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

Johnson, R. S.; Foskolou, I. P.; Cunha, P. P.; Minogue, E.; Nicolet, B.; Guislain, A.; Jorgensen, C.; Zandhuis, N. D.; Barbieri, L.; Bargiela, D.; Nathanael, D.; Tyrakis, P.; Palazon, A.; Wolkers, M.

doi:10.1101/2022.08.18.504372

bioRxiv · 10.1101/2022.08.18.504372

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

Johnson, R. S.·Foskolou, I. P.·Cunha, P. P.·Minogue, E.·Nicolet, B.·Guislain, A.·Jorgensen, C.·Zandhuis, N. D.·Barbieri, L.·Bargiela, D.·Nathanael, D.·Tyrakis, P.·Palazon, A.·Wolkers, M.

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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 a-ketoglutarate (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 anti-tumour 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.

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Johnson, R. S., Foskolou, I. P., Cunha, P. P., Minogue, E., Nicolet, B., Guislain, A., Jorgensen, C., Zandhuis, N. D., Barbieri, L., Bargiela, D., Nathanael, D., Tyrakis, P., Palazon, A., Wolkers, M.. 2022-08-18. The two enantiomers of 2-hydroxyglutarate differentially regulate cytotoxic T cell function. https://doi.org/10.1101/2022.08.18.504372

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