Reference : Pyruvate dehydrogenase fuels a critical citrate pool that is essential for Th17 cell ...

	Document type :	Scientific journals : Article
	Discipline(s) :	Life sciences : Biochemistry, biophysics & molecular biology
	To cite this reference:	http://hdl.handle.net/10993/55697

Title :	Pyruvate dehydrogenase fuels a critical citrate pool that is essential for Th17 cell effector functions
Language :	English
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 [Luxembourg Center for Systems Biomedicine, University of Luxembourg, 4362 Esch-sur-Alzette, Luxembourg]
	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]
Publication date :	2023
Journal title :	Cell Reports
Publisher :	Elsevier
Peer reviewed :	Yes
Audience :	International
ISSN :	2211-1247
e-ISSN :	2211-1247
City :	Amsterdam
Country :	Netherlands
Keywords :	[en] Immunology ; Immunology ; IL-17
Abstract :	[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.
Permalink :	http://hdl.handle.net/10993/55697
DOI :	10.1016/j.celrep.2023.112153

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