Mechanisms of Integrin-Mediated Costimulation in T Cells

整合素介导的 T 细胞共刺激机制

• 批准号: 7582727
• 负责人: STEPHEN C BUNNELL
• 金额: $ 38.92万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-02-16 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7582727
• 关键词: Actins; Adhesions; Affect; Antigens; Asthma; Atherosclerosis; Autoimmune Diseases; Autoimmune Process; Behavior; Binding; CD4 Positive T Lymphocytes; Cell Adhesion; Cell Line; Cell Shape; Cell physiology; Cells; Complex; Coupled; Cytoskeletal Proteins; Cytoskeleton; Data; Diabetes Mellitus; Disease; Distal; Etiology; Event; Goals; Growth Factor; Health; Human; Imaging Techniques; Immobilization; Immune; Immune System Diseases; Immune response; Inflammatory; Inflammatory Bowel Diseases; Integrin alpha4beta1; Integrins; Knock-in Mouse; LCP2 gene; Lateral; Ligation; Link; Malignant Neoplasms; Mass Spectrum Analysis; Measures; Mediating; Medical; Microtubules; Motor; Movement; Multiple Sclerosis; Muscle Rigidity; Myosin ATPase; Myosin Type II; OspA protein; Pathogenesis; Pathway interactions; Peripheral; Phosphorylation; Play; Point Mutation; Proteins; Regulation; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Site; Structure; Synapses; System; Systemic Lupus Erythematosus; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; Talin; Testing; Traction; Transgenic Organisms; Work; adapter protein; cell growth; drug development; experience; in vivo; insight; novel; pathogen; prevent; public health relevance; reconstitution; response; tool; trafficking; transmission process; tumor

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.

描述（由申请人提供）：整合素 1421 (VLA-4) 导致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。尽管 VLA-4 被广泛认为通过指导细胞运输和增强细胞粘附来促进 T 细胞功能，但 VLA-4 可以有效地共刺激 T 细胞激活。这种共刺激的机制尚不清楚，但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，我们提供了初步数据，描述了 VLA-4 连接对 TCR 诱导的信号复合物运动的先前未知的影响。我们的具体假设是，包含 SLP-76 和 ADAP 的结构是传输 VLA-4 连接时引发的张力依赖性共刺激信号所必需的。拟议工作的基本原理是，它将加深对 TCR 和 VLA-4 下游信号通路整合的基本机制的理解。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 依赖性共刺激信号：1) ADAP 如何促进 SLP-76 微簇的组装和易位？ 2) 共刺激如何依赖于 VLA-4 依赖性微簇固定？ 3) 细胞骨架张力如何促进 VLA-4 的 T 细胞共刺激？这些研究探索了 VLA-4 连接的新效应，即 TCR 诱导复合物的横向固定，并将其用作剖析 VLA-4 共刺激所涉及途径的工具。我们期望这些研究能够明确 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，从而为癌症提供有用的见解。公共卫生相关性：免疫反应通常可以预防病原体和肿瘤，但也可能被不适当地激活，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发挥着至关重要的作用。这项研究将阐明整合素如何增强 T 细胞反应，从而促进健康或疾病。通过这种方式，我们希望能够深入了解常见疾病的根本原因，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。