Analysis of adaptor protein (LAT) in TCR signaling

描述（由申请人提供）：T细胞活化连接子（LAT）是一种棕榈酰化的跨膜衔接蛋白，是通过TCR传递信号不可或缺的。当TCR结合时，它在多个酪氨酸残基上磷酸化，使其能够结合Grb2、Gads、PLC-¿1和其他信号分子。已发表的研究清楚地表明，LAT在胸腺细胞发育和T细胞活化中是必不可少的。此外，LAT对T细胞稳态至关重要。表达不能结合PLC-¿1的LATY136F突变体的小鼠由于T细胞扩增和细胞因子产生不受控制而发展为严重的淋巴增生性疾病。此外，成熟T细胞中LAT缺失的小鼠也会患上类似的疾病。虽然LAT在tcr介导的信号传导中的作用已经被很好地理解，但LAT如何调节T细胞稳态、细胞因子产生和自身免疫仍然未知。这里描述的三个具体目标就是为了解决这个问题。在具体目标1中，我们将使用LAT条件敲除小鼠，研究LAT介导的滋补信号在控制T细胞扩增和细胞因子产生中的作用。我们将研究细胞因子位点的表观遗传变化以及LAT突变对调节细胞因子产生的转录因子表达的影响。在具体目标2中，我们将研究LAT突变对细胞因子介导的信号传导的影响。我们还将研究TCR-和细胞因子介导的途径是否相互作用，这是之前的研究表明的。在具体目标3中，我们将研究LAT功能在T细胞发育中的作用，以及为什么LAT突变在T细胞中引起自身免疫。完成这些特定目标将增强我们对tcr介导的信号在T细胞扩增和细胞因子产生调节中的基本理解。此外，这些研究将为我们了解和更好地治疗自身免疫性疾病提供必要的知识。

DESCRIPTION (provided by applicant): Linker for activation of T cells (LAT) is a palmitoylated transmembrane adaptor protein that is indispensable for signaling through the TCR. Upon TCR engagement, it is phosphorylated on multiple tyrosine residues, allowing it to bind Grb2, Gads, PLC-¿1, and other signaling molecules. Published studies have clearly demonstrated that LAT is essential in thymocyte development and T cell activation. Additionally, LAT is critical for T cel homeostasis. Mice expressing the LATY136F mutant, which cannot bind PLC-¿1, develop a severe lymphoproliferative disease due to uncontrolled T cell expansion and cytokine production. Moreover, mice with LAT deleted in mature T cells develop a similar disease. While LAT function in TCR-mediated signaling is well understood, how LAT regulates T cell homeostasis, cytokine production, and autoimmunity remains unknown. The three specific aims described here are designed to address this question. In specific aim 1, we will investigate the role of LAT-mediated tonic signaling in the control of T cell expansion and cytokine production using LAT conditional knockout mice. We will study epigenetic changes at cytokine loci and the effect of LAT mutation on the expression of transcription factors that regulate cytokine production. In specific aim 2, we will investigate the effect of LAT mutation on cytokine-mediated signaling. We will also examine whether TCR- and cytokine-mediated pathways crosstalk, which previous studies have suggested. In specific aim 3, we will study the role of LAT function in the development of ¿¿ T cells and why LAT mutation in ¿¿ T cells causes autoimmunity. Completion of these specific aims will enhance our fundamental understanding of TCR-mediated signaling in the regulation of T cell expansion and cytokine production. Furthermore, these studies will provide us with knowledge that is imperative to understand and better treat autoimmune diseases.