Cell Reports (Mar 2023)
Pyruvate dehydrogenase fuels a critical citrate pool that is essential for Th17 cell effector functions
- Leticia Soriano-Baguet,
- Melanie Grusdat,
- Henry Kurniawan,
- Mohaned Benzarti,
- Carole Binsfeld,
- Anouk Ewen,
- Joseph Longworth,
- Lynn Bonetti,
- Luana Guerra,
- Davide G. Franchina,
- Takumi Kobayashi,
- Veronika Horkova,
- Charlène Verschueren,
- Sergio Helgueta,
- Deborah Gérard,
- Tushar H. More,
- Antonia Henne,
- Catherine Dostert,
- Sophie Farinelle,
- Antoine Lesur,
- Jean-Jacques Gérardy,
- Christian Jäger,
- Michel Mittelbronn,
- Lasse Sinkkonen,
- Karsten Hiller,
- Johannes Meiser,
- Dirk Brenner
Affiliations
- Leticia Soriano-Baguet
- 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
- Melanie Grusdat
- 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
- Henry Kurniawan
- 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
- Mohaned Benzarti
- 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
- Carole Binsfeld
- 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
- Anouk Ewen
- 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
- Joseph Longworth
- 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
- Lynn Bonetti
- 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
- Luana Guerra
- 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
- Davide G. Franchina
- 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
- Takumi Kobayashi
- 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
- Veronika Horkova
- 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
- Charlène Verschueren
- 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
- Sergio Helgueta
- Luxembourg Center of Neuropathology, 3555 Dudelange, Luxembourg; Epigenetics Team, Systems Biology Group, Department of Life Sciences and Medicine, University of Luxembourg, Belvaux, Luxembourg
- Deborah Gérard
- Epigenetics Team, Systems Biology Group, Department of Life Sciences and Medicine, University of Luxembourg, Belvaux, Luxembourg
- Tushar H. More
- Department of Bioinformatics and Biochemistry, Braunschweig Integrated Center of Systems Biology, Technische Universität Braunschweig, Rebenring 56, 38106 Braunschweig, Germany
- Antonia Henne
- Department of Bioinformatics and Biochemistry, Braunschweig Integrated Center of Systems Biology, Technische Universität Braunschweig, Rebenring 56, 38106 Braunschweig, Germany
- Catherine Dostert
- 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
- Sophie Farinelle
- 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
- Antoine Lesur
- Metabolomics Platform, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg, Luxembourg
- Jean-Jacques Gérardy
- Luxembourg Center of Neuropathology, 3555 Dudelange, Luxembourg; National Center of Pathology, Laboratoire National de Santé (LNS), Dudelange, Luxembourg
- Christian Jäger
- Luxembourg Center for Systems Biomedicine, University of Luxembourg, 4362 Esch-sur-Alzette, Luxembourg
- Michel Mittelbronn
- 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
- Lasse Sinkkonen
- Epigenetics Team, Systems Biology Group, Department of Life Sciences and Medicine, University of Luxembourg, Belvaux, Luxembourg
- Karsten Hiller
- Department of Bioinformatics and Biochemistry, Braunschweig Integrated Center of Systems Biology, Technische Universität Braunschweig, Rebenring 56, 38106 Braunschweig, Germany
- Johannes Meiser
- 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
- Dirk Brenner
- 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; Corresponding author
- Journal volume & issue
-
Vol. 42,
no. 3
p. 112153
Abstract
Summary: 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.
