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

2-Hydroxyglutarate (2HG) is a byproduct of the tricarboxylic acid (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 cluster of differentiation (CD)8+ T cell biology, where we find they have 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 α-ketoglutarate (αKG)-dependent enzymes. Treatment of CD8+ T cells with exogenous S-2HG, but not R-2HG, increased CD8+ T cell fitness in vivo and enhanced anti-tumor 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. [Display omitted] •Octyl-ester S-2HG and R-2HG differentially modulate CD8+ T cell differentiation•S-2HG and R-2HG have different inhibitory potencies against aKG-dependent enzymes•CD8+ T cells pre-treated with octyl-ester S-2HG have enhanced anti-tumor activity Foskolou et al. show that the enantiomeric forms S-2HG and R-2HG have distinct functions in CD8+ T proliferation, differentiation, and function. Treatment of CD8+ T cells with exogenous cell-permeable S-2HG, but not R-2HG, increased CD8+ T cell fitness in vivo and enhanced anti-tumor activity.