Regulation of T Cell Activation and Differentiation by TIM-1

TIM-1 对 T 细胞活化和分化的调节

基本信息

批准号：
7925979
负责人：
Lawrence P. Kane
金额：
$ 15.78万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
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：
2009-09-22 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7925979
关键词：
1-Phosphatidylinositol 3-Kinase Adaptor Signaling Protein Address Allergic Antigens Asthma Autoimmune Diseases Biochemical Biological CD4 Positive T Lymphocytes Cell Differentiation process Cell Line Cell Surface Proteins Cell surface Cells Complex Cytoplasmic Tail Data Developed Countries Developing Countries Development Diagnosis Disease Effector Cell Elements Extrinsic asthma Family Generations Genetic Genetic Polymorphism Genetic Transcription Helper-Inducer T-Lymphocyte Human Immune response Immunoglobulins Incidence Interleukin-4 Kinetics Knock-in Mouse Knowledge Lead Link Mediating Modeling Mucins Mus Pathogenesis Peptide/MHC Complex Phosphorylation Phosphotransferases Phosphotyrosine Play Positioning Attribute Predisposition Process Proteins Publishing Recruitment Activity Regulation Relative (related person)Reporter Research Personnel Resistance Role Signal Pathway Signal Transduction Signaling Molecule Signaling Protein Site T cell regulation T-Cell Activation T-Cell Receptor T-Lymphocyte Testing Th1 Cells Th2 Cells Transcription Factor AP-1 Tyrosine atopy cell type cytokine extracellular immune function in vivo interest mouse model novel pathogen programs promoter receptor research study transcription factor

项目摘要

DESCRIPTION (provided by applicant): Cell-surface proteins of the TIM (T cell immunoglobulin and mucin domain) family have emerged recently as important regulators of immune function. However, virtually nothing is known about the signal transduction mechanisms used by these proteins. We have been particularly interested in understanding the function and regulation of TIM-1, which is expressed preferentially by Th2 effector cells. Extracellular polymorphisms in both human and murine TIM-1 are strongly associated with susceptibility or resistance to the development of asthma. We and others have recently found that TIM-1 can enhance T cell activation and differentiation. TIM-1 expression augments the activation of signaling pathways that target the NFAT and AP-1 transcription factors and appears to lead to a preferential skewing of T cells to the Th2 lineage. Furthermore, we have found that TIM-1 co-stimulatory signaling is mediated by a conserved tyrosine contained within its cytoplasmic tail. We hypothesize that expression of TIM-1 enhances T cell activation and polarization of helper T cells to the Th2 lineage, through phosphotyrosine-dependent co-stimulatory signaling that enhances induction of NFAT and AP-1. We will test this hypothesis with three specific aims. In Aim 1, we will identify the mechanisms underlying TIM-1's effects on helper T cell differentiation. In Aim 2, we will identify the kinase(s) responsible for phosphorylation of TIM-1 Y276, signaling proteins recruited to that site and the role of Y276 in vivo through the generation of a Y276F knock-in mouse model. In Aim 3, we will determine the effects of TIM-1 on cytoplasmic signaling pathways that regulate NFAT and AP-1. Relevance: Allergic asthma develops as the result of inappropriate immune responses to environmental antigens. Completion of the experiments outlined in this proposal will lead to a more complete understanding of a novel cell surface molecule, TIM-1, that has been implicated in immune function and susceptibility to asthma. Such knowledge may result in the identification of novel targets for therapy and/or diagnosis of asthma.

描述（由申请人提供）：TIM（T细胞免疫球蛋白和粘蛋白结构域）家族的细胞表面蛋白最近已成为免疫功能的重要调节剂。然而，实际上对这些蛋白质使用的信号转导机制一无所知。我们对了解 TIM-1 的功能和调节特别感兴趣，TIM-1 优先由 Th2 效应细胞表达。人类和小鼠 TIM-1 的细胞外多态性与哮喘发展的易感性或抵抗力密切相关。我们和其他人最近发现TIM-1可以增强T细胞的活化和分化。 TIM-1 表达增强了针对 NFAT 和 AP-1 转录因子的信号通路的激活，并似乎导致 T 细胞优先偏向 Th2 谱系。此外，我们发现 TIM-1 共刺激信号是由其细胞质尾部包含的保守酪氨酸介导的。我们假设 TIM-1 的表达通过磷酸酪氨酸依赖性共刺激信号增强 NFAT 和 AP-1 的诱导，从而增强 T 细胞活化和辅助 T 细胞向 Th2 谱系的极化。我们将通过三个具体目标来检验这一假设。在目标 1 中，我们将确定 TIM-1 对辅助 T 细胞分化影响的机制。在目标 2 中，我们将通过生成 Y276F 敲入小鼠模型来鉴定负责 TIM-1 Y276 磷酸化的激酶、招募到该位点的信号蛋白以及 Y276 在体内的作用。在目标 3 中，我们将确定 TIM-1 对调节 NFAT 和 AP-1 的细胞质信号通路的影响。相关性：过敏性哮喘是由于对环境抗原产生不适当的免疫反应而发生的。完成该提案中概述的实验将有助于更全面地了解一种新型细胞表面分子 TIM-1，该分子与免疫功能和哮喘易感性有关。这些知识可能会导致确定哮喘治疗和/或诊断的新靶点。