S-2-hydroxyglutarate regulates CD8(+) T-lymphocyte fate

Article

关键词: CELL-DIFFERENTIATION;    ALPHA-KETOGLUTARATE;    ONCOMETABOLITE 2-HYDROXYGLUTARATE;    GENE-EXPRESSION;    MUTANT IDH;    MEMORY;    EFFECTOR;    CANCER;    METABOLISM;    ANTIGEN;   

DOI  :  10.1038/nature20165

来源: SCIE

【 摘 要 】

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-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-cell differentiation in response to this metabolite. Modulation of histone and DNA demethylation, as well as HIF-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 cells. Thus, S-2-hydroxyglutarate acts as an immunometabolite that links environmental context, through a metabolic-epigenetic axis, to immune fate and function.

【 授权许可】

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