The role of the T cell receptor in regulatory T cell homeostasis and expansion

T 细胞受体在调节性 T 细胞稳态和扩增中的作用

• 批准号: 8218851
• 负责人: Taku Kambayashi
• 金额: $ 40万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-01-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8218851
• 关键词: 76-kDa SH2 domain-containing leukocyte protein; Acute; Affect; Affinity; Antigens; Autoimmune Diseases; Autoimmunity; Biology; Bone Marrow; Bypass; CD80 gene; Chimera organism; Coculture Techniques; Cyclosporine; Data; Dendritic Cells; Disease; Disease Outcome; Ensure; Environment; Failure; Goals; Homeostasis; Human; In Vitro; Injection of therapeutic agent; Interleukin-2; LCP2 gene; Lymphoid; MHC Class II Genes; Maintenance; Mediating; Medical center; Molecular; Mus; Mutant Strains Mice; Pathway interactions; Pennsylvania; Play; Prevention; Production; Proliferating; Receptor Activation; Receptor Signaling; Regulatory T-Lymphocyte; Reporting; Research; Role; Route; Signal Transduction; Signaling Molecule; Specificity; Splenocyte; T-Cell Receptor; T-Lymphocyte; T-Lymphocyte Subsets; TNFSF4 gene; Testing; Translating; Universities; clinically relevant; graft vs host disease; immunopathology; in vivo; inhibitor/antagonist; mouse model; novel; prevent; research facility; response

DESCRIPTION (provided by applicant): This proposal describes a 5-year research plan focusing on how signal transduction through the T cell receptor (TCR) contributes to the homeostasis and expansion of regulatory T cells (Treg)s. Tregs are a subset of T cells with suppressive function and are crucial for preventing immunopathology by inhibiting conventional T cell (Tconv) activation. A failure to develop Tregs or to maintain Tregs in the periphery results in fatal autoimmune disease. In contrast, an increase in Tregs protects against a variety of T cell-mediated disorders including graft-versus-host disease (GVHD). Thus, understanding the mechanisms by which Tregs proliferate and are maintained is of critical importance. However, the precise cellular and molecular requirements for Treg homeostasis and expansion are incompletely understood. We have recently reported that Tconvs and dendritic cells (DC)s play a critical role in controlling Treg homeostasis and expansion. Our preliminary data suggest that (1) Tregs require DCs but not TCR stimulation for their proliferation, (2) TCR stimulation of Tconvs by DCs for IL-2 production is required for Treg proliferation, and (3) blockade of TCR stimulation in conjunction with exogenous IL-2 inhibits Tconv activation but maintains Treg proliferation. These data support our hypothesis that the homeostatic maintenance and proliferation of Tregs depend on Tconvs and DCs, and occur through both TCR/MHC II-dependent and - independent routes. We propose that TCR stimulation allows the preferential expansion of Tregs with relevant antigen specificities, while the MHC II/TCR-independent mode of Treg proliferation ensures survival of Tregs with TCRs of multiple specificities to continuously maintain a diverse repertoire of Tregs. In this proposal, we aim to extend our preliminary in vitro findings to in vivo studies. Our research plan starts by examining the precise contribution of TCR signaling by Tregs to their homeostasis in vivo. Our second aim will test the role of TCR signaling by Tconvs for IL-2 production in supporting Treg homeostasis in vivo. Finally, we will translate our hypothesis to clinically relevant questions by exploiting the differential requirement of TCR signaling in Treg and Tconv proliferation and determine whether a combination of IL-2 and a TCR signaling inhibitor such as CSA could be used to more effectively treat Tconv-mediated diseases such as GVHD. The proposed studies will enhance our understanding of Treg homeostasis and potentially yield novel molecules, strategies, and pathways to modulate Tregs in multiple disease settings. Our expertise in signal transduction and Treg biology together with our expert consultants (Drs. Andy Caton, Gary Koretzky, Robert Eisenberg, and Andras Schaffer), and the quality of the research facilities at the University of Pennsylvania Medical Center comprise an ideal environment in which to conduct this proposed research plan. PUBLIC HEALTH RELEVANCE: Regulatory T cells play a critical role in the prevention of immunopathology and can be used to treat a variety of T cell-mediated diseases including autoimmunity and graft-versus-host disease. The goal of this proposal is to investigate the cellular and molecular requirements, in particular the role of dendritic cells and the T cell receptor, in regulatory T cell homeostasis and expansion. The proposed studies will enhance our understanding of regulatory T cell homeostasis and potentially yield novel molecules, strategies, and pathways to modulate regulatory T cells in multiple disease settings.

描述（由申请人提供）：该提案描述了一项为期5年的研究计划，重点是通过T细胞受体（TCR）信号转导如何促进调节性T细胞（TREG）S的扩展。 Treg是具有抑制功能的T细胞的子集，对于通过抑制常规T细胞（TCONV）激活来预防免疫病理至关重要。未能发展treg或在外围维持Treg会导致致命的自身免疫性疾病。相比之下，Tregs的增加可以预防各种T细胞介导的疾病，包括移植物抗宿主病（GVHD）。因此，理解Treg繁殖并维持的机制至关重要。但是，尚不完全了解Treg稳态和扩张的精确细胞和分子需求。 我们最近报道说，TCONV和树突状细胞（DC）在控制Treg稳态和扩张中起着关键作用。我们的初步数据表明，（1）Tregs需要DC，但不需要TCR刺激以使其增殖，（2）TCR刺激DC通过DCS进行IL-2产生的TCOR刺激，而TREG增殖是必需的，并且（3）与Exenenos IL-2抑制TCONV的TCR刺激阻断了TCR刺激，但抑制TCONV抑制TCONV激活，但维持Treg Extigation treg rilliferation treg pluliferation。这些数据支持我们的假设，即Treg的体内稳态维持和增殖取决于TCONV和DC，并通过TCR/MHC II依赖性和 - 独立途径进行。我们提出，TCR刺激允许具有相关抗原特异性的TREG的优先扩展，而MHC II/TCR无关Treg增殖模式可确保TREG的存活，具有多种特异性的TCR，以不断维持Tregs多样的Tregs。 在此提案中，我们旨在将我们的初步体外发现扩展到体内研究。我们的研究计划首先检查Tregs对其体内体内稳态的确切贡献。我们的第二个目标将测试TCONVS对IL-2产生的TCR信号传导在体内支持Treg稳态中的作用。最后，我们将通过利用TREG和TCONV增殖中TCR信号的差异要求将假设转化为临床相关的问题，并确定IL-2和TCR信号抑制剂（例如CSA）的组合是否可以用于更有效地治疗TCONV介导的TCONV介导的疾病，例如GVHD。拟议的研究将增强我们对Treg稳态的理解，并可能产生新的分子，策略和途径，以调节多种疾病环境中的Treg。我们在信号转导和TREG生物学方面的专业知识以及我们的专家顾问（Andy Caton博士，Gary Koretzky，Robert Eisenberg和Andras Schaffer），以及宾夕法尼亚大学医学中心的研究设施的质量，构成了一个理想的环境，可以进行此提议研究计划。 公共卫生相关性：调节性T细胞在预防免疫病理学中起着至关重要的作用，可用于治疗各种T细胞介导的疾病，包括自身免疫性和移植物抗宿主病。该建议的目的是研究细胞和分子需求，特别是树突状细胞和T细胞受体的作用，在调节性T细胞稳态和扩张中。拟议的研究将增强我们对调节性T细胞稳态的理解，并可能产生新的分子，策略和途径，以调节多种疾病环境中调节性T细胞。