Glycolytic ATP fuels phosphoinositide 3-kinase signaling to support effector T helper 17 cell responses Journal Article
| Authors: | Xu, K.; Yin, N.; Peng, M.; Stamatiades, E. G.; Chhangawala, S.; Shyu, A.; Li, P.; Zhang, X.; Do, M. H.; Capistrano, K. J.; Chou, C.; Leslie, C. S.; Li, M. O. |
| Article Title: | Glycolytic ATP fuels phosphoinositide 3-kinase signaling to support effector T helper 17 cell responses |
| Abstract: | 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. © 2021 Elsevier Inc. |
| Keywords: | autoimmunity; th17 cell; glycolysis; pi3k; atp; ldha; redox balance |
| Journal Title: | Immunity |
| Volume: | 54 |
| Issue: | 5 |
| ISSN: | 1074-7613 |
| Publisher: | Cell Press |
| Date Published: | 2021-05-11 |
| Start Page: | 976 |
| End Page: | 987.e7 |
| Language: | English |
| DOI: | 10.1016/j.immuni.2021.04.008 |
| PUBMED: | 33979589 |
| PROVIDER: | scopus |
| PMCID: | PMC8130647 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 June 2021 -- Source: Scopus |
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