Regulatory T cell differentiation is controlled by αKG-induced alterations in mitochondrial metabolism and lipid homeostasis.

Autor:	Matias MI; Institut de Génétique Moléculaire de Montpellier, Univ Montpellier, CNRS, Montpellier, France., Yong CS; Institut de Génétique Moléculaire de Montpellier, Univ Montpellier, CNRS, Montpellier, France; Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Australia., Foroushani A; Laboratory of Immune System Biology, NIAID, NIH, Bethesda, MD, USA., Goldsmith C; Cancer Research Center of Lyon, University Lyon 1, Inserm/ CNRS, Labex DEVweCAN, Lyon France., Mongellaz C; Institut de Génétique Moléculaire de Montpellier, Univ Montpellier, CNRS, Montpellier, France., Sezgin E; Science for Life Laboratory, Department of Women's and Children's Health, Karolinska Institute, Solna, Sweden., Levental KR; Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA, USA., Talebi A; Laboratory of Lipid Metabolism and Cancer, Leuven Cancer Institute, Leuven, Belgium., Perrault J; Institut de Génétique Moléculaire de Montpellier, Univ Montpellier, CNRS, Montpellier, France., Rivière A; Institut de Génétique Moléculaire de Montpellier, Univ Montpellier, CNRS, Montpellier, France., Dehairs J; Laboratory of Lipid Metabolism and Cancer, Leuven Cancer Institute, Leuven, Belgium., Delos O; MetaboHUB-MetaToul, National Infrastructure of Metabolomics and Fluxomics, Toulouse, France; I2MC, Université de Toulouse, Inserm, Toulouse, France., Bertand-Michel J; MetaboHUB-MetaToul, National Infrastructure of Metabolomics and Fluxomics, Toulouse, France; I2MC, Université de Toulouse, Inserm, Toulouse, France., Portais JC; MetaboHUB-MetaToul, National Infrastructure of Metabolomics and Fluxomics, Toulouse, France., Wong M; Laboratory of Immune System Biology, NIAID, NIH, Bethesda, MD, USA., Marie JC; Cancer Research Center of Lyon, University Lyon 1, Inserm/ CNRS, Labex DEVweCAN, Lyon France., Kelekar A; Department of Laboratory Medicine and Pathology, Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA., Kinet S; Institut de Génétique Moléculaire de Montpellier, Univ Montpellier, CNRS, Montpellier, France., Zimmermann VS; Institut de Génétique Moléculaire de Montpellier, Univ Montpellier, CNRS, Montpellier, France., Levental I; Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA, USA., Yvan-Charvet L; Université Côte d'Azur, INSERM U1065, Nice, France., Swinnen JV; Laboratory of Lipid Metabolism and Cancer, Leuven Cancer Institute, Leuven, Belgium., Muljo SA; Laboratory of Immune System Biology, NIAID, NIH, Bethesda, MD, USA., Hernandez-Vargas H; Cancer Research Center of Lyon, University Lyon 1, Inserm/ CNRS, Labex DEVweCAN, Lyon France., Tardito S; Cancer Research UK, Beatson Institute, Glasgow, UK; Institute of Cancer Sciences, University of Glasgow, Glasgow, UK., Taylor N; Institut de Génétique Moléculaire de Montpellier, Univ Montpellier, CNRS, Montpellier, France; Pediatric Oncology Branch, NCI, CCR, NIH, Bethesda, MD, USA. Electronic address: taylorn4@mail.nih.gov., Dardalhon V; Institut de Génétique Moléculaire de Montpellier, Univ Montpellier, CNRS, Montpellier, France. Electronic address: vdardalhon@igmm.cnrs.fr.
Jazyk:	angličtina
Zdroj:	Cell reports [Cell Rep] 2021 Nov 02; Vol. 37 (5), pp. 109911.
DOI:	10.1016/j.celrep.2021.109911
Abstrakt:	Suppressive regulatory T cell (Treg) differentiation is controlled by diverse immunometabolic signaling pathways and intracellular metabolites. Here we show that cell-permeable α-ketoglutarate (αKG) alters the DNA methylation profile of naive CD4 T cells activated under Treg polarizing conditions, markedly attenuating FoxP3+ Treg differentiation and increasing inflammatory cytokines. Adoptive transfer of these T cells into tumor-bearing mice results in enhanced tumor infiltration, decreased FoxP3 expression, and delayed tumor growth. Mechanistically, αKG leads to an energetic state that is reprogrammed toward a mitochondrial metabolism, with increased oxidative phosphorylation and expression of mitochondrial complex enzymes. Furthermore, carbons from ectopic αKG are directly utilized in the generation of fatty acids, associated with lipidome remodeling and increased triacylglyceride stores. Notably, inhibition of either mitochondrial complex II or DGAT2-mediated triacylglyceride synthesis restores Treg differentiation and decreases the αKG-induced inflammatory phenotype. Thus, we identify a crosstalk between αKG, mitochondrial metabolism and triacylglyceride synthesis that controls Treg fate. Competing Interests: Declaration of interests C.M., S.K., V.D., and N.T. are inventors on patents describing the use of ligands for detection of and modulation of metabolite transporters (N.T. gave up her rights), licensed to METAFORA-biosystems. (Copyright © 2021. Published by Elsevier Inc.)
Databáze:	MEDLINE
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