HIF1α-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg 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(H)17 and Foxp3-expressing regulatory T cells (T-reg cells) and controls cell fate determination. T(H)17 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(H)17 development while promoting T-reg cell generation. Moreover, the transcription factor hypoxia-inducible factor 1 alpha (HIF1 alpha) was selectively expressed in T(H)17 cells and its induction required signaling through mTOR, a central regulator of cellular metabolism. HIF1 alpha-dependent transcriptional program was important for mediating glycolytic activity, thereby contributing to the lineage choices between T(H)17 and T-reg cells. Lack of HIF1 alpha resulted in diminished T(H)17 development but enhanced T-reg cell differentiation and protected mice from autoimmune neuroinflammation. Our studies demonstrate that HIF1 alpha-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of T(H)17 and T-reg cells.