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

Foskolou, I.P.; Cunha, P.P.; Sanchez-Lopez, E.; Minogue, E.A.; Nicolet, B.P.; Guislain, A.; ... ; Johnson, R.S. (2023)

Article / Letter to editor

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.

• All authors: Foskolou, I.P.; Cunha, P.P.; Sanchez-Lopez, E.; Minogue, E.A.; Nicolet, B.P.; Guislain, A.; Jorgensen, C.; Kostidis, S.; Zandhuis, N.D.; Barbieri, L.; Bargiela, D.; Nathanael, D.; Tyrakis, P.A.; Palazon, A.; Giera, M.; Wolkers, M.C.; Johnson, R.S.
• Date: 2023-08-24
• Journal: Cell Reports
• Volume: 42
• Issue: 9
• DOI: doi:10.1016/j.celrep.2023.113013
• Link: https://www.sciencedirect.com/science/article/pii/S2211124723010240?via%...