A central role for mTOR in Determining T Cell Activation versus Tolerance

描述(由申请人提供)：TCR识别的结果取决于识别抗原的环境。虽然TCR参与(信号1)预示着识别，但这种识别是否会导致免疫原性反应取决于APC上是否存在共刺激分子(信号2)。IL-12、干扰素-3、IL-4、IL-6、转化生长因子-β等细胞因子。在炎症环境中，T细胞分化起着至关重要的作用。基于这些环境信号，T细胞可能分化为以TH1、TH2和TH17细胞为特征的效应亚群，或以Foxp3表达、Lag-3表达和IL-10分泌为特征的调节细胞。我们认为，进化上高度保守的苏氨酸/丝氨酸蛋白激酶，哺乳动物雷帕霉素靶标(MTOR)在整合这些线索和决定抗原识别结果方面发挥着关键作用。为了了解mTOR调节T细胞功能的机制和途径，我们在T细胞中产生了条件性mTOR基因敲除小鼠。MTOR缺陷的T细胞发育正常，在最初的刺激下产生正常水平的IL-2。然而，在缺乏mTOR的情况下，TCR的参与使这些细胞无能，表现为不能产生IL-2和干扰素？此外，mTOR缺陷的T细胞不能分化为TH1、TH2或TH17效应细胞。相反，在正常激活条件下，无论是在体外还是在体内，这些细胞都会发育成调节性T细胞。在这项建议中，我们将使用mTOR零、Rheb零、Rictor零和TSC2零T细胞来确定TORC1和TORC2在调节T细胞激活和适应性效应器与调节谱系承诺中的作用。利用肿瘤免疫、病毒感染、变应原、EAE和骨髓移植的体内模型，我们将进一步确定mTOR及其下游信号在调节免疫反应中的作用。我们的方法将对免疫抑制剂治疗自身免疫性疾病和器官移植的基本原理设计以及设计增强抗肿瘤免疫的策略具有重要意义。 公共卫生相关性：在这项提案中，我们将检验mTOR在调节适应性效应器和调节性T细胞谱系承诺方面发挥独特而核心作用的假设。这些研究将为T细胞介导的免疫调节提供重要的见解。此外，我们的发现将对开发治疗自身免疫和预防移植排斥反应的新的治疗方案具有潜在的意义。

DESCRIPTION (provided by applicant): The outcome of TCR recognition is dictated by the context in which the antigen is recognized. While TCR engagement (Signal 1) heralds recognition, whether this recognition will lead to an immunogenic response is dictated by the presence of costimulatory molecules (Signal 2) on the APC. Furthermore, cytokines such as IL-12, IFN-3, IL-4, IL-6 and TGF-? in the inflammatory milieu play critical roles in skewing T cell differentiation. Based on these environmental cues T cells may differentiate into effector subsets characterized by TH1, TH2 and TH17 cells or regulatory cells characterized by Foxp3 expression, LAG-3 expression and IL-10 secretion. We propose that the highly evolutionarily conserved threonine/serine protein kinase the mammalian Target of Rapamycin (mTOR) plays a critical role in integrating these cues and dictating the outcome of antigen recognition. In an effort to understand the mechanisms and pathways by which mTOR regulates T cell function we generated conditional mTOR knockout mice in T cells. mTOR deficient T cells develop normally and produce normal levels of IL-2 upon initial stimulation. However, TCR engagement in the absence of mTOR renders such cells anergic, as revealed by a failure to produce IL-2 and IFN-?. Furthermore, mTOR deficient T cells fail to differentiate into TH1,TH2 or TH17 effector cells. Instead, under normally activating conditions, both in vitro and in vivo these cells develop into regulatory T cells. In this proposal we will employ mTOR null, Rheb null, Rictor null and TSC2 null T cells to determine the role of TORC1 and TORC2 in regulating T cell activation and adaptive effector versus regulatory lineage commitment. Using in vivo models of tumor immunity, viral infection, allergen, EAE and bone marrow transplantation we will further determine the role of mTOR and its downstream signaling in regulating immune responses. Our approach will have important implications with regard to the rationale design of immunosuppressive agents for the treatment of autoimmune disorders and organ transplantation as well as devising strategies to enhance anti-tumor immunity. PUBLIC HEALTH RELEVANCE: In this proposal we will test the hypothesis that mTOR plays a unique and central role in regulating adaptive effector and regulatory T cell lineage commitment. These studies should provide important insight into the regulation of T cell mediated immunity. In addition, our findings will have potential implications for the development of novel therapeutic regimens for the treatment of autoimmunity and the prevention of graft rejection in transplantation.