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 该提案描述了一项为期 5 年的研究计划，重点关注如何通过 T 细胞受体进行信号转导 (TCR) 有助于调节性 T 细胞 (Treg) 的稳态和扩增。 Tregs 是 T 的子集 具有抑制功能的细胞，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。无法发育 Tregs 或无法维持周围的 Tregs 会导致致命的自身免疫 疾病。相比之下，Tregs 的增加可以预防多种 T 细胞介导的疾病，包括 移植物抗宿主病（GVHD）。因此，了解 Tregs 增殖和增殖的机制 维护至关重要。然而，Treg 的精确细胞和分子要求 稳态和扩张尚不完全清楚。 我们最近报道称 Tconv 和树突状细胞 (DC) 在控制 Treg 中发挥着关键作用 稳态和扩张。我们的初步数据表明 (1) Tregs 需要 DC，但不需要 TCR 刺激 为了使其增殖，(2) Treg 需要 DC 刺激 Tconv 来产生 IL-2 (3) 阻断 TCR 刺激与外源性 IL-2 结合抑制 Tconv 激活 但维持Treg增殖。这些数据支持我们的假设，即稳态维持和 Tregs 的增殖依赖于 Tconv 和 DC，并通过 TCR/MHC II 依赖和 - 独立路线。我们建议 TCR 刺激可以优先扩展具有相关性的 Tregs。 抗原特异性，而 MHC II/TCR 独立的 Treg 增殖模式确保了 Tregs 的存活 具有多种特异性的 TCR，以持续维持 Tregs 的多样性。 在本提案中，我们的目标是将我们的初步体外研究结果扩展到体内研究。我们的研究计划 首先检查 Tregs 的 TCR 信号传导对其体内稳态的精确贡献。我们的 第二个目标是测试 Tconvs 产生的 TCR 信号在 IL-2 产生中在支持 Treg 稳态中的作用。 体内。最后，我们将通过利用差异将我们的假设转化为临床相关问题 Treg 和 Tconv 增殖中 TCR 信号传导的要求，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，例如 作为移植物抗宿主病。拟议的研究将增强我们对 Treg 稳态和潜在产量的理解 在多种疾病环境中调节 Tregs 的新分子、策略和途径。我们的专业知识 与我们的专家顾问（Andy Caton 博士、Gary Koretzky 博士、 罗伯特·艾森伯格和安德拉斯·谢弗)，以及大学研究设施的质量 宾夕法尼亚医学中心为开展这项拟议的研究计划提供了理想的环境。