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

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.