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

Area of Science:

• Immunology
• Metabolism

Background:

• 2-Hydroxyglutarate (2HG) is a metabolic byproduct of the tricarboxylic acid (TCA) cycle.
• 2HG exists as two enantiomers: S-2HG and R-2HG, with distinct biological roles.
• The specific functions of 2HG enantiomers in CD8+ T cell biology remain largely unexplored.

Purpose of the Study:

• To investigate the differential effects of S-2HG and R-2HG on CD8+ T cell proliferation, differentiation, and function.
• To analyze the structural determinants underlying the distinct impacts of 2HG enantiomers on alpha-ketoglutarate (αKG)-dependent enzymes.

Main Methods:

• Treatment of CD8+ T cells with exogenous S-2HG and R-2HG.
• In vivo assessment of CD8+ T cell fitness and anti-tumor activity.
• Analysis of structural determinants impacting αKG-dependent enzymes.

Main Results:

• S-2HG, but not R-2HG, significantly improved CD8+ T cell fitness in vivo.
• Exogenous S-2HG administration enhanced anti-tumor activity.
• Differential effects of S-2HG and R-2HG on T cell proliferation, differentiation, and function were observed.

Conclusions:

• S-2HG and R-2HG exhibit distinct regulatory roles in CD8+ T cell biology.
• S-2HG demonstrates potential as an immunomodulatory agent to enhance anti-tumor immunity.
• These findings underscore the importance of considering 2HG enantiomers separately in T cell regulation.