TIGAR coordinates polyol and glutamine metabolism to regulate CD4+ T cells

TIGAR is identified as a key regulator of CD4⁺ T-cell differentiation, linking metabolic pathways to immune responses, but findings are based on rodent models and require further validation in humans.

Summary and findings

This study investigates the role of the metabolic enzyme TIGAR in regulating CD4⁺ T-cell differentiation and metabolism. The findings indicate that TIGAR deficiency affects glutamine utilization and alters T-cell differentiation pathways. The study also identifies a link between TIGAR and polyol metabolism in the context of immune responses.

Abstract

Abstract CD4⁺ T cells undergo extensive metabolic reprogramming during activation and differentiation, yet how metabolic enzymes coordinate metabolite utilisation with lineage commitment remains poorly understood. Here, we identify the metabolic enzyme TP53-induced glycolysis and apoptosis regulator (TIGAR) as a critical regulator of CD4⁺ T-cell fate. Although classically linked to glycolysis, TIGAR unexpectedly regulated CD4⁺ T-cell differentiation independently of these canonical functions. We found that TIGAR deficiency impaired glutamine utilisation, enhanced Th1 differentiation, and suppressed Th17 and regulatory T-cell generation in CD4⁺ T cells. Mechanistically, TIGAR deficiency upregulated aldose reductase, a key enzyme of polyol metabolism, and both pharmacological inhibition of aldose reductase and sorbitol supplementation recapitulated key aspects of the TIGAR-deficient phenotype, establishing the polyol pathway as a metabolic regulator of CD4⁺ T-cell differentiation and migration. In vivo, T cell-specific TIGAR ablation enhanced inflammatory IFNγ-producing CD4⁺ T-cell responses during Citrobacter rodentium infection and exacerbated T cell-mediated colitis. Consistent with these findings, Mendelian randomisation identified genetically predicted aldose reductase expression as a causal risk factor for inflammatory bowel disease in humans. Together, our findings uncover a TIGAR–polyol metabolic axis linking mitochondrial metabolism to CD4⁺ T-cell fate and intestinal inflammation, establishing polyol metabolism as a previously unrecognised metabolic checkpoint and potential therapeutic target in immune-mediated disease.

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