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

基本信息

批准号：
8277329
负责人：
JONATHAN D POWELL
金额：
$ 40.18万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
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/8277329
关键词：
Adaptor Signaling Protein Allergens Amino Acids Antibodies Antigens Autoimmune Diseases Autoimmunity Autophagocytosis Biogenesis Bone Marrow Bone Marrow Transplantation CD28 gene Cell Lineage Cell Proliferation Cell physiology Cells Cellular Immunity Chimerism Companions Cues Data Development Effector Cell Environment Experimental Autoimmune Encephalomyelitis Failure Generations Graft Rejection Growth Factor IL2RA gene 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 Regulation Regulatory T-Lymphocyte Role Serine Signal Transduction Signaling Molecule Sirolimus T cell anergy T cell differentiation 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 human FRAP1 protein immunogenic in vivo in vivo Model inhibitor/antagonist insight mTOR protein novel therapeutics protein complex response

项目摘要

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.

TCR识别的结果取决于抗原的背景认可。在TCR参与度（信号1）预示识别时，是否识别将导致免疫原性反应取决于 APC上的共刺激分子（信号2）。此外，诸如IL-12等细胞因子，炎症环境中的IFN- - ，IL-4，IL-6和TGF-¿在偏斜T细胞中起关键作用分化。基于这些环境提示，T细胞可能会分化为效应子以Th1，Th2和Th17细胞或调节细胞为特征的子集，其特征是 FOXP3表达，滞后3表达和IL-10分泌。我们建议高度进化构成苏氨酸/丝氨酸蛋白激酶的哺乳动物靶标雷帕霉素（MTOR）在整合这些线索并决定抗原识别的结果。为了了解机制和 MTOR调节T细胞功能的途径我们生成有条件的mTOR T细胞中的敲除小鼠。 MTOR缺乏T细胞正常发展并产生正常初始刺激后的IL-2水平。但是，在没有TCR的情况下 MTOR导致这种细胞厌氧，这是由于未能产生IL-2和IFN-€所揭示的。此外，MTOR缺乏的T细胞无法分化为Th1，Th2或Th17效应器细胞。相反，在正常激活条件下，体外和体内这些细胞发展为调节性T细胞。在此提案中，我们将雇用MTOR NULL，RHEB NULL， rictor null和tsc2 null T细胞确定torc1和torc2在调节T细胞激活和适应性效应子与调节谱系承诺。使用肿瘤免疫学，病毒感染，过敏原，EAE和骨髓的体内模型移植我们将进一步确定MTOR及其下游信号的作用控制免疫反应。我们的方法将对关于免疫抑制剂的理由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。