Mechanisms of Integrin-Mediated Costimulation in T Cells

描述(申请人提供)：整合素1421(VLA-4)有助于常见自身免疫性疾病的病因学，包括多发性硬化症、炎症性肠病和系统性红斑狼疮。虽然VLA-4被广泛认为通过引导细胞转运和增强细胞黏附来促进T细胞功能，但VLA-4有效地共刺激T细胞激活。这种共刺激作用的机制尚不清楚，可能在人类免疫疾病的病因学中发挥重要作用。我们的长期目标是了解如何操纵VLA-4的共刺激功能，以调节体内T细胞的激活。我们的近期目标是确定VLA-4如何调节T细胞对抗原的反应。在这里，我们提供了初步的数据，描述了以前未知的VLA-4连接对TCR诱导的信号复合体移动的影响。我们的具体假设是，含有SLP-76和ADAP的结构是传递VLA-4连接启动的张力依赖的共刺激信号所必需的。拟议工作的理由是，它将加强对基本机制的了解，这些基本机制能够整合TCR和VLA-4下游的信号通路。三个目标将研究ADAP如何促进T细胞共刺激以及细胞骨架张力如何促进VLA-4依赖的共刺激信号：1)ADAP如何促进SLP-76微簇的组装和移位？2)共刺激如何依赖于VLA-4依赖的微簇的固定？3)细胞骨架张力如何促进VLA-4对T细胞的共刺激？这些研究探索了VLA-4连接的一种新效应，即TCR诱导的复合体的侧向固定，并将其作为工具来剖析VLA-4参与共刺激的途径。我们期望这些研究能够确定VLA-4连接共刺激T细胞激活的机制。这将对我们对自身免疫性疾病的理解产生积极的影响，并将有助于识别药物开发的独特细胞内靶点。这项工作还将产生对将细胞形状与细胞生长和增殖联系起来的系统的见解，为癌症提供有用的见解。公共卫生相关性：免疫反应通常可保护机体免受病原体和肿瘤的侵袭，但也可能被不适当地激活，从而导致炎症性疾病和自身免疫性疾病。整合素是帮助激活T细胞的蛋白质，T细胞在调节这些免疫反应方面发挥着关键作用。这项研究将阐明整合素如何增强T细胞反应，从而对健康或疾病做出贡献。通过这种方式，我们期望获得对常见疾病的潜在原因的有用见解，包括哮喘、多发性硬化症、糖尿病、炎症性肠病和动脉粥样硬化。

DESCRIPTION (provided by applicant): The integrin 1421 (VLA-4) contributes to the etiology of common autoimmune disorders, including multiple sclerosis, inflammatory bowel disease, and systemic lupus erythematosus. Although VLA-4 is widely viewed as contributing to T cell function by directing cell trafficking and by enhancing cell adhesion, VLA-4 potently costimulates T cell activation. The mechanisms underlying this costimulation are not well understood and may play a significant role in the etiology of human immune disorders. Our long-range goal is to understand how to manipulate the costimulatory functions of VLA-4 in order to regulate T cell activation in vivo. Our immediate objective is to determine how VLA-4 modulates T cell responses to antigen. Here, we present preliminary data characterizing a previously unknown effect of VLA-4 ligation on the movement of signaling complexes induced by the TCR. Our specific hypothesis is that structures containing SLP-76 and ADAP are required for the transmission of tension-dependent costimulatory signals initiated upon VLA-4 ligation. The rationale for the proposed work is that it will provide an enhanced understanding of the fundamental mechanisms that enable the integration of the signaling pathways downstream of the TCR and VLA-4. Three aims will examine how ADAP contributes to T cell costimulation and how cytoskeletal tension contributes to VLA-4 dependent costimulatory signals: 1) How does ADAP contribute to the assembly and translocation of SLP-76 microclusters? 2) How does costimulation depend on the VLA-4-dependent immobilization of microclusters? 3) How does cytoskeletal tension contribute to T cell costimulation by VLA-4? These studies explore a novel effect of VLA-4 ligation, the lateral immobilization of TCR-induced complexes, and use it as a tool to dissect the pathways involved in costimulation by VLA-4. We expect these studies to define the mechanisms by which VLA-4 ligation costimulates T cell activation. This will have a positive impact on our understanding of autoimmune disease, and will assist in the identification of unique intracellular targets for drug development. This work will also generate insights into the systems linking cell shape to cell growth and proliferation, providing useful insights into cancer. PUBLIC HEALTH RELEVANCE: Immune responses normally protect against pathogens and tumors, but can be activated inappropriately, resulting is inflammatory disorders and autoimmune diseases. Integrins are proteins that help activate T cells, which play a crucial role in the regulation these immune responses. This study will clarify how integrins enhance T cell responses that can contribute to either health or disease. In this manner, we expect to gain useful insights into the underlying causes of common medical conditions, including asthma, multiple sclerosis, diabetes, inflammatory bowel disease, and atherosclerosis.