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

mTOR 在确定 T 细胞激活与耐受性方面的核心作用

• 批准号: 7728472
• 负责人: JONATHAN D POWELL
• 金额: $ 41万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-15 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7728472
• 关键词: Adaptor Signaling Protein; Allergens; Amino Acids; Antibodies; Antigens; Autoimmune Diseases; Autoimmunity; Autophagocytosis; Biogenesis; Bone Marrow; Bone Marrow Transplantation; CD28 gene; Cell Differentiation process; Cell Lineage; Cell physiology; Cells; Cellular Immunity; Chimerism; Companions; Cues; Data; Development; Effector Cell; Environment; Experimental Autoimmune Encephalomyelitis; Failure; Generations; Graft Rejection; Growth Factor; Immune response; Immunity; Immunosuppressive Agents; In Vitro; Inflammatory; Interferons; Interleukin-10; Interleukin-12; Interleukin-2; Interleukin-4; Interleukin-6; Knockout Mice; Lead; MADH3 gene; Mammalian Cell; Mediating; Metabolism; Modeling; Mus; Nutrient; Organ Transplantation; Outcome; Pathway interactions; Phosphorylation; Play; Prevention; Process; Protein-Serine-Threonine Kinases; Proteins; Raptors; Regulation; Role; Serine; Signal Transduction; Signaling Molecule; Sirolimus; T-Cell Activation; T-Lymphocyte; Testing; Translations; Transplantation; Treatment Protocols; Tuberous sclerosis protein complex; Tumor Immunity; Virus Diseases; Yeasts; anergy; base; cell growth; cytokine; design; immunogenic; in vivo; in vivo Model; inhibitor/antagonist; insight; mTOR protein; novel therapeutics; protein complex; public health relevance; response

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.

描述（由申请人提供）：TCR识别的结果取决于抗原被识别的环境。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上共刺激分子（信号2）的存在。此外，IL-12、IFN-3、IL-4、IL-6、TGF-？在T细胞分化中起关键作用。基于这些环境线索，T细胞可能分化为以TH1、TH2和TH17细胞为特征的效应细胞亚群或以Foxp3表达、LAG-3表达和IL-10分泌为特征的调节细胞。我们认为，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）在整合这些信号和决定抗原识别结果方面起着关键作用。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mTOR敲除小鼠。mTOR缺陷T细胞在初始刺激时正常发育并产生正常水平的IL-2。然而，在mTOR缺失的情况下，TCR的参与会使这些细胞失能，如不能产生IL-2和IFN-?所揭示的那样。此外，mTOR缺陷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，这些细胞在体内和体外都发育成调节性T细胞。在本提案中，我们将使用mTOR无效、Rheb无效、Rictor无效和TSC2无效的T细胞来确定TORC1和TORC2在调节T细胞激活和适应性效应与调节谱系承诺中的作用。通过肿瘤免疫、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及其下游信号在调节免疫应答中的作用。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。