S-2-hydroxyglutarate regulates CD8 + T-lymphocyte fate

Nature. 2016 Dec 8;540(7632):236-241. doi: 10.1038/nature20165. Epub 2016 Oct 26.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD8-Positive T-Lymphocytes / cytology*
  • CD8-Positive T-Lymphocytes / drug effects*
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / metabolism
  • Cell Differentiation / drug effects*
  • DNA / chemistry
  • DNA / metabolism
  • DNA Methylation / drug effects
  • Dioxygenases / metabolism
  • Glutarates / immunology
  • Glutarates / metabolism
  • Glutarates / pharmacology*
  • Histones / metabolism
  • Homeostasis / drug effects
  • Hypoxia / metabolism
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Ketoglutaric Acids / metabolism
  • Lymphocyte Activation
  • Lysine / metabolism
  • Mice
  • Oxygen / metabolism
  • Protein Stability
  • Receptors, Antigen, T-Cell / immunology
  • Von Hippel-Lindau Tumor Suppressor Protein / metabolism

Substances

  • Glutarates
  • Hif1a protein, mouse
  • Histones
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Ketoglutaric Acids
  • Receptors, Antigen, T-Cell
  • alpha-hydroxyglutarate
  • DNA
  • Dioxygenases
  • Von Hippel-Lindau Tumor Suppressor Protein
  • VHL protein, mouse
  • Lysine
  • Oxygen