculaire de Montpellier, CNRS, UMR 5535, Université de Montpellier, F-34293 Montpellier</wicri:regionArea><wicri:noRegion>34293 Montpellier</wicri:noRegion><wicri:noRegion>34293 Montpellier</wicri:noRegion></affiliation></author><author><name sortKey="Taylor, Naomi" sort="Taylor, Naomi" uniqKey="Taylor N" 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Montpellier, CNRS, UMR 5535, Université de Montpellier, F-34293 Montpellier, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Institut de Génétique Moléculaire de Montpellier, CNRS, UMR 5535, Université de Montpellier, F-34293 Montpellier</wicri:regionArea><placeName><region type="region" nuts="2">Occitanie (région administrative)</region><region type="old region" nuts="2">Languedoc-Roussillon</region><settlement type="city">Montpellier</settlement></placeName></affiliation></author><author><name sortKey="Tai, Xuguang" sort="Tai, Xuguang" uniqKey="Tai X" first="Xuguang" last="Tai">Xuguang Tai</name><affiliation wicri:level="2"><nlm:affiliation>Experimental Immunology Branch, National Cancer Institute, Bethesda, MD 20892, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Experimental Immunology Branch, National Cancer Institute, Bethesda, MD 20892</wicri:regionArea><placeName><region type="state">Maryland</region></placeName></affiliation></author><author><name sortKey="Robert, Philippe A" sort="Robert, Philippe A" uniqKey="Robert P" first="Philippe A" last="Robert">Philippe A. Robert</name><affiliation wicri:level="1"><nlm:affiliation>Institut de Génétique Moléculaire de Montpellier, CNRS, UMR 5535, Université de Montpellier, F-34293 Montpellier, France. Department of Systems Immunology, Braunschweig Integrated Centre of Systems Biology, 38124 Braunschweig, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institut de Génétique Moléculaire de Montpellier, CNRS, UMR 5535, Université de Montpellier, F-34293 Montpellier, France. Department of Systems Immunology, Braunschweig Integrated Centre of Systems Biology, 38124 Braunschweig</wicri:regionArea><wicri:noRegion>38124 Braunschweig</wicri:noRegion><wicri:noRegion>38124 Braunschweig</wicri:noRegion><wicri:noRegion>38124 Braunschweig</wicri:noRegion></affiliation></author><author><name sortKey="Craveiro, Marco" sort="Craveiro, Marco" uniqKey="Craveiro M" first="Marco" last="Craveiro">Marco Craveiro</name><affiliation wicri:level="1"><nlm:affiliation>Institut de Génétique Moléculaire de Montpellier, CNRS, UMR 5535, Université de Montpellier, F-34293 Montpellier, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Institut de Génétique Moléculaire de Montpellier, CNRS, UMR 5535, Université de Montpellier, F-34293 Montpellier</wicri:regionArea><wicri:noRegion>34293 Montpellier</wicri:noRegion><wicri:noRegion>34293 Montpellier</wicri:noRegion></affiliation></author><author><name sortKey="Cretenet, Gaspard" sort="Cretenet, Gaspard" uniqKey="Cretenet G" first="Gaspard" last="Cretenet">Gaspard Cretenet</name><affiliation wicri:level="1"><nlm:affiliation>Institut de Génétique Moléculaire de Montpellier, CNRS, UMR 5535, Université de Montpellier, F-34293 Montpellier, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Institut de Génétique Moléculaire de Montpellier, CNRS, UMR 5535, Université de Montpellier, F-34293 Montpellier</wicri:regionArea><wicri:noRegion>34293 Montpellier</wicri:noRegion><wicri:noRegion>34293 Montpellier</wicri:noRegion></affiliation></author><author><name sortKey="Oburoglu, Leal" sort="Oburoglu, Leal" uniqKey="Oburoglu L" first="Leal" last="Oburoglu">Leal Oburoglu</name><affiliation wicri:level="1"><nlm:affiliation>Institut de Génétique Moléculaire de Montpellier, CNRS, UMR 5535, Université de Montpellier, F-34293 Montpellier, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Institut de Génétique Moléculaire de Montpellier, CNRS, UMR 5535, Université de Montpellier, F-34293 Montpellier</wicri:regionArea><wicri:noRegion>34293 Montpellier</wicri:noRegion><wicri:noRegion>34293 Montpellier</wicri:noRegion></affiliation></author><author><name sortKey="Mongellaz, Cedric" sort="Mongellaz, Cedric" uniqKey="Mongellaz C" first="Cédric" last="Mongellaz">Cédric Mongellaz</name><affiliation wicri:level="1"><nlm:affiliation>Institut de Génétique Moléculaire de Montpellier, CNRS, UMR 5535, Université de Montpellier, F-34293 Montpellier, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Institut de Génétique Moléculaire de Montpellier, CNRS, UMR 5535, Université de Montpellier, F-34293 Montpellier</wicri:regionArea><wicri:noRegion>34293 Montpellier</wicri:noRegion><wicri:noRegion>34293 Montpellier</wicri:noRegion></affiliation></author><author><name sortKey="Floess, Stefan" sort="Floess, Stefan" uniqKey="Floess S" first="Stefan" last="Floess">Stefan Floess</name><affiliation wicri:level="1"><nlm:affiliation>Department of Experimental Immunology, Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Experimental Immunology, Helmholtz Centre for Infection Research, 38124 Braunschweig</wicri:regionArea><wicri:noRegion>38124 Braunschweig</wicri:noRegion><wicri:noRegion>38124 Braunschweig</wicri:noRegion><wicri:noRegion>38124 Braunschweig</wicri:noRegion></affiliation></author><author><name sortKey="Fritz, Vanessa" sort="Fritz, Vanessa" uniqKey="Fritz V" first="Vanessa" last="Fritz">Vanessa Fritz</name><affiliation wicri:level="1"><nlm:affiliation>Institut de Génétique Moléculaire de Montpellier, CNRS, UMR 5535, Université de Montpellier, F-34293 Montpellier, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Institut de Génétique Moléculaire de Montpellier, CNRS, UMR 5535, Université de Montpellier, F-34293 Montpellier</wicri:regionArea><wicri:noRegion>34293 Montpellier</wicri:noRegion><wicri:noRegion>34293 Montpellier</wicri:noRegion></affiliation></author><author><name sortKey="Matias, Maria I" sort="Matias, Maria I" uniqKey="Matias M" first="Maria I" last="Matias">Maria I. Matias</name><affiliation wicri:level="1"><nlm:affiliation>Institut de Génétique Moléculaire de Montpellier, CNRS, UMR 5535, Université de Montpellier, F-34293 Montpellier, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Institut de Génétique Moléculaire de Montpellier, CNRS, UMR 5535, Université de Montpellier, F-34293 Montpellier</wicri:regionArea><wicri:noRegion>34293 Montpellier</wicri:noRegion><wicri:noRegion>34293 Montpellier</wicri:noRegion></affiliation></author><author><name sortKey="Yong, Carmen" sort="Yong, Carmen" uniqKey="Yong C" first="Carmen" last="Yong">Carmen Yong</name><affiliation wicri:level="1"><nlm:affiliation>Institut de Génétique Moléculaire de Montpellier, CNRS, UMR 5535, Université de Montpellier, F-34293 Montpellier, France. Cancer Immunology Research Program, Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria 3010, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Institut de Génétique Moléculaire de Montpellier, CNRS, UMR 5535, Université de Montpellier, F-34293 Montpellier, France. Cancer Immunology Research Program, Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria 3010</wicri:regionArea><wicri:noRegion>Victoria 3010</wicri:noRegion></affiliation></author><author><name sortKey="Surh, Natalie" sort="Surh, Natalie" uniqKey="Surh N" first="Natalie" last="Surh">Natalie Surh</name><affiliation wicri:level="1"><nlm:affiliation>Institut de Génétique Moléculaire de Montpellier, CNRS, UMR 5535, Université de Montpellier, F-34293 Montpellier, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Institut de Génétique Moléculaire de Montpellier, CNRS, UMR 5535, Université de Montpellier, F-34293 Montpellier</wicri:regionArea><wicri:noRegion>34293 Montpellier</wicri:noRegion><wicri:noRegion>34293 Montpellier</wicri:noRegion></affiliation></author><author><name sortKey="Marie, Julien C" sort="Marie, Julien C" uniqKey="Marie J" first="Julien C" last="Marie">Julien C. Marie</name><affiliation wicri:level="3"><nlm:affiliation>Cancer Research Center of Lyon, INSERM U1052, CNRS 5286, Université Lyon 1, 69373 Lyon cedex 03, France. DKFZ German Cancer Research Center, 69121 Heidelberg, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Cancer Research Center of Lyon, INSERM U1052, CNRS 5286, Université Lyon 1, 69373 Lyon cedex 03, France. DKFZ German Cancer Research Center, 69121 Heidelberg</wicri:regionArea><placeName><region type="land" nuts="1">Bade-Wurtemberg</region><region type="district" nuts="2">District de Karlsruhe</region><settlement type="city">Heidelberg</settlement></placeName></affiliation></author><author><name sortKey="Huehn, Jochen" sort="Huehn, Jochen" uniqKey="Huehn J" first="Jochen" last="Huehn">Jochen Huehn</name><affiliation wicri:level="1"><nlm:affiliation>Department of Experimental Immunology, Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Experimental Immunology, Helmholtz Centre for Infection Research, 38124 Braunschweig</wicri:regionArea><wicri:noRegion>38124 Braunschweig</wicri:noRegion><wicri:noRegion>38124 Braunschweig</wicri:noRegion><wicri:noRegion>38124 Braunschweig</wicri:noRegion></affiliation></author><author><name sortKey="Zimmermann, Valerie" sort="Zimmermann, Valerie" uniqKey="Zimmermann V" first="Valérie" last="Zimmermann">Valérie Zimmermann</name><affiliation wicri:level="1"><nlm:affiliation>Institut de Génétique Moléculaire de Montpellier, CNRS, UMR 5535, Université de Montpellier, F-34293 Montpellier, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Institut de Génétique Moléculaire de Montpellier, CNRS, UMR 5535, Université de Montpellier, F-34293 Montpellier</wicri:regionArea><wicri:noRegion>34293 Montpellier</wicri:noRegion><wicri:noRegion>34293 Montpellier</wicri:noRegion></affiliation></author><author><name sortKey="Kinet, Sandrina" sort="Kinet, Sandrina" uniqKey="Kinet S" first="Sandrina" last="Kinet">Sandrina Kinet</name><affiliation wicri:level="1"><nlm:affiliation>Institut de Génétique Moléculaire de Montpellier, CNRS, UMR 5535, Université de Montpellier, F-34293 Montpellier, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Institut de Génétique Moléculaire de Montpellier, CNRS, UMR 5535, Université de Montpellier, F-34293 Montpellier</wicri:regionArea><wicri:noRegion>34293 Montpellier</wicri:noRegion><wicri:noRegion>34293 Montpellier</wicri:noRegion></affiliation></author><author><name sortKey="Dardalhon, Valerie" sort="Dardalhon, Valerie" uniqKey="Dardalhon V" first="Valérie" last="Dardalhon">Valérie Dardalhon</name><affiliation wicri:level="1"><nlm:affiliation>Institut de Génétique Moléculaire de Montpellier, CNRS, UMR 5535, Université de Montpellier, F-34293 Montpellier, France. valerie.dardalhon@igmm.cnrs.fr taylor@igmm.cnrs.fr.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Institut de Génétique Moléculaire de Montpellier, CNRS, UMR 5535, Université de Montpellier, F-34293 Montpellier</wicri:regionArea><wicri:noRegion>34293 Montpellier</wicri:noRegion><wicri:noRegion>34293 Montpellier</wicri:noRegion></affiliation></author><author><name sortKey="Taylor, Naomi" sort="Taylor, Naomi" uniqKey="Taylor N" first="Naomi" last="Taylor">Naomi Taylor</name><affiliation wicri:level="1"><nlm:affiliation>Institut de Génétique Moléculaire de Montpellier, CNRS, UMR 5535, Université de Montpellier, F-34293 Montpellier, France. valerie.dardalhon@igmm.cnrs.fr taylor@igmm.cnrs.fr.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Institut de Génétique Moléculaire de Montpellier, CNRS, UMR 5535, Université de Montpellier, F-34293 Montpellier</wicri:regionArea><wicri:noRegion>34293 Montpellier</wicri:noRegion><wicri:noRegion>34293 Montpellier</wicri:noRegion></affiliation></author></analytic><series><title level="j">Science signaling</title><idno type="eISSN">1937-9145</idno><imprint><date when="2015" type="published">2015</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals</term><term>Cell Differentiation (immunology)</term><term>Glutamine (immunology)</term><term>Glutamine (metabolism)</term><term>Ketoglutaric Acids (immunology)</term><term>Ketoglutaric Acids (metabolism)</term><term>Mice</term><term>Multiprotein Complexes (immunology)</term><term>Multiprotein Complexes (metabolism)</term><term>T-Lymphocytes, Regulatory (immunology)</term><term>T-Lymphocytes, Regulatory (metabolism)</term><term>TOR Serine-Threonine Kinases (immunology)</term><term>TOR Serine-Threonine Kinases (metabolism)</term><term>Th1 Cells (immunology)</term><term>Th1 Cells (metabolism)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Acides cétoglutariques (immunologie)</term><term>Acides cétoglutariques (métabolisme)</term><term>Animaux</term><term>Complexes multiprotéiques (immunologie)</term><term>Complexes multiprotéiques (métabolisme)</term><term>Différenciation cellulaire (immunologie)</term><term>Glutamine (immunologie)</term><term>Glutamine (métabolisme)</term><term>Lymphocytes T régulateurs (immunologie)</term><term>Lymphocytes T régulateurs (métabolisme)</term><term>Lymphocytes auxiliaires Th1 (immunologie)</term><term>Lymphocytes auxiliaires Th1 (métabolisme)</term><term>Souris</term><term>Sérine-thréonine kinases TOR (immunologie)</term><term>Sérine-thréonine kinases TOR (métabolisme)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="immunology" xml:lang="en"><term>Glutamine</term><term>Ketoglutaric Acids</term><term>Multiprotein Complexes</term><term>TOR Serine-Threonine Kinases</term></keywords><keywords scheme="MESH" qualifier="immunologie" xml:lang="fr"><term>Acides cétoglutariques</term><term>Complexes multiprotéiques</term><term>Différenciation cellulaire</term><term>Glutamine</term><term>Lymphocytes T régulateurs</term><term>Lymphocytes auxiliaires Th1</term><term>Sérine-thréonine kinases TOR</term></keywords><keywords scheme="MESH" qualifier="immunology" xml:lang="en"><term>Cell Differentiation</term><term>T-Lymphocytes, Regulatory</term><term>Th1 Cells</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Glutamine</term><term>Ketoglutaric Acids</term><term>Multiprotein Complexes</term><term>T-Lymphocytes, Regulatory</term><term>TOR Serine-Threonine Kinases</term><term>Th1 Cells</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Acides cétoglutariques</term><term>Complexes multiprotéiques</term><term>Glutamine</term><term>Lymphocytes T régulateurs</term><term>Lymphocytes auxiliaires Th1</term><term>Sérine-thréonine kinases TOR</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Mice</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Animaux</term><term>Souris</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">T cell activation requires that the cell meet increased energetic and biosynthetic demands. We showed that exogenous nutrient availability regulated the differentiation of naïve CD4(+) T cells into distinct subsets. Activation of naïve CD4(+) T cells under conditions of glutamine deprivation resulted in their differentiation into Foxp3(+) (forkhead box P3-positive) regulatory T (Treg) cells, which had suppressor function in vivo. Moreover, glutamine-deprived CD4(+) T cells that were activated in the presence of cytokines that normally induce the generation of T helper 1 (TH1) cells instead differentiated into Foxp3(+) Treg cells. We found that α-ketoglutarate (αKG), the glutamine-derived metabolite that enters into the mitochondrial citric acid cycle, acted as a metabolic regulator of CD4(+) T cell differentiation. Activation of glutamine-deprived naïve CD4(+) T cells in the presence of a cell-permeable αKG analog increased the expression of the gene encoding the TH1 cell-associated transcription factor Tbet and resulted in their differentiation into TH1 cells, concomitant with stimulation of mammalian target of rapamycin complex 1 (mTORC1) signaling. Together, these data suggest that a decrease in the intracellular amount of αKG, caused by the limited availability of extracellular glutamine, shifts the balance between the generation of TH1 and Treg cells toward that of a Treg phenotype.</div></front></TEI><affiliations><list><country><li>Allemagne</li><li>Australie</li><li>France</li><li>États-Unis</li></country><region><li>Bade-Wurtemberg</li><li>District de Karlsruhe</li><li>Languedoc-Roussillon</li><li>Maryland</li><li>Occitanie (région administrative)</li></region><settlement><li>Heidelberg</li><li>Montpellier</li></settlement></list><tree><country name="France"><region name="Occitanie (région administrative)"><name sortKey="Klysz, Dorota" sort="Klysz, Dorota" uniqKey="Klysz D" first="Dorota" last="Klysz">Dorota Klysz</name></region><name sortKey="Craveiro, Marco" sort="Craveiro, Marco" uniqKey="Craveiro M" first="Marco" last="Craveiro">Marco Craveiro</name><name sortKey="Cretenet, Gaspard" sort="Cretenet, Gaspard" uniqKey="Cretenet G" first="Gaspard" last="Cretenet">Gaspard Cretenet</name><name sortKey="Dardalhon, Valerie" sort="Dardalhon, Valerie" uniqKey="Dardalhon V" first="Valérie" last="Dardalhon">Valérie Dardalhon</name><name sortKey="Fritz, Vanessa" sort="Fritz, Vanessa" uniqKey="Fritz V" first="Vanessa" last="Fritz">Vanessa Fritz</name><name sortKey="Kinet, Sandrina" sort="Kinet, Sandrina" uniqKey="Kinet S" first="Sandrina" last="Kinet">Sandrina Kinet</name><name sortKey="Matias, Maria I" sort="Matias, Maria I" uniqKey="Matias M" first="Maria I" last="Matias">Maria I. Matias</name><name sortKey="Mongellaz, Cedric" sort="Mongellaz, Cedric" uniqKey="Mongellaz C" first="Cédric" last="Mongellaz">Cédric Mongellaz</name><name sortKey="Oburoglu, Leal" sort="Oburoglu, Leal" uniqKey="Oburoglu L" first="Leal" last="Oburoglu">Leal Oburoglu</name><name sortKey="Surh, Natalie" sort="Surh, Natalie" uniqKey="Surh N" first="Natalie" last="Surh">Natalie Surh</name><name sortKey="Taylor, Naomi" sort="Taylor, Naomi" uniqKey="Taylor N" first="Naomi" last="Taylor">Naomi Taylor</name><name sortKey="Zimmermann, Valerie" sort="Zimmermann, Valerie" uniqKey="Zimmermann V" first="Valérie" last="Zimmermann">Valérie Zimmermann</name></country><country name="États-Unis"><region name="Maryland"><name sortKey="Tai, Xuguang" sort="Tai, Xuguang" uniqKey="Tai X" first="Xuguang" last="Tai">Xuguang Tai</name></region></country><country name="Allemagne"><noRegion><name sortKey="Robert, Philippe A" sort="Robert, Philippe A" uniqKey="Robert P" first="Philippe A" last="Robert">Philippe A. Robert</name></noRegion><name sortKey="Floess, Stefan" sort="Floess, Stefan" uniqKey="Floess S" first="Stefan" last="Floess">Stefan Floess</name><name sortKey="Huehn, Jochen" sort="Huehn, Jochen" uniqKey="Huehn J" first="Jochen" last="Huehn">Jochen Huehn</name><name sortKey="Marie, Julien C" sort="Marie, Julien C" uniqKey="Marie J" first="Julien C" last="Marie">Julien C. Marie</name></country><country name="Australie"><noRegion><name sortKey="Yong, Carmen" sort="Yong, Carmen" uniqKey="Yong C" first="Carmen" last="Yong">Carmen Yong</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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