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

Abstract

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+ Tcell biology, where we find they have highly divergent effects on proliferation, differentiation, and Tcell 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+ Tcells with exogenous S-2HG, but not R-2HG, increased CD8+ Tcell fitness invivo 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 Tcell function.