title: S-2-hydroxyglutarate regulates CD8+T-lymphocyte fate.
abstract: R-2-hydroxyglutarate accumulates to millimolar levels in cancer cells with gain-of-function isocitrate dehydrogenase 1/2 mutations. These levels of R-2-hydroxyglutarate affect 2-oxoglutarate-dependent dioxygenases. Both metabolite enantiomers, R- and S-2-hydroxyglutarate, are detectible in healthy individuals, yet their physiological function remains elusive. Here we show that 2-hydroxyglutarate accumulates in mouse CD8+T cells in response to T-cell receptor triggering, and accumulates to millimolar levels in physiological oxygen conditions through a hypoxia-inducible factor 1-alpha (HIF-1α)-dependent mechanism. S-2-hydroxyglutarate predominates over R-2-hydroxyglutarate in activated T cells, and we demonstrate alterations in markers of CD8+T-cell differentiation in response to this metabolite. Modulation of histone and DNA demethylation, as well as HIF-1α stability, mediate these effects. S-2-hydroxyglutarate treatment greatly enhances the in vivo proliferation, persistence and anti-tumour capacity of adoptively transferred CD8+T cells. Thus, S-2-hydroxyglutarate acts as an immunometabolite that links environmental context, through a metabolic-epigenetic axis, to immune fate and function.
authors: Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK.|Cancer Research UK, Cambridge Institute, University of Cambridge, Cambridge, UK.
authors: Petros A
authors: PA
authors: Tyrakis
authors: Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK.
authors: Asis
authors: A
authors: Palazon
authors: Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK.
authors: David
authors: D
authors: Macias
authors: Cancer Science Institute of Singapore, National University of Singapore, Singapore.
authors: Kian L
authors: KL
authors: Lee
authors: Molecular Biology Section, UC San Diego, La Jolla, California, USA.
authors: Anthony T
authors: AT
authors: Phan
authors: Department of Cell and Molecular Biology, Karolinska Institute, Stockholm, Sweden.
authors: Pedro
authors: P
authors: Veliça
authors: Cancer Science Institute of Singapore, National University of Singapore, Singapore.
authors: Jia
authors: J
authors: You
authors: Cancer Science Institute of Singapore, National University of Singapore, Singapore.
authors: Grace S
authors: GS
authors: Chia
authors: Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK.
authors: Jingwei
authors: J
authors: Sim
authors: Molecular Biology Section, UC San Diego, La Jolla, California, USA.
authors: Andrew
authors: A
authors: Doedens
authors: Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK.
authors: Alice
authors: A
authors: Abelanet
authors: Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK.
authors: Colin E
authors: CE
authors: Evans
authors: Cancer Research UK, Cambridge Institute, University of Cambridge, Cambridge, UK.
authors: John R
authors: JR
authors: Griffiths
authors: Cancer Science Institute of Singapore, National University of Singapore, Singapore.|Department of Cell and Molecular Biology, Karolinska Institute, Stockholm, Sweden.
authors: Lorenz
authors: L
authors: Poellinger
authors: Molecular Biology Section, UC San Diego, La Jolla, California, USA.
authors: Ananda W
authors: AW
authors: Goldrath
authors: Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK.|Department of Cell and Molecular Biology, Karolinska Institute, Stockholm, Sweden.
authors: Randall S
authors: RS
authors: Johnson
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology* / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects*; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D019175:DNA Methylation / Q000187:drug effects; D049308:Dioxygenases / Q000378:metabolism; D005977:Glutarates / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology*; D006657:Histones / Q000378:metabolism; D006706:Homeostasis / Q000187:drug effects; D000860:Hypoxia / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007656:Ketoglutaric Acids / Q000378:metabolism; D008213:Lymphocyte Activation; D008239:Lysine / Q000378:metabolism; D051379:Mice; D010100:Oxygen / Q000378:metabolism; D055550:Protein Stability; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000378:metabolism
chemical_list: D005977:Glutarates; C497443:Hif1a protein, mouse; D006657:Histones; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007656:Ketoglutaric Acids; D011948:Receptors, Antigen, T-Cell; C019417:alpha-hydroxyglutarate; D004247:DNA; D049308:Dioxygenases; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C494469:VHL protein, mouse; D008239:Lysine; D010100:Oxygen