[en] Pyruvate dehydrogenase (PDH) is the central enzyme connecting glycolysis and the tricarboxylic acid (TCA) cycle. The importance of PDH function in T helper 17 (Th17) cells still remains to be studied. Here, we show that PDH is essential for the generation of a glucose-derived citrate pool needed for Th17 cell proliferation, survival, and effector function. In vivo, mice harboring a T cell-specific deletion of PDH are less susceptible to developing experimental autoimmune encephalomyelitis. Mechanistically, the absence of PDH in Th17 cells increases glutaminolysis, glycolysis, and lipid uptake in a mammalian target of rapamycin (mTOR)-dependent manner. However, cellular citrate remains critically low in mutant Th17 cells, which interferes with oxidative phosphorylation (OXPHOS), lipid synthesis, and histone acetylation, crucial for transcription of Th17 signature genes. Increasing cellular citrate in PDH-deficient Th17 cells restores their metabolism and function, identifying a metabolic feedback loop within the central carbon metabolism that may offer possibilities for therapeutically targeting Th17 cell-driven autoimmunity.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Soriano-Baguet, Leticia; Experimental and Molecular Immunology, Department of Infection and Immunity, Luxembourg Institute of Health
Grusdat, Melanie; Experimental and Molecular Immunology, Department of Infection and Immunity, Luxembourg Institute of Health
Kurniawan, Henry; Experimental and Molecular Immunology, Department of Infection and Immunity, Luxembourg Institute of Health
Benzarti, Mohaned; Cancer Metabolism Group, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg,
Binsfeld, Carole; Experimental and Molecular Immunology, Department of Infection and Immunity, Luxembourg Institute of Health
Ewen, Anouk; Experimental and Molecular Immunology, Department of Infection and Immunity, Luxembourg Institute of Health
LONGWORTH, Joseph ; Experimental and Molecular Immunology, Department of Infection and Immunity, Luxembourg Institute of Health
Bonetti, Lynn; Experimental and Molecular Immunology, Department of Infection and Immunity, Luxembourg Institute of Health
Guerra, Luana; Experimental and Molecular Immunology, Department of Infection and Immunity, Luxembourg Institute of Health
Franchina, Davide G; Experimental and Molecular Immunology, Department of Infection and Immunity, Luxembourg Institute of Health
Kobayashi, Takumi; Experimental and Molecular Immunology, Department of Infection and Immunity, Luxembourg Institute of Health
Horkova, Veronika; Experimental and Molecular Immunology, Department of Infection and Immunity, Luxembourg Institute of Health
Verschueren, Charlène; Experimental and Molecular Immunology, Department of Infection and Immunity, Luxembourg Institute of Health
Helgueta, Sergio; Luxembourg Center of Neuropathology, Dudelange, Luxembourg ; Department of Life Sciences and Medicine, University of Luxembourg, Belvaux, Luxembourg
GERARD, Déborah ; University of Luxembourg > Faculty of Science, Technology and Medicine (FSTM) > Department of Life Sciences and Medicine (DLSM)
More, Tushar H; Department of Bioinformatics and Biochemistry, Braunschweig Integrated Center of Systems Biology, Technische Universität Braunschweig, Germany
Henne, Antonia; Department of Bioinformatics and Biochemistry, Braunschweig Integrated Center of Systems Biology, Technische Universität Braunschweig, Germany
Dostert, Catherine; Experimental and Molecular Immunology, Department of Infection and Immunity, Luxembourg Institute of Health
Farinelle, Sophie; Experimental and Molecular Immunology, Department of Infection and Immunity, Luxembourg Institute of Health
Lesur, Antoine; Metabolomics Platform, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg, Luxembourg
Gérardy, Jean-Jacques; Luxembourg Center of Neuropathology, Dudelange, Luxembourg ; National Center of Pathology, Laboratoire National de Santé (LNS), Dudelange, Luxembourg.
JÄGER, Christian ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Scientific Central Services > Metabolomics Platform
MITTELBRONN, Michel ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Neuropathology
SINKKONEN, Lasse ; University of Luxembourg > Faculty of Science, Technology and Medicine (FSTM) > Department of Life Sciences and Medicine (DLSM)
Hiller, Karsten; Department of Bioinformatics and Biochemistry, Braunschweig Integrated Center of Systems Biology, Technische Universität Braunschweig, Germany
Meiser, Johannes; Cancer Metabolism Group, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg
Brenner, Dirk; Experimental and Molecular Immunology, Department of Infection and Immunity, Luxembourg Institute of Health, Luxembourg
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