Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Immunology and Microbial Pathogenesis Graduate Program, Weill Cornell Graduate School of Medical Sciences, Cornell University, New York, NY 10065, USA.
Science. 2021 Jan 22;371(6527):405-410. doi: 10.1126/science.abb2683.
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.
感染会触发针对微生物抗原的 T 细胞的扩增和效应器分化，与代谢重编程有关。我们发现，磷酸肌醇 3-激酶（PI3K）信号通路会诱导 CD8 T 效应细胞中糖酵解酶乳酸脱氢酶 A（LDHA）的表达。反过来，LDHA 的缺失会抑制 Akt 的 PI3K 依赖性磷酸化及其转录因子靶标 Foxo1，导致抗菌免疫缺陷。LDHA 缺乏会破坏细胞氧化还原控制，并减少效应 T 细胞中的三磷酸腺苷（ATP）产生，从而导致 PI3K 信号转导减弱。因此，营养代谢和生长因子信号转导是高度整合的过程，糖酵解 ATP 作为变阻器，可衡量 PI3K-Akt-Foxo1 信号转导在 T 细胞免疫中的作用。这种信号转导的能量代谢机制可能解释了瓦伯格效应。
