S-2-hydroxyglutarate regulates CD8⁺ T-lymphocyte fate

Area of Science:

• Immunometabolism
• Epigenetics
• Cellular Metabolism

Background:

• R-2-hydroxyglutarate (2-HG) accumulation is linked to cancer via isocitrate dehydrogenase mutations.
• The physiological roles of both R- and S-2-hydroxyglutarate enantiomers are not well understood.
• 2-hydroxyglutarate is detected in healthy individuals, indicating potential physiological relevance.

Purpose of the Study:

• To investigate the accumulation and function of 2-hydroxyglutarate in CD8+ T cells.
• To elucidate the mechanism of 2-hydroxyglutarate accumulation in T cells.
• To determine the impact of S-2-hydroxyglutarate on T cell function and anti-tumor immunity.

Main Methods:

• Analysis of 2-hydroxyglutarate levels in mouse CD8+ T cells upon T-cell receptor stimulation.
• Investigation of hypoxia-inducible factor 1-alpha (HIF-1α) dependence for 2-hydroxyglutarate accumulation.
• Assessment of S-2-hydroxyglutarate effects on T cell differentiation markers, histone/DNA demethylation, and HIF-1α stability.
• Evaluation of S-2-hydroxyglutarate's impact on CD8+ T cell proliferation, persistence, and anti-tumor capacity in vivo.

Main Results:

• 2-hydroxyglutarate accumulates in mouse CD8+ T cells following T-cell receptor triggering, dependent on HIF-1α.
• S-2-hydroxyglutarate predominates in activated T cells and alters CD8+ T cell differentiation markers.
• S-2-hydroxyglutarate modulates histone and DNA demethylation and influences HIF-1α stability.
• Treatment with S-2-hydroxyglutarate significantly enhances the in vivo anti-tumor function of CD8+ T cells.

Conclusions:

• S-2-hydroxyglutarate functions as a critical immunometabolite in CD8+ T cells.
• This metabolite connects environmental cues to immune cell fate via a metabolic-epigenetic axis.
• S-2-hydroxyglutarate enhances T cell proliferation, persistence, and anti-tumor efficacy, offering therapeutic potential.