S-2-hydroxyglutarate regulates CD8+ T-lymphocyte fate.
Tyrakis, Petros A
Lee, Kian L
Phan, Anthony T
Chia, Grace S
Goldrath, Ananda W
Nature Publishing Group
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Tyrakis, P. A., Palazon, A., Macias, D., Lee, K. L., Phan, A. T., Veliça, P., You, J., et al. (2016). S-2-hydroxyglutarate regulates CD8+ T-lymphocyte fate.. Nature, 540 236-241. https://doi.org/10.1038/nature20165
R-2-hydroxyglutarate accumulates to millimolar levels in cancers with gain-of-function isocitrate dehydrogenase 1/2 mutations. These levels of R-2-hydroxyglutarate affect 2-oxoglutarate-dependent dioxygenases. Both R- and S-2-hydroxyglutarate, the other enantiomer of this metabolite, are detectible in healthy individuals, yet their physiological function remains elusive. Here we show that CD8(+) T-lymphocytes accumulate 2-hydroxyglutarate in response to T-cell receptor triggering. This increases to millimolar levels in physiological oxygen conditions, via a hypoxia inducible factor 1 alpha-dependent mechanism. S-2-hydroxyglutarate predominates over R-2-hydroxyglutarate in activated T cells, and we demonstrate alterations in markers of CD8(+) T-lymphocyte differentiation in response to this metabolite. Modulation of histone and DNA demethylation as well as hypoxia inducible factor 1 alpha stability mediate these effects. S-2-hydroxyglutarate treatment greatly enhances the in vivo proliferation, persistence and anti-tumour capacity of adoptively transferred CD8(+) T-lymphocytes. Thus S-2-hydroxyglutarate acts as an immunometabolite that links environmental context, via a metabolic-epigenetic axis, to immune fate and function.
CD8-Positive T-Lymphocytes, Animals, Mice, Oxygen, Glutarates, Ketoglutaric Acids, Dioxygenases, Lysine, Receptors, Antigen, T-Cell, Histones, DNA, Lymphocyte Activation, Cell Differentiation, DNA Methylation, Homeostasis, Von Hippel-Lindau Tumor Suppressor Protein, Hypoxia-Inducible Factor 1, alpha Subunit, Protein Stability, Hypoxia
Cancer Research UK (CB4110)
Wellcome Trust (092738/Z/10/Z)
European Commission (331756)
External DOI: https://doi.org/10.1038/nature20165
This record's URL: https://www.repository.cam.ac.uk/handle/1810/261568