Regulation of TH17 plasticity and stemness by mTORC1

程序描述/摘要 世系承诺和维持是各种生物系统中的基本过程。在 免疫系统中，T细胞反应失调是许多过敏性和炎症性疾病的原因。 Th17细胞在多发性硬化症(MS)及其实验性小鼠模型中起关键致病作用 自身免疫性脑脊髓炎(EAE)。TH17细胞的一个独特特征是其固有的可塑性，赋予了 成熟的效应细胞TH17具有其他T细胞亚群的特征，尤其是TH1细胞，但这一过程是如何进行的 是受控制的，其功能意义仍然难以捉摸。T细胞代谢程序与细胞的协调 命运的决定是获得性免疫的一个基本过程，但代谢途径如何与 免疫信号在T细胞命运决定和自身免疫失调中的作用尚不清楚。尤其是， 代谢程序在效应器T细胞可塑性和致病性中的作用基本上仍未被研究。 我们假设TH17细胞固有的异质性是其谱系可塑性的基础；末端分化和持续干性之间的平衡取决于mTORC1信号和代谢重新编程，并有助于自身免疫性炎症。目的1.确定转录机制和发育轨迹 潜在的TH17末端分化和茎。目标2.建立信号和代谢 MTORC1在TH17反应中的作用机制。目的3.建立TH17的代谢调控和信号通路 可塑性。关于调节TH17谱系可塑性的分子途径的描述很少。我们争辩说 对TH17可塑性的代谢控制的洞察可能建立T细胞命运控制的新范式 机制，并显示自身免疫性疾病的合法治疗机会。

Program Description/Abstract Lineage commitment and maintenance are fundamental processes in a variety of biological systems. In the immune system, dysregulated T cell responses are the cause of many allergic and inflammatory disorders. TH17 cells play a key pathogenic role in Multiple sclerosis (MS) and its murine model, experimental autoimmune encephalomyelitis (EAE). A unique feature of TH17 cells is their inherent plasticity that endows mature effector TH17 cells with characteristics of other T cell subsets especially TH1 cells, but how this process is controlled and its functional significance remain elusive. Coordination of T cell metabolic programs with cell fate decisions is a fundamental process in adaptive immunity, but how metabolic pathways intersect with immune signals in T cell fate decisions and autoimmune dysregulation is poorly defined. In particular, the function of metabolic programs in effector T cell plasticity and pathogenicity remains essentially unexplored. We hypothesize that the inherent heterogeneity of TH17 cells underlies their lineage plasticity; the balance between terminal differentiation and sustained stemness depends upon mTORC1 signaling and metabolic reprogramming, and contributes to autoimmune inflammation. Aim 1. Determine transcriptional mechanisms and developmental trajectory underlying TH17 terminal differentiation and stemness. Aim 2. Establish the signaling and metabolic mechanisms of mTORC1 in TH17 responses. Aim 3. Establish metabolic control and signaling circuits of TH17 plasticity. There has been little description of molecular pathways regulating TH17 lineage plasticity. We argue that insight into metabolic control of TH17 plasticity could establish a new paradigm of T cell fate control mechanisms, and manifest legitimate therapeutic opportunities for autoimmune diseases.