The glucose transporter GLUT3 controls T helper 17 cell responses through glycolytic-epigenetic reprogramming

Metabolic reprogramming is a hallmark of activated T cells. The switch from oxidative phosphorylation to aerobic glycolysis provides energy and intermediary metabolites for the biosynthesis of macromolecules to support clonal expansion and effector function. Here, we show that glycolytic reprogramming additionally controls inflammatory gene expression via epigenetic remodeling. We found that the glucose transporter GLUT3 is essential for the effector functions of Th17 cells in models of autoimmune colitis and encephalomyelitis. At the molecular level, we show that GLUT3-dependent glucose uptake controls a metabolic-transcriptional circuit that regulates the pathogenicity of Th17 cells. Metabolomic, epigenetic, and transcriptomic analyses linked GLUT3 to mitochondrial glucose oxidation and ACLY-dependent acetyl-CoA generation as a rate-limiting step in the epigenetic regulation of inflammatory gene expression. Our findings are also important from a translational perspective because inhibiting GLUT3-dependent acetyl-CoA generation is a promising metabolic checkpoint to mitigate Th17-cell-mediated inflammatory diseases. [Display omitted] •GLUT3 controls the effector function of pathogenic Th17 cells•Ablation of GLUT3 in T cells prevents Th17-cell-mediated autoimmunity•GLUT3-dependent acetyl-CoA production controls the epigenetic program of T cells•Pharmacological inhibition of acetyl-CoA generation ameliorates autoimmunity Hochrein et al. report that inflammatory T cells express high levels of GLUT3. Ablation of GLUT3 curtailed Th17-cell-mediated immune responses and protected mice from autoimmune colitis and encephalomyelitis. GLUT3-dependent glucose metabolism controls the generation of nucleo-cytosolic acetyl-CoA and the epigenetic regulation of cytokine responses through histone acetylation.