Mechanisms of Integrin-Mediated Costimulation in T Cells

整合素介导的 T 细胞共刺激机制

基本信息

批准号：
8039189
负责人：
STEPHEN C BUNNELL
金额：
$ 36.39万
依托单位：
TUFTS UNIVERSITY BOSTON
依托单位国家：
美国
项目类别：
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/8039189
关键词：
Actins Adhesions Affect Antigens Asthma Atherosclerosis Autoimmune Diseases Autoimmune Process Behavior Binding CD4 Positive T Lymphocytes Cell Adhesion Cell Line Cell Proliferation 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 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 response 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 reconstitution response tool trafficking transmission process tumor

Actins Adhesions Affect Antigens Asthma Atherosclerosis Autoimmune Diseases Autoimmune Process Behavior Binding CD4 Positive T Lymphocytes Cell Adhesion Cell Line Cell Proliferation 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 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 response 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 reconstitution response tool trafficking transmission process tumor

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项目摘要

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）：整联蛋白1421（VLA-4）有助于常见自身免疫性疾病的病因，包括多发性硬化症，炎症性肠病和全身性红斑狼疮。尽管VLA-4被广泛认为是通过指导细胞运输和增强细胞粘附来促进T细胞功能的原因，但VLA-4可以很好地刺激T细胞激活。这种共刺激的基础机制尚未得到充分理解，并且可能在人类免疫疾病的病因中起重要作用。我们的远程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。我们的直接目标是确定VLA-4如何调节T细胞对抗原的反应。在这里，我们介绍了VLA-4连接对TCR诱导的信号传导复合物运动的先前未知效应的初步数据。我们的具体假设是，含有SLP-76和ADAP的结构是在VLA-4连接时发起的张力依赖性共刺激信号所必需的。提议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。三个目标将检查ADAP如何对T细胞共刺激有效，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）共刺激如何取决于微量群体的VLA-4依赖性固定化？ 3）细胞骨架张力如何促进VLA-4的T细胞共刺激？这些研究探讨了VLA-4连接的新作用，TCR诱导的复合物的横向固定化，并将其用作剖析VLA-4涉及的途径的工具。我们希望这些研究能够定义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，并将有助于识别药物开发的独特细胞内靶标。这项工作还将对将细胞形状与细胞生长和增殖的系统产生见解，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，但可以不适当地激活，因此是炎症性疾病和自身免疫性疾病。整合素是有助于激活T细胞的蛋白质，在调节这些免疫反应中起着至关重要的作用。这项研究将阐明整联蛋白如何增强T细胞反应，从而有助于健康或疾病。通过这种方式，我们期望获得有关常见医疗状况的根本原因的有用见解，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。