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: 8601200
• 负责人: Taku Kambayashi
• 金额: $ 39.2万
• 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/8601200
• 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; abstracting; clinically relevant; graft vs host disease; immunopathology; in vivo; inhibitor/antagonist; mouse model; novel; prevent; research facility; response

Abstract 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 repored 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.

抽象的 该提案描述了一个为期5年的研究计划，重点介绍了如何通过T细胞受体转导的信号转导 （TCR）有助于调节T细胞（Treg）s的稳态和扩展。 Treg是T的子集 具有抑制作用的细胞，对于通过抑制常规T细胞来预防免疫病理至关重要 （TCONV）激活。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的增加可以防止各种T细胞介导的疾病 移植物与宿主病（GVHD）。因此，了解Tregs繁殖的机制 保持至关重要。但是，Treg的精确细胞和分子需求 稳态和扩张尚不完全理解。 我们最近回忆说，TCONV和树突状细胞（DC）在控制Treg中起着关键作用 稳态和扩张。我们的初步数据表明（1）Treg需要DC，但不需要TCR刺激 为了增殖，（2）DC对TCR刺激IL-2的产生是TREG的 增殖和（3）与外源IL-2结合结合的TCR刺激阻断了TCONV激活 但保持Treg增殖。这些数据支持我们的假设，即稳态维护和 Treg的增殖取决于TCONV和DC，并通过TCR/MHC II依赖性和 - 发生 - 独立路线。我们建议TCR刺激使Treg具有相关的优先扩展 抗原特异性，而Treg增殖的MHC II/TCR无关模式可确保Treg的存活 具有多种特异性的TCR，可连续保持多样化的Treg曲目。 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TREG对其体内体内稳态的TCR信号的精确贡献。我们的 第二个目标将测试TCONVS在支持TREG稳态中TCR的作用 体内。最后，我们将通过利用差异来将我们的假设转化为临床相关问题 在Treg和TCONV增殖中对TCR信号的需求，并确定IL-2和 TCR信号抑制剂（例如CSA）可用于更有效地治疗TCONV介导的疾病 作为GVHD。拟议的研究将增强我们对Treg稳态的理解和潜在的产量 在多种疾病环境中调节Treg的新分子，策略和途径。我们的专业知识 信号转导和Treg生物学以及我们的专家顾问（Andy Caton博士，Gary Koretzky， 罗伯特·艾森伯格（Robert Eisenberg）和安德拉斯·沙弗（Andras Schaffer），以及大学研究设施的质量 宾夕法尼亚州医疗中心构成了一个理想的环境，在该环境中，可以在其中制定该拟议的研究计划。