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

doi:10.1038/nature20165

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

Pediatrics

Research output: Contribution to journal › Article › peer-review

327 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 language	English (US)
Pages (from-to)	236-241
Number of pages	6
Journal	Nature
Volume	540
Issue number	7632
DOIs	https://doi.org/10.1038/nature20165
State	Published - Dec 8 2016

Funding

P.A.T. was funded by CRUK, the MRC (1495954) and Wellcome Trust. J.R.G. was funded by CRUK. A.P. was funded by Marie-Curie IEF. A.T.P. was funded by UCSD NIH Grant (5T32GM007240-36). A.W.G. was funded by the NIH (A1096852, A1072117), Leukemia and Lymphoma Society, and Pew Scholars Fund. K.L.L., J.Y., G.S.C. and L.P. were funded by the Singapore National Research Foundation and Singapore Ministry of Education, the NMRC Clinician Scientist (NMRC/CIRG/1389/2014.) and the Swedish Research Council. R.S.J. and co-workers are funded by the Wellcome Trust (grant WT092738MA), the Swedish Cancer Foundation (Cancerfonden), and the Swedish Research Council (Vetenskapsrådet).

ASJC Scopus subject areas

General

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/nature20165

Cite this

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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.",

author = "Tyrakis, {Petros A.} and Asis Palazon and David Macias and Lee, {Kian L.} and Phan, {Anthony T.} and Pedro Veli{\c c}a and Jia You and Chia, {Grace S.} and Jingwei Sim and Andrew Doedens and Alice Abelanet and Evans, {Colin E.} and Griffiths, {John R.} and Lorenz Poellinger and Goldrath, {Ananda W.} and Johnson, {Randall S.}",

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AU - Phan, Anthony T.

AU - Veliça, Pedro

AU - You, Jia

AU - Chia, Grace S.

AU - Sim, Jingwei

AU - Doedens, Andrew

AU - Abelanet, Alice

AU - Evans, Colin E.

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