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获得性免疫中的一个基本问题。在抗原刺激下，NAéve T细胞进行克隆性扩增和谱系分化，以介导免疫效应功能。与静息状态相比，T细胞表现出显著的生物能量和生物合成需求的增加，尤其是糖酵解的增加。依赖糖酵解在氧气存在的情况下产生ATP，称为有氧糖酵解或Warburg效应，是T细胞(和癌细胞)增殖的标志。事实上，新陈代谢的上调被认为是促进T细胞激活的必要步骤或“检查点”，但新陈代谢途径如何与免疫信号在T细胞命运决定和自身免疫失调中相交尚不清楚。在T细胞效应群中，TH17细胞在许多自身免疫性疾病中起着关键的致病作用，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)。TH17细胞的分化与诱导调节性T细胞(Treg)的产生密切相关，TH17与Treg细胞之间的平衡主要受细胞因子环境的影响。我们最近发现TH17和Treg细胞在糖酵解活性和糖酵解酶的表达上有明显的差异。低氧诱导因子1(HIF1)是糖酵解基因表达的主要转录因子，在TH17细胞中被选择性诱导。HIF1基因缺失可影响糖酵解酶的表达和TH17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表明，mTORC1信号是细胞生长和代谢的重要调节因子，参与了这一过程。此外，发病后HIF1基因的急性缺失或糖酵解途径的药物抑制对EAE有治疗作用。我们假设mTORC1、HIF1(和相关的转录因子)和T细胞糖酵解之间的相互作用协调了TH17分化和自身免疫性疾病的代谢检查点。具体地说，我们将确定：(1)TH17细胞中的糖酵解如何受到免疫信号的调节；(2)糖酵解途径如何协调TH17分化的代谢检查点；(3)T细胞糖酵解途径对于TH17介导的疾病的治疗靶向和维持TH17反应是否重要。关于调节T细胞代谢途径治疗自身免疫性和炎症性疾病的报道很少。从这一应用中获得的见解可能会显著影响我们对T细胞代谢和TH17细胞生物学的理解，并显示合法的治疗机会。

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.