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

Iosifina P. Foskolou*, Pedro P. Cunha, Elena Sánchez-López, Eleanor A. Minogue, Benoît P. Nicolet, Aurélie Guislain, Christian Jorgensen, Sarantos Kostidis, Nordin D. Zandhuis, Laura Barbieri, David Bargiela, Demitris Nathanael, Petros A. Tyrakis, Asis Palazon, Martin Giera, Monika C. Wolkers, Randall S. Johnson*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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+ 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.

Original languageEnglish
Article number113013
Number of pages23
JournalCell Reports
Volume42
Issue number9
Early online date24 Aug 2023
DOIs
Publication statusPublished - 26 Sept 2023

Keywords

  • 2-hydroxyglutarate
  • adoptive cell transfer
  • CD8+ T cell function
  • CD8+ T cell memory
  • CP: Immunology
  • oncometabolites

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