Metabolic checkpoint in TH17 cell differentiation

描述（由申请人提供）：T细胞代谢程序与细胞命运决定的协调是适应性免疫中的基本问题。在抗原刺激后，幼稚T细胞经历克隆扩增和谱系分化以介导免疫效应子功能。同时，T细胞表现出比静息状态显著增加的生物能量和生物合成需求，其中糖酵解特别显著增加。在氧气存在的情况下依赖糖酵解产生ATP，称为有氧糖酵解或瓦尔堡效应，是T细胞（和癌细胞）增殖的标志。事实上，已经提出代谢的上调是促进T细胞活化的必要步骤或“检查点”，但是代谢途径如何与T细胞命运决定和自身免疫失调中的免疫信号交叉的定义很差。在T细胞效应群中，TH 17细胞在许多自身免疫性疾病中发挥关键的致病作用，包括多发性硬化症及其小鼠模型实验性自身免疫性脑脊髓炎（EAE）。Th 17细胞的分化与诱导调节性T细胞（Treg）的产生密切相关，Th 17和Treg细胞之间的平衡主要由细胞因子环境塑造。我们最近发现，TH 17和Treg细胞在糖酵解活性和糖酵解酶表达方面存在显著差异。低氧诱导因子1 <$$>（HIF 1 <$）是一种糖酵解基因表达的主要转录因子，在TH 17细胞中被选择性诱导。HIF 1 <$的缺失可抑制糖酵解酶的表达和TH 17细胞的分化，从而改善EAE的发病机制。我们的初步研究进一步暗示了mTORC 1信号传导，这是细胞生长和代谢的重要调节因子。此外，发病后急性缺失HIF 1 ²或药物抑制糖酵解途径对EAE具有治疗作用。我们假设mTORC 1，HIF 1？（和相关转录因子）和T细胞糖酵解之间的相互作用协调了TH 17分化和自身免疫性疾病的代谢检查点。具体来说，我们将确定：（1）糖酵解如何受到TH 17细胞中免疫信号的调节;（2）糖酵解途径如何协调TH 17分化的代谢检查点;（3）T细胞糖酵解途径是否对TH 17介导的疾病的治疗靶向和维持TH 17应答很重要。关于调节T细胞代谢途径以治疗自身免疫性和炎性疾病的描述很少。从该应用中获得的见解可能会显著影响我们对T细胞代谢和TH 17细胞生物学的理解，并表现出合理的治疗机会。

DESCRIPTION (provided by applicant): Coordination of T cell metabolic programs with cell fate decisions is a fundamental issue in adaptive immunity. Upon antigen stimulation, na¿ve T cells undergo clonal expansion and lineage differentiation to mediate immune effector functions. Concomitantly, T cells exhibit a marked increase of the bioenergetic and biosynthetic demands over the resting state, with a particularly striking increase in glycolysis. The reliance on glycolysis to generate ATP in the presence of oxygen, known as aerobic glycolysis or the Warburg effect, is a hallmark of proliferating T cells (and cancer cells). Indeed, upregulation of metabolism has been proposed to be a necessary step or "checkpoint" to facilitate T cell activation, but how the metabolic pathways intersect with immune signals in T cell fate decisions and autoimmune dysregulation is poorly defined. Among T cell effector populations, TH17 cells play a key pathogenic role in many autoimmune disorders, including multiple sclerosis and its murine model experimental autoimmune encephalomyelitis (EAE). Differentiation of TH17 cells is closely related to the generation of induced regulatory T cells (Treg), and the balance between TH17 and Treg cells is mainly shaped by the cytokine environment. We recently show that TH17 and Treg cells have marked differences in their glycolytic activity and expression of glycolytic enzymes. Hypoxia-inducible factor 1¿ (HIF1¿), a master transcription factor for glycolytic gene expression, is selectively induced in TH17 cells. Deletion of HIF1¿ impairs the expression of glycolytic enzymes and the differentiation of TH17 cells, and ameliorates the pathogenesis of EAE. Our preliminary studies further implicated mTORC1 signaling, an important regulator of cell growth and metabolism, in this process. Moreover, acute deletion of HIF1¿ or pharmacological inhibition of glycolytic pathway after disease onset exerted therapeutic effects on EAE. We hypothesize that the interplay between mTORC1, HIF1¿ (and related transcription factors) and T cell glycolysis orchestrates a metabolic checkpoint for TH17 differentiation and autoimmune diseases. Specifically, we will determine: (1) how glycolysis is regulated by immune signals in TH17 cells; (2) how the glycolytic pathway orchestrates a metabolic checkpoint for TH17 differentiation; (3) whether T cell glycolytic pathway is important for therapeutic targeting of TH17-mediated diseases and for the maintenance of TH17 responses. There has been little description on modulating T cell metabolic pathways for the treatment of autoimmune and inflammatory diseases. Insights gained from this application may significantly impact our understanding of T cell metabolism and TH17 cell biology and manifest legitimate therapeutic opportunities.