A metabolic circuit in T cell immunity Naïve T cells are metabolically reprogrammed when they differentiate into T effector (Teff) 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. Teff 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 Teff 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 A metabolic positive-feedback loop enables immunological T cell effector function. Infection triggers expansion and effector differentiation of T cells specific for microbial antigens in association with metabolic reprograming. We found that the glycolytic enzyme lactate dehydrogenase A (LDHA) is induced in CD8+ T effector cells through phosphoinositide 3-kinase (PI3K) signaling. 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 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 the control of T cell immunity. Such a bioenergetic mechanism for the regulation of signaling may explain the Warburg effect.

中文翻译：

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糖酵解促进磷酸肌醇 3-激酶信号传导以增强 T 细胞免疫

T 细胞免疫中的代谢回路 幼稚 T 细胞在分化为 T 效应 (Teff) 细胞时被代谢重编程，从依赖线粒体氧化磷酸化转变为有氧糖酵解。徐等人。发现乳酸脱氢酶 A (LDHA)，一种将丙酮酸转化为乳酸的糖酵解酶，是该过程的关键参与者。在感染单核细胞增生李斯特菌的小鼠中分化的 Teff 细胞通过磷酸肌醇 3-激酶 (PI3K) 信号传导开启 LDHA。通过促进三磷酸腺苷 (ATP) 的产生，LDHA 反过来促进了有效 Teff 细胞反应所需的转录因子 Foxo1 的 PI3K 依赖性失活。因此，糖酵解 ATP 就像一个变阻器，可以测量和调节 PI3K 依赖性信号。这种类型的正反馈电路也可以为在癌细胞中观察到的 Warburg 效应提供机械解释。科学，这个问题 p。405 代谢正反馈回路启用免疫 T 细胞效应器功能。感染触发与代谢重编程相关的微生物抗原特异性 T 细胞的扩增和效应子分化。我们发现糖酵解酶乳酸脱氢酶 A (LDHA) 通过磷酸肌醇 3-激酶 (PI3K) 信号传导在 CD8+ T 效应细胞中被诱导。反过来，LDHA 的消融会抑制 Akt 及其转录因子靶标 Foxo1 的 PI3K 依赖性磷酸化，从而导致抗菌免疫缺陷。LDHA 缺乏会削弱细胞氧化还原控制并减少效应 T 细胞中三磷酸腺苷 (ATP) 的产生，导致 PI3K 信号减弱。因此，营养代谢和生长因子信号是高度整合的过程，糖酵解 ATP 作为变阻器来衡量 PI3K-Akt-Foxo1 信号在 T 细胞免疫控制中的作用。这种调节信号的生物能机制可以解释 Warburg 效应。