[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 :
Laboratory medicine & medical technology
Author, co-author :
Soriano-Baguet, Leticia; Experimental and Molecular Immunology, Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg, Immunology and Genetics, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 7, Avenue des Hauts Fourneaux, Esch-sur-Alzette, Luxembourg
Grusdat, Melanie; Experimental and Molecular Immunology, Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg, Immunology and Genetics, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 7, Avenue des Hauts Fourneaux, Esch-sur-Alzette, Luxembourg
Kurniawan, Henry; Experimental and Molecular Immunology, Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg, Immunology and Genetics, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 7, Avenue des Hauts Fourneaux, Esch-sur-Alzette, Luxembourg
Benzarti, Mohaned; Cancer Metabolism Group, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg, Luxembourg, Faculty of Science, Technology, and Medicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg
Binsfeld, Carole; Experimental and Molecular Immunology, Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg, Immunology and Genetics, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 7, Avenue des Hauts Fourneaux, Esch-sur-Alzette, Luxembourg
Ewen, Anouk; Experimental and Molecular Immunology, Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg, Immunology and Genetics, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 7, Avenue des Hauts Fourneaux, Esch-sur-Alzette, Luxembourg
Longworth, Joseph; Experimental and Molecular Immunology, Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg, Immunology and Genetics, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 7, Avenue des Hauts Fourneaux, Esch-sur-Alzette, Luxembourg
Bonetti, Lynn; Experimental and Molecular Immunology, Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg, Immunology and Genetics, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 7, Avenue des Hauts Fourneaux, Esch-sur-Alzette, Luxembourg
Guerra, Luana; Experimental and Molecular Immunology, Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg, Immunology and Genetics, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 7, Avenue des Hauts Fourneaux, Esch-sur-Alzette, Luxembourg
Franchina, Davide G; Experimental and Molecular Immunology, Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg, Immunology and Genetics, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 7, Avenue des Hauts Fourneaux, Esch-sur-Alzette, Luxembourg
Kobayashi, Takumi; Experimental and Molecular Immunology, Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg, Immunology and Genetics, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 7, Avenue des Hauts Fourneaux, Esch-sur-Alzette, Luxembourg
Horkova, Veronika; Experimental and Molecular Immunology, Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg, Immunology and Genetics, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 7, Avenue des Hauts Fourneaux, Esch-sur-Alzette, Luxembourg
Verschueren, Charlène; Experimental and Molecular Immunology, Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg, Immunology and Genetics, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 7, Avenue des Hauts Fourneaux, Esch-sur-Alzette, Luxembourg
Helgueta Romero, Sergio ; Université de Liège - ULiège > GIGA > GIGA Neurosciences - Molecular Regulation of Neurogenesis
Gérard, Deborah; Epigenetics Team, Systems Biology Group, Department of Life Sciences and Medicine, University of Luxembourg, Belvaux, Luxembourg
More, Tushar H; Department of Bioinformatics and Biochemistry, Braunschweig Integrated Center of Systems Biology, Technische Universität Braunschweig, Rebenring 56, 38106 Braunschweig, Germany
Henne, Antonia; Department of Bioinformatics and Biochemistry, Braunschweig Integrated Center of Systems Biology, Technische Universität Braunschweig, Rebenring 56, 38106 Braunschweig, Germany
Dostert, Catherine; Experimental and Molecular Immunology, Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg, Immunology and Genetics, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 7, Avenue des Hauts Fourneaux, Esch-sur-Alzette, Luxembourg
Farinelle, Sophie; Experimental and Molecular Immunology, Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg, Immunology and Genetics, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 7, Avenue des Hauts Fourneaux, Esch-sur-Alzette, Luxembourg
Lesur, Antoine; Metabolomics Platform, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg, Luxembourg
Gérardy, Jean-Jacques; Luxembourg Center of Neuropathology, 3555 Dudelange, Luxembourg, National Center of Pathology, Laboratoire National de Santé (LNS), Dudelange, Luxembourg
Jäger, Christian; Luxembourg Center for Systems Biomedicine, University of Luxembourg, 4362 Esch-sur-Alzette, Luxembourg
Mittelbronn, Michel; Faculty of Science, Technology, and Medicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg, Luxembourg Center of Neuropathology, 3555 Dudelange, Luxembourg, National Center of Pathology, Laboratoire National de Santé (LNS), Dudelange, Luxembourg, Luxembourg Center for Systems Biomedicine, University of Luxembourg, 4362 Esch-sur-Alzette, Luxembourg, Department of Life Sciences and Medicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg, Department of Cancer Research, Luxembourg Institute of Health, 1526 Luxembourg, Luxembourg
Sinkkonen, Lasse; Epigenetics Team, Systems Biology Group, Department of Life Sciences and Medicine, University of Luxembourg, Belvaux, Luxembourg
Hiller, Karsten; Department of Bioinformatics and Biochemistry, Braunschweig Integrated Center of Systems Biology, Technische Universität Braunschweig, Rebenring 56, 38106 Braunschweig, Germany
Meiser, Johannes; Cancer Metabolism Group, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg, Luxembourg, Metabolomics Platform, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg, Luxembourg
Brenner, Dirk; Experimental and Molecular Immunology, Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg, Immunology and Genetics, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 7, Avenue des Hauts Fourneaux, Esch-sur-Alzette, Luxembourg, Odense Research Center for Anaphylaxis, Department of Dermatology and Allergy Center, Odense University Hospital, University of Southern Denmark, Odense, Denmark. Electronic address: dirk.brenner@lih.lu
D.B. is supported by FNR -ATTRACT ( A14/BM/7632103 ) and FNR -CORE grants ( C21/BM/15796788 and C18/BM/12691266 ). D.B., T.K., and C.D. are supported by FNRS -Televie grants 7.4587.20 and/or 7.497.19 ; D.B., L.B., L.G., and L.S.-B. by FNR -PRIDE ( PRIDE/11012546/NEXTIMMUNE ); D.B. and A.E. by PRIDE17/11823097/MicrOH ; D.B. and D.G.F. by FNR -RIKEN ( TregBar/11228353 ); S.H. by FNR -PRIDE ( PRIDE17/12244779/PARK-Q ); D.G. by a postdoctoral fellowship from the Fondation du Pélican de Mie et Pierre Hippert-Faber ; J.M. by FNR -ATTRACT ( A18/BM/11809970 ); and M.M. by FNR PEARL ( P16/BM/11192868 ).We are grateful to Max Löhning (Charité University Berlin) and Alexander Skupin (University of Luxembourg) for helpful discussions, Dr. Aurelien Ginolhac (University of Luxembourg) for bioinformatic analysis, the Metabolomics Platform of the Luxembourg Center for Systems Biomedicine (LCSB; University of Luxembourg) for metabolomics data, Dr. Rashi Halder of the Sequencing Platform of the LCSB for sequencing data (RRID: SCR_021931), the High-Performance Computing (HPC) platform (University of Luxembourg), and the National Cytometry Platform (LIH; Luxembourg) for support with flow cytometry. We also thank Samantha Storn, Anaïs Oudin, all Animal Facility staff, and LIH's Animal Welfare Structure for animal services at LIH, Luxembourg, and Djalil Coowar, Jennifer Behm, Marthe Schmit and all Animal Facility staff for animal services at the University of Luxembourg. D.B. is supported by FNR-ATTRACT (A14/BM/7632103) and FNR-CORE grants (C21/BM/15796788 and C18/BM/12691266). D.B. T.K. and C.D. are supported by FNRS-Televie grants 7.4587.20 and/or 7.497.19; D.B. L.B. L.G. and L.S.-B. by FNR-PRIDE (PRIDE/11012546/NEXTIMMUNE); D.B. and A.E. by PRIDE17/11823097/MicrOH; D.B. and D.G.F. by FNR-RIKEN (TregBar/11228353); S.H. by FNR-PRIDE (PRIDE17/12244779/PARK-Q); D.G. by a postdoctoral fellowship from the Fondation du Pélican de Mie et Pierre Hippert-Faber; J.M. by FNR-ATTRACT (A18/BM/11809970); and M.M. by FNR PEARL (P16/BM/11192868). L.S.-B. performed most experiments, assisted by M.G. H.K. L.B. A.E. L.G. D.G.F. C.B. C.V. and S.F. L.S.-B. M.G. and C.B. isolated brains and spleens from EAE mice. L.S.-B. H.K. A.E. and D.G.F. performed Seahorse flux assays. Isotopic and metabolic tracing experiments were performed by L.S.-B. M.G. and H.K. and analyzed by M.B. and J.M. Histone and palmitate tracing experiments were performed and analyzed by T.H.M. and A.H. Analysis of RNA-seq data was performed by J.L. and S.H. ATAC-seq and data analysis were performed by S.H. D.G. and L.S. T.K. C.D. J.-J.G. C.J. M.M. L.S. K.H. and J.M. provided reagents and expert comments. D.B. supervised the project. L.S.-B. and D.B. conceptualized the work, designed all experiments, analyzed data, and wrote the manuscript. All authors reviewed and edited the final manuscript. The authors declare no competing interests. We support inclusive, diverse, and equitable conduct of research.
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