Glycolysis Promotes Phosphoinositide 3-Kinase Signaling In Support of T Helper 17 Cell-Mediated Autoimmunity. Glycolysis Promotes Phosphoinositide 3-Kinase Signaling In Support of T Helper 17 Cell-Mediated Autoimmunity

T helper (Th) cell differentiation is driven by antigen and accessory signals that activate phosphoinositide 3-kinase (PI3K) to induce transcriptional and metabolic reprogramming including aerobic glycolysis (the Warburg effect). Here, we show that ATP generated through glycolysis fuels PI3K signaling to promote pathogenic Th17 cell responses. Mice with T cell-specific ablation of the glycolytic enzyme lactate dehydrogenase A (LDHA) were resistant to Th17 cell-mediated experimental autoimmune encephalomyelitis in association with defective T cell activation, migration, proliferation, and differentiation. LDHA deficiency crippled the cellular redox balance and inhibited ATP production causing attenuated phosphoinositide (3,4,5)-trisphosphate generation, and diminished activation of the Akt kinase and phosphorylation of its transcription factor target Foxo1. Th17 cell-specific expression of an Akt-insensitive Foxo1 mutant recapitulated the Th17 cell differentiation defects caused by LDHA deficiency. Thus, PI3K signaling and glycolytic bioenergetics constitute a positive feedback regulatory circuit essential for Th17 cell-mediated autoimmunity. Overall design: WT and LDHA-KO Th17 cells were subjected to RNA-Seq analysis. (2 samples in each group)

辅助性T细胞（T helper, Th）的分化受抗原与协同刺激信号驱动，这类信号可激活磷脂酰肌醇3-激酶（phosphoinositide 3-kinase, PI3K），进而诱导转录重编程与代谢重编程，包括有氧糖酵解（瓦伯格效应，Warburg effect）。本研究证实，糖酵解生成的ATP可为PI3K信号通路供能，从而促进致病性辅助性T细胞17（Th17）的应答反应。
T细胞特异性敲除糖酵解酶乳酸脱氢酶A（lactate dehydrogenase A, LDHA）的小鼠，可抵抗Th17细胞介导的实验性自身免疫性脑脊髓炎，同时伴随T细胞活化、迁移、增殖与分化功能受损。LDHA缺失会破坏细胞氧化还原稳态，抑制ATP生成，导致磷脂酰肌醇(3,4,5)-三磷酸的产生量下降，同时减弱Akt激酶（Akt kinase）的活化水平及其转录因子靶标叉头框蛋白O1（Foxo1）的磷酸化程度。
在Th17细胞中特异性表达Akt不敏感型Foxo1突变体，可重现LDHA缺失所引发的Th17细胞分化缺陷。综上，PI3K信号通路与糖酵解能量代谢构成了正反馈调控环路，该环路对于Th17细胞介导的自身免疫反应至关重要。
实验设计：对野生型（wild type, WT）与LDHA敲除（LDHA-KO）的Th17细胞进行RNA测序（RNA-Seq）分析，每组设置2个样本。