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

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. Cd4(Cre)Ldha(fl/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 Cd4(Cre)Ldha(fl/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.

Automated summary

The Warburg effect, characterized by aerobic glycolysis, is an important metabolic feature of effector T cells, driving their responses through ATP production via LDHA. LDHA deficiency impairs T cell activation, proliferation, and differentiation by disrupting the PI3K-Akt-Foxo1 signaling pathway. This study highlights the crucial role of Warburg metabolism in regulating effector T cell responses.