Glycolysis fuels phosphoinositide 3-kinase signaling to bolster T cell immunity
Ke Xu, Na Yin, Min Peng, Efstathios G. Stamatiades, Amy Shyu, Peng Li, Xian Zhang, H. Mytrang, Zhaoquan Wang, Kristelle J. Capistrano, Chun Chou, Andrew G. Levine, Alexander Y. Rudensky, Ming O. Li
Abstract
A metabolic circuit in T cell immunity Naïve T cells are metabolically reprogrammed when they differentiate into T effector (T eff ) cells, transitioning from a reliance on mitochondrial oxidative phosphorylation to aerobic glycolysis. Xu et al. found that lactate dehydrogenase A (LDHA), a glycolytic enzyme that converts pyruvate to lactate, is a key player in this process. T eff cells that differentiate in mice infected with the bacterium Listeria monocytogenes turned on LDHA through phosphoinositide 3-kinase (PI3K) signaling. By promoting adenosine triphosphate (ATP) production, LDHA in turn facilitated PI3K-dependent inactivation of the transcription factor Foxo1 needed for effective T eff cell responses. Thus, glycolytic ATP acts like a rheostat that both gauges and regulates PI3K-dependent signaling. This type of positive feedback circuit may also provide a mechanistic explanation for the Warburg effect observed in cancer cells. Science , this issue p. 405