HIF1α-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of T_H17 and T_reg cells

Upon antigen stimulation, the bioenergetic demands of T cells increase dramatically over the resting state. Although a role for the metabolic switch to glycolysis has been suggested to support increased anabolic activities and facilitate T cell growth and proliferation, whether cellular metabolism controls T cell lineage choices remains poorly understood. We report that the glycolytic pathway is actively regulated during the differentiation of inflammatory T_H17 and Foxp3-expressing regulatory T cells (T_reg cells) and controls cell fate determination. T_H17 but not T_reg cell-inducing conditions resulted in strong up-regulation of the glycolytic activity and induction of glycolytic enzymes. Blocking glycolysis inhibited T_H17 development while promoting T_reg cell generation. Moreover, the transcription factor hypoxia-inducible factor 1α (HIF1α) was selectively expressed in T_H17 cells and its induction required signaling through mTOR, a central regulator of cellular metabolism. HIF1α-dependent transcriptional program was important for mediating glycolytic activity, thereby contributing to the lineage choices between T_H17 and T_reg cells. Lack of HIF1α resulted in diminished T_H17 development but enhanced T_reg cell differentiation and protected mice from autoimmune neuroinflammation. Our studies demonstrate that HIF1α-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of T_H17 and T_reg cells.