近日，美国纪念斯隆-凯特琳癌症研究中心Ming O. Li及其课题组发现，糖酵解ATP促进磷酸肌醇3-激酶信号转导来支持效应Th17细胞反应。该研究于2021年5月11日发表于国际一流学术期刊《免疫》。

研究人员表示，有氧糖酵解（Warburg效应）通过乳酸脱氢酶A（LDHA）将葡萄糖转化为乳酸，并且是效应T细胞的代谢特征。细胞通过各种机制产生ATP，而Warburg代谢相对来说是能量效率低下的葡萄糖分解代谢途径。

研究人员检查了通过有氧糖酵解产生的ATP在抗原驱动T细胞反应中的作用。Cd4^CreLdha^fl/fl小鼠对Th17细胞介导的实验性自身免疫性脑脊髓炎有抗性，并表现出有缺陷的T细胞活化、迁移、增殖和分化。LDHA缺乏会破坏细胞氧化还原平衡并抑制ATP产生，从而减少PI3K依赖的Akt激酶激活，进而导致磷酸化介导的Foxo1（T细胞激活程序的转录阻遏物）抑制。Akt不敏感型Foxo1的Th17细胞特异性表达概括了Cd4^CreLdha^fl/fl小鼠中看到的缺陷。LDHA的诱导需要PI3K信号传导，而LDHA缺乏会损害PI3K催化的PIP3生成。因此，Warburg代谢会增加糖酵解ATP的产生，从而推动以PI3K为中心的正反馈调节回路，最终驱动效应T细胞反应。

附：英文原文

Title: Glycolytic ATP fuels phosphoinositide 3-kinase signaling to support effector T helper 17 cell responses

Author: Ke Xu, Na Yin, Min Peng, Efstathios G. Stamatiades, Sagar Chhangawala, Amy Shyu, Peng Li, Xian Zhang, Mytrang H. Do, Kristelle J. Capistrano, Chun Chou, Christina S. Leslie, Ming O. Li

Issue&Volume: 2021/05/11

Abstract: Aerobic glycolysis—the Warburg effect—converts glucose to lactate via the enzyme lactatedehydrogenase A (LDHA) and is a metabolic feature of effector T cells. Cells generateATP through various mechanisms and Warburg metabolism is comparatively an energy-inefficientglucose catabolism pathway. Here, we examined the effect of ATP generated via aerobicglycolysis in antigen-driven T cell responses. Cd4CreLdhafl/fl mice were resistant to Th17-cell-mediated experimental autoimmune encephalomyelitisand exhibited defective T cell activation, migration, proliferation, and differentiation.LDHA deficiency crippled cellular redox balance and inhibited ATP production, diminishingPI3K-dependent activation of Akt kinase and thereby phosphorylation-mediated inhibitionof Foxo1, a transcriptional repressor of T cell activation programs. Th17-cell-specificexpression of an Akt-insensitive Foxo1 recapitulated the defects seen in Cd4CreLdhafl/fl mice. Induction of LDHA required PI3K signaling and LDHA deficiency impaired PI3K-catalyzedPIP3 generation. Thus, Warburg metabolism augments glycolytic ATP production, fuelinga PI3K-centered positive feedback regulatory circuit that drives effector T cell responses.

DOI: 10.1016/j.immuni.2021.04.008

Source: https://www.cell.com/immunity/fulltext/S1074-7613(21)00170-9