Phosphoenolpyruvate regulates JunB-dependent Th17 transcriptional program

Aerobic glycolysis, a metabolic pathway essential for effector T cell survival and proliferation, regulates the differentiation of autoimmune T helper (Th)17 cells, but the mechanism underlying this regulation is largely unknown. Here, we identify a glycolytic intermediate metabolite, phosphoenolpyruvate (PEP), as a negative regulator of Th17 differentiation. PEP supplementation or inhibition of the downstream glycolytic enzymes in differentiating Th17 cells increases intracellular PEP levels and inhibits the expression of Th17 signature molecules such as IL-17A. However, PEP supplementation does not significantly affect metabolic reprogramming, cell proliferation, and survival of differentiating Th17 cells. Mechanistically, PEP binds to JunB, an AP-1 transcription factor, which is required for differentiation of pathogenic Th17 cells, but not non-pathogenic Th17 cells, and inhibits DNA-binding of the JunB/BATF/IRF4 complex at the Il17a locus. Furthermore, daily administration of PEP into mice inhibits the generation of Th17 cells and ameliorates Th17-dependent autoimmune encephalomyelitis. These data demonstrate that PEP links aerobic glycolysis to the Th17 transcriptional program by interacting with JunB, suggesting the therapeutic potential of PEP for autoimmune diseases.