Phosphoenolpyruvate regulates the Th17 transcriptional program and inhibits autoimmunity

Aerobic glycolysis, a metabolic pathway essential for effector T cell survival and proliferation, regulates 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 downstream glycolytic enzymes in differentiating Th17 cells increases intracellular PEP levels and inhibits interleukin (IL)-17A expression. PEP supplementation inhibits expression of signature molecules for Th17 and Th2 cells but does not signif-icantly affect glycolysis, cell proliferation, or survival of T helper cells. Mechanistically, PEP binds to JunB and inhibits DNA binding of the JunB/basic leucine zipper transcription factor ATF-like (BATF)/interferon regula-tory factor 4 (IRF4) complex, thereby modulating the Th17 transcriptional program. Furthermore, daily admin-istration of PEP to mice inhibits generation of Th17 cells and ameliorates Th17-dependent autoimmune encephalomyelitis. These data demonstrate that PEP links aerobic glycolysis to the Th17 transcriptional program, suggesting the therapeutic potential of PEP for autoimmune diseases.

Automated summary

Aerobic glycolysis, essential for effector T cell survival and proliferation, regulates Th17 differentiation through the negative regulation of phosphoenolpyruvate (PEP). PEP supplementation or inhibition of downstream glycolytic enzymes increases PEP levels and inhibits IL-17A expression. Mechanistically, PEP binds to JunB and inhibits DNA binding of the JunB/BATF/IRF4 complex, thereby modulating the Th17 transcriptional program. PEP administration inhibits Th17 generation and improves Th17-dependent autoimmune encephalomyelitis.