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

Accepted version
Peer-reviewed

Type

Article

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Authors

Tyrakis, Petros A 
Palazon, Asis 
Macias, David 
Lee, Kian L 
Phan, Anthony T 

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.

Description

Keywords

Animals, CD8-Positive T-Lymphocytes, Cell Differentiation, DNA, DNA Methylation, Dioxygenases, Glutarates, Histones, Homeostasis, Hypoxia, Hypoxia-Inducible Factor 1, alpha Subunit, Ketoglutaric Acids, Lymphocyte Activation, Lysine, Mice, Oxygen, Protein Stability, Receptors, Antigen, T-Cell, Von Hippel-Lindau Tumor Suppressor Protein

Journal Title

Nature

Conference Name

Journal ISSN

0028-0836
1476-4687

Volume Title

540

Publisher

Springer Science and Business Media LLC
Sponsorship
Cancer Research UK (CB4110)
Wellcome Trust (092738/Z/10/Z)
European Commission (331756)
National Institute of Allergy and Infectious Diseases (R01AI096852)
Cancer Research UK (11562)