Mechanisms of Integrin-Mediated Costimulation in T Cells

描述（由申请人提供）：整合素1421（VLA-4）是常见自身免疫性疾病的病因，包括多发性硬化症、炎症性肠病和系统性红斑狼疮。尽管VLA-4被广泛认为通过引导细胞运输和通过增强细胞粘附来促进T细胞功能，但VLA-4有效地共刺激T细胞活化。这种共刺激的机制还不清楚，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细胞活化。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，我们提出了一个以前未知的VLA-4连接的TCR诱导的信号复合物的运动的影响，表征的初步数据。我们的具体假设是，含有SLP-76和ADAP的结构是VLA-4结扎后启动的张力依赖性共刺激信号的传输所必需的。所提出的工作的基本原理是，它将提供对能够整合TCR和VLA-4下游信号通路的基本机制的增强理解。三个目标将研究ADAP如何有助于T细胞共刺激和细胞骨架张力如何有助于VLA-4依赖的共刺激信号：1）ADAP如何有助于SLP-76微簇的组装和易位？2)共刺激如何依赖于VLA-4依赖的微团簇固定？3)细胞骨架张力如何通过VLA-4促进T细胞共刺激？这些研究探索了VLA-4连接的一种新效应，即TCR诱导复合物的侧向固定，并将其用作剖析VLA-4共刺激所涉及的途径的工具。我们希望这些研究能够确定VLA-4连接共刺激T细胞活化的机制。这将对我们理解自身免疫性疾病产生积极影响，并将有助于确定药物开发的独特细胞内靶点。这项工作还将深入了解将细胞形状与细胞生长和增殖联系起来的系统，为癌症提供有用的见解。公共卫生相关性：免疫反应通常保护免受病原体和肿瘤，但可以被不适当地激活，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中起着至关重要的作用。这项研究将阐明整合素如何增强T细胞反应，从而有助于健康或疾病。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.