Please use this identifier to cite or link to this item: https://doi.org/10.1038/nature20165
Title: S-2-hydroxyglutarate regulates CD8+ T-lymphocyte fate
Authors: 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.
Issue Date: 2016
Publisher: Nature Publishing Group
Citation: 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. ScholarBank@NUS Repository. https://doi.org/10.1038/nature20165
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. ? 2016 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.
Source Title: Nature
URI: https://scholarbank.nus.edu.sg/handle/10635/164150
ISSN: 280836
DOI: 10.1038/nature20165
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