title: Glutamine-dependent α-ketoglutarate production regulates the balance between T helper 1 cell and regulatory T cell generation.
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.
authors.affiliation: Institut de Génétique Moléculaire de Montpellier, CNRS, UMR 5535, Université de Montpellier, F-34293 Montpellier, France.
authors.forename: Dorota
authors.initials: D
authors.lastname: Klysz
authors.affiliation: Experimental Immunology Branch, National Cancer Institute, Bethesda, MD 20892, USA.
authors.forename: Xuguang
authors.initials: X
authors.lastname: Tai
authors.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.
authors.forename: Philippe A
authors.initials: PA
authors.lastname: Robert
authors.affiliation: Institut de Génétique Moléculaire de Montpellier, CNRS, UMR 5535, Université de Montpellier, F-34293 Montpellier, France.
authors.forename: Marco
authors.initials: M
authors.lastname: Craveiro
authors.affiliation: Institut de Génétique Moléculaire de Montpellier, CNRS, UMR 5535, Université de Montpellier, F-34293 Montpellier, France.
authors.forename: Gaspard
authors.initials: G
authors.lastname: Cretenet
authors.affiliation: Institut de Génétique Moléculaire de Montpellier, CNRS, UMR 5535, Université de Montpellier, F-34293 Montpellier, France.
authors.forename: Leal
authors.initials: L
authors.lastname: Oburoglu
authors.affiliation: Institut de Génétique Moléculaire de Montpellier, CNRS, UMR 5535, Université de Montpellier, F-34293 Montpellier, France.
authors.forename: Cédric
authors.initials: C
authors.lastname: Mongellaz
authors.affiliation: Department of Experimental Immunology, Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Floess
authors.affiliation: Institut de Génétique Moléculaire de Montpellier, CNRS, UMR 5535, Université de Montpellier, F-34293 Montpellier, France.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Fritz
authors.affiliation: Institut de Génétique Moléculaire de Montpellier, CNRS, UMR 5535, Université de Montpellier, F-34293 Montpellier, France.
authors.forename: Maria I
authors.initials: MI
authors.lastname: Matias
authors.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.
authors.forename: Carmen
authors.initials: C
authors.lastname: Yong
authors.affiliation: Institut de Génétique Moléculaire de Montpellier, CNRS, UMR 5535, Université de Montpellier, F-34293 Montpellier, France.
authors.forename: Natalie
authors.initials: N
authors.lastname: Surh
authors.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.
authors.forename: Julien C
authors.initials: JC
authors.lastname: Marie
authors.affiliation: Department of Experimental Immunology, Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Huehn
authors.affiliation: Institut de Génétique Moléculaire de Montpellier, CNRS, UMR 5535, Université de Montpellier, F-34293 Montpellier, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Zimmermann
authors.affiliation: Institut de Génétique Moléculaire de Montpellier, CNRS, UMR 5535, Université de Montpellier, F-34293 Montpellier, France.
authors.forename: Sandrina
authors.initials: S
authors.lastname: Kinet
authors.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.
authors.forename: Valérie
authors.initials: V
authors.lastname: Dardalhon
authors.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.
authors.forename: Naomi
authors.initials: N
authors.lastname: Taylor
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000276:immunology*; D005973:Glutamine / Q000276:immunology* / Q000378:metabolism; D007656:Ketoglutaric Acids / Q000276:immunology* / Q000378:metabolism; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D046912:Multiprotein Complexes / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000276:immunology / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism
chemical_list: D007656:Ketoglutaric Acids; D046912:Multiprotein Complexes; D005973:Glutamine; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases