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

TCR识别的结果由抗原被识别的背景决定。 认可.虽然TCR参与（信号1）预示着认可，但这是否 识别将导致免疫原性应答是由存在 APC上的共刺激分子（信号2）。此外，细胞因子如IL-12， 炎症环境中的IFN-γ、IL-4、IL-6和TGF-β在T细胞的偏斜中起关键作用。 分化基于这些环境线索，T细胞可以分化为效应细胞。 特征为TH 1、TH 2和TH 17细胞的亚群或特征为 Foxp 3表达、LAG-3表达和IL-10分泌。我们建议， 进化上保守的苏氨酸/丝氨酸蛋白激酶 雷帕霉素（mTOR）在整合这些线索和支配细胞凋亡中起着关键作用。 抗原识别的结果。为了理解这些机制， mTOR调节T细胞功能的途径，我们产生了条件性mTOR 敲除小鼠的T细胞。mTOR缺陷型T细胞正常发育并产生正常的 IL-2的水平。然而，在缺乏TCR的情况下， mTOR使这些细胞失去反应性，如不能产生IL-2和IFN-γ所揭示的。 此外，mTOR缺陷型T细胞不能分化为TH 1、TH 2或TH 17效应细胞 细胞相反，在正常活化条件下，在体外和体内，这些细胞 发育成调节性T细胞。在这个提议中，我们将采用mTOR null，Rheb null， Rictor无效和TSC 2无效T细胞以确定TORC 1和TORC 2在 调节T细胞活化和适应性效应物与调节谱系定型。 使用肿瘤免疫、病毒感染、过敏原、EAE和骨髓的体内模型 我们将进一步确定mTOR及其下游信号传导的作用 调节免疫反应。我们的方法将对以下方面产生重要影响： 关于免疫抑制剂的基本原理设计， 自身免疫性疾病和器官移植，以及制定战略， 增强抗肿瘤免疫力。

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-¿, 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.