The two enantiomers of 2-hydroxyglutarate differentially regulate cytotoxic T cell function

Abstract

2-hydroxyglutarate (2HG) is a by-product of the TCA cycle, and is readily detected in the tissues of healthy individuals. 2HG is found in two enantiomeric forms: S-2HG and R-2HG. Here, we investigate the differential roles of these two enantiomers in CD8+ T cell biology, where we found they had highly divergent effects on proliferation, differentiation, and T cell function. We show here an analysis of structural determinants that likely underlie these differential effects on specific aketoglutarate (aKG)-dependent enzymes. Treatment of CD8+ T cells with exogenous S-2HG, but not R-2HG, increased CD8+ T cell fitness in vivo, and enhanced antitumour activity. These data show that S-2HG and R-2HG should be considered as two distinct and important actors in the regulation of T cell function.

Metabolic dialogues: regulators of chimeric antigen receptor T cell function in the tumor microenvironment

“…Similarly, mutations in isocitrate dehydrogenase 1 (IDH1), occurring in malignant gliomas, result in the production of R-2hydroxyglutarate (R-2HG). This oncometabolite impairs CD8 + T effector function via inhibition of the glycolytic enzyme LDH [141,142]. Thus, tumor cells secrete metabolites that negatively affect anti-tumor T cells via an extraordinarily broad range of mechanisms (Fig.…”