biostudies-literatureFoskolou IPFundação para a Ciência e a TecnologiaAllos TherapeuticsKarolinska InstitutetWellcome Trust113013https://www.ebi.ac.uk/biostudies/studies/S-EPMC7618115biostudies-literatureUnknown42(9)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.Cell reportsThe two enantiomers of 2-hydroxyglutarate differentially regulate cytotoxic T cell function.PMC7618115092738214283/Z/18/ZSFRH/BD/115612/2016Johnson RSZandhuis NDCunha PPJorgensen CWolkers MCSanchez-Lopez EFoskolou IPNathanael DNicolet BPGuislain APalazon AKostidis SGiera MTyrakis PABarbieri LBargiela DMinogue EAfalseThe 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.2023-01-01T00:00:00Z2023 Sep2026-04-08T18:33:16.129Z2026-04-08T09:51:48.482ZS-EPMC76181153763275210.1016/j.celrep.2023.113013