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

Petros A. Tyrakis, Asis Palazon, David Macias, Kian L. Lee, Anthony T. Phan, Pedro Veliça, Jia You, Grace S. Chia, Jingwei Sim, Andrew Doedens, Alice Abelanet, Colin E. Evans, John R. Griffiths, Lorenz Poellinger, Ananda W. Goldrath, Randall S. Johnson*

*Corresponding author for this work

Research output: Contribution to journalArticle

128 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)236-241
Number of pages6
JournalNature
Volume540
Issue number7632
DOIs
StatePublished - Dec 8 2016

ASJC Scopus subject areas

  • General

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    Tyrakis, P. A., Palazon, A., Macias, D., Lee, K. L., Phan, A. T., Veliça, P., You, J., Chia, G. S., Sim, J., Doedens, A., Abelanet, A., Evans, C. E., Griffiths, J. R., Poellinger, L., Goldrath, A. W., & Johnson, R. S. (2016). S-2-hydroxyglutarate regulates CD8+ T-lymphocyte fate. Nature, 540(7632), 236-241. https://doi.org/10.1038/nature20165