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

TCR识别的结果由抗原所处的环境决定 被认可了。虽然TCR参与(信号1)预示着认可，但无论这 识别会导致免疫原性反应是由存在的 APC上的共刺激分子(信号2)。此外，IL-12等细胞因子， 炎症环境中的干扰素、白介素4、白介素6和转化生长因子β在T细胞偏斜中起关键作用 差异化。基于这些环境信号，T细胞可能分化为效应器 以TH1、TH2和TH17细胞或调节细胞为特征的亚群 Foxp3表达、LAG-3表达和IL-10分泌。我们建议高度重视 进化保守的苏氨酸/丝氨酸蛋白激酶是哺乳动物的靶标 雷帕霉素(MTOR)在整合这些线索和口述 抗原识别的结果。为了努力理解这些机制和 MTOR调节T细胞功能的途径我们产生了条件mTOR T细胞中的基因敲除小鼠。MTOR缺陷的T细胞正常发育和产生正常 初始刺激时的IL-2水平。然而，TCR在缺少 MTOR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效应器 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 发育成调节性T细胞。在本提案中，我们将使用mTOR零、RHEB零 Rictor零T细胞和TSC2零T细胞在确定TORC1和TORC2中的作用 调节T细胞激活和适应性效应器与调节谱系承诺。 使用肿瘤免疫、病毒感染、过敏原、EAE和骨髓的体内模型 移植后我们将进一步确定mTOR的作用及其下游信号转导 在调节免疫反应方面。我们的方法将对 关于免疫抑制剂治疗慢性粒细胞白血病的合理设计 自身免疫性疾病和器官移植，以及制定策略 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.