| First Author | Tyrakis PA | Year | 2016 |
| Journal | Nature | Volume | 540 |
| Issue | 7632 | Pages | 236-241 |
| PubMed ID | 27798602 | Mgi Jnum | J:243079 |
| Mgi Id | MGI:5907571 | Doi | 10.1038/nature20165 |
| Citation | Tyrakis PA, et al. (2016) S-2-hydroxyglutarate regulates CD8+ T-lymphocyte fate. Nature 540(7632):236-241 |
| abstractText | 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-1alpha)-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-1alpha 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. |
