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。我们一直特别感兴趣的是了解TIM-1的功能和调节，这是由Th 2效应细胞优先表达。人类和小鼠TIM-1的细胞外多态性与哮喘的易感性或抵抗性密切相关。我们和其他人最近发现TIM-1可以增强T细胞活化和分化。TIM-1表达增强了靶向NFAT和AP-1转录因子的信号传导途径的激活，并似乎导致T细胞优先偏向Th 2谱系。此外，我们已经发现TIM-1共刺激信号传导是由其胞质尾内包含的保守酪氨酸介导的。我们假设TIM-1的表达通过增强NFAT和AP-1诱导的磷酸酪氨酸依赖性共刺激信号传导增强T细胞活化和辅助性T细胞向Th 2谱系的极化。我们将以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对辅助性T细胞分化的作用机制。在目标2中，我们将通过产生Y276 F敲入小鼠模型来鉴定负责TIM-1 Y276磷酸化的激酶、募集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的细胞质信号传导途径的影响。相关性：过敏性哮喘的发生是由于对环境抗原的不适当的免疫反应。完成本提案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。这些知识可能导致识别用于治疗和/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.