Glycolysis Fuels Phosphoinositide 3-Kinase Signaling to Bolster T Cell Immunity

Xu, K.; Yin, N.; Peng, M.; Stamatiades, E.; Shyu, A.; Li, P.; Zhang, X.; Do, M.; Wang, Z.; Capistrano, K.; Chou, C.; Levine, A.; Rudensky, A.; Li, M.

doi:10.1101/2020.03.12.989707

bioRxiv · 10.1101/2020.03.12.989707

Glycolysis Fuels Phosphoinositide 3-Kinase Signaling to Bolster T Cell Immunity

Xu, K.·Yin, N.·Peng, M.·Stamatiades, E.·Shyu, A.·Li, P.·Zhang, X.·Do, M.·Wang, Z.·Capistrano, K.·Chou, C.·Levine, A.·Rudensky, A.·Li, M.

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Abstract

Infection triggers clonal expansion and effector differentiation of microbial antigen-specific T cells in association with metabolic reprograming. Here, we show that the glycolytic enzyme lactate dehydrogenase A (LDHA) is induced in CD8+ T effector cells via phosphoinositide 3-kinase (PI3K)-dependent mechanisms. In turn, ablation of LDHA inhibits PI3K-dependent phosphorylation of Akt and its transcription factor target Foxo1, causing defective antimicrobial immunity. LDHA deficiency cripples cellular redox control and diminishes glycolytic adenosine triphosphate (ATP) production in effector T cells, resulting in attenuated PI3K signaling. Thus, nutrient metabolism and growth factor signaling are highly integrated processes with glycolytic ATP serving as a rheostat to gauge PI3K/Akt/Foxo1 signaling in T cell immunity control. Such a bioenergetics mechanism of signaling regulation implies a root cause for the century-old phenomenon of Warburg effect, and could guide development of novel therapeutics for infectious diseases and cancer. One Sentence SummaryA PI3K and LDHA circuit enables T cell immunity

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Xu, K., Yin, N., Peng, M., Stamatiades, E., Shyu, A., Li, P., Zhang, X., Do, M., Wang, Z., Capistrano, K., Chou, C., Levine, A., Rudensky, A., Li, M.. 2020-03-13. Glycolysis Fuels Phosphoinositide 3-Kinase Signaling to Bolster T Cell Immunity. https://doi.org/10.1101/2020.03.12.989707

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