Glycolytic ATP fuels phosphoinositide 3-kinase signaling to support effector T helper 17 cell responses

• DOI: 10.1016/j.immuni.2021.04.008
• Publication Date: 2021-05-11T15:47:10Z
• Authors: Ke Xu; Na Yin; Min Peng; Efstathios G. Sta...; Sagar Chhangawala; Amy Shyu; Peng Li; Xian Zhang; Mytrang H. Do; Kristelle J. Capi...; Chun Chou; Christina S. Leslie; Ming O. Li
• Keywords: Male; 0301 basic medicine; 0303 health sciences; L-Lactate Dehydrogenase; Cell Differentiation; Mice, Transgenic; Glycogen Storage Disease; Cell Line; Gene Expression Regulation, Neoplastic; Mice, Inbred C57BL; Mice; 03 medical and health sciences; Adenosine Triphosphate; Glucose; Animals; Th17 Cells; Female; Phosphatidylinositol 3-Kinase; Glycolysis; Cell Proliferation; Signal Transduction

Aerobic glycolysis-the Warburg effect-converts glucose to lactate via the enzyme lactate dehydrogenase A (LDHA) and is a metabolic feature of effector T cells. Cells generate ATP through various mechanisms and Warburg metabolism is comparatively an energy-inefficient glucose catabolism pathway. Here, we examined the effect of ATP generated via aerobic glycolysis in antigen-driven T cell responses. Cd4CreLdhafl/fl mice were resistant to Th17-cell-mediated experimental autoimmune encephalomyelitis and exhibited defective T cell activation, migration, proliferation, and differentiation. LDHA deficiency crippled cellular redox balance and inhibited ATP production, diminishing PI3K-dependent activation of Akt kinase and thereby phosphorylation-mediated inhibition of Foxo1, a transcriptional repressor of T cell activation programs. Th17-cell-specific expression of an Akt-insensitive Foxo1 recapitulated the defects seen in Cd4CreLdhafl/fl mice. Induction of LDHA required PI3K signaling and LDHA deficiency impaired PI3K-catalyzed PIP3 generation. Thus, Warburg metabolism augments glycolytic ATP production, fueling a PI3K-centered positive feedback regulatory circuit that drives effector T cell responses.