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

描述（由申请人提供）：TCR识别的结果由识别抗原的环境决定。虽然TCR接合（信号1）预示着识别，但这种识别是否会导致免疫原性应答取决于APC上共刺激分子（信号2）的存在。此外，细胞因子，如IL-12，IFN-3，IL-4，IL-6和TGF-？在炎症环境中的免疫调节在T细胞分化的偏斜中起关键作用。基于这些环境线索，T细胞可以分化成以TH 1、TH 2和TH 17细胞为特征的效应子亚群或以Foxp 3表达、LAG-3表达和IL-10分泌为特征的调节细胞。我们提出，高度进化保守的苏氨酸/丝氨酸蛋白激酶哺乳动物雷帕霉素靶蛋白（mTOR）在整合这些线索和决定抗原识别的结果中起着至关重要的作用。为了理解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敲除小鼠。mTOR缺陷型T细胞正常发育，并在初始刺激时产生正常水平的IL-2。然而，在缺乏mTOR的情况下，TCR参与使这些细胞无反应性，如不能产生IL-2和IFN-β所揭示的。此外，mTOR缺陷型T细胞不能分化成TH 1、TH 2或TH 17效应细胞。相反，在正常活化条件下，这些细胞在体外和体内都发育成调节性T细胞。在该提议中，我们将使用mTOR null、Rheb null、Rictor null和TSC 2 null T细胞来确定TORC 1和TORC 2在调节T细胞活化和适应性效应子与调节谱系定型中的作用。利用肿瘤免疫、病毒感染、过敏原、EAE和骨髓移植的体内模型，我们将进一步确定mTOR及其下游信号传导在调节免疫应答中的作用。我们的方法将有重要的意义，关于免疫抑制剂的设计原理，用于治疗自身免疫性疾病和器官移植，以及设计策略，以提高抗肿瘤免疫。 公共卫生相关性：在这个提议中，我们将测试mTOR在调节适应性效应子和调节性T细胞谱系定型中发挥独特和核心作用的假设。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，我们的研究结果将有潜在的影响，为发展新的治疗方案，治疗自身免疫和预防移植排斥反应的移植。

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.