Regulation of T Cell Activation and Differentiation by TIM-1

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成为免疫功能的重要调节因子。然而，对这些蛋白质所使用的信号转导机制几乎一无所知。我们对了解TIM-1的功能和调控特别感兴趣，TIM-1由Th2效应细胞优先表达。人和小鼠TIM-1细胞外基因的多态与哮喘的易感性或抵抗力密切相关。我们和其他人最近发现TIM-1可以促进T细胞的激活和分化。TIM-1的表达增强了针对NFAT和AP-1转录因子的信号通路的激活，并似乎导致T细胞偏向Th2血统。此外，我们还发现TIM-1共刺激信号是由其胞质尾部含有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的共刺激信号增强NFAT和AP-1的诱导，从而增强T细胞的激活和辅助性T细胞对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‘S影响辅助性T细胞分化的机制。在目标2中，我们将通过建立Y276F敲入小鼠模型，确定负责TIM-1 Y276磷酸化的激酶(S)、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在调节NFAT和AP-1的细胞质信号通路中的作用。相关性：过敏性哮喘是对环境抗原的不适当免疫反应的结果。完成这项提议中概述的实验将导致对一种新的细胞表面分子TIM-1的更全面的了解，TIM-1与免疫功能和哮喘易感性有关。这种知识可能导致确定治疗和/或诊断哮喘的新靶点。

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.