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 and Randall S. Johnson ()
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Petros A. Tyrakis: Development and Neuroscience, University of Cambridge
Asis Palazon: Development and Neuroscience, University of Cambridge
David Macias: Development and Neuroscience, University of Cambridge
Kian. L. Lee: Cancer Science Institute of Singapore, National University of Singapore
Anthony. T. Phan: Molecular Biology Section, UC San Diego
Pedro Veliça: Karolinska Institute
Jia You: Cancer Science Institute of Singapore, National University of Singapore
Grace S. Chia: Cancer Science Institute of Singapore, National University of Singapore
Jingwei Sim: Development and Neuroscience, University of Cambridge
Andrew Doedens: Molecular Biology Section, UC San Diego
Alice Abelanet: Development and Neuroscience, University of Cambridge
Colin E. Evans: Development and Neuroscience, University of Cambridge
John R. Griffiths: Cancer Research UK, Cambridge Institute, University of Cambridge
Lorenz Poellinger: Cancer Science Institute of Singapore, National University of Singapore
Ananda W. Goldrath: Molecular Biology Section, UC San Diego
Randall S. Johnson: Development and Neuroscience, University of Cambridge

Nature, 2016, vol. 540, issue 7632, 236-241

Abstract: 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.

Date: 2016
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DOI: 10.1038/nature20165

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