Analysis of adaptor protein (LAT) in TCR signaling

描述(申请人提供)：激活T细胞的连接物(LAT)是一种棕榈酰化的跨膜接头蛋白，对于通过TCR的信号传递是必不可少的。一旦与TCR结合，它就会在多个酪氨酸残基上被磷酸化，从而与Grb2、Gads、PLC-1和其他信号分子结合。已发表的研究清楚地表明，LAT在胸腺细胞发育和T细胞激活中是必不可少的。此外，LAT对T细胞的动态平衡至关重要。表达LATY136F突变体的小鼠不能结合PLC-1，由于T细胞扩张和细胞因子产生失控，会发展成一种严重的淋巴增殖性疾病。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介导的信号转导中的作用已被熟知，但LAT如何调节T细胞的稳态、细胞因子的产生和自身免疫仍不清楚。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，我们将利用LAT条件性基因敲除小鼠，研究LAT介导的强直信号在控制T细胞增殖和细胞因子产生中的作用。我们将研究细胞因子基因座的表观遗传学变化以及LAT突变对调节细胞因子产生的转录因子表达的影响。在特定的目标2中，我们将研究LAT突变对细胞因子介导的信号转导的影响。我们还将检查TCR和细胞因子介导的通路是否存在串扰，这是以前的研究提出的。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T细胞中的LAT突变导致自身免疫。这些特定目标的完成将加强我们对TCR介导的信号在调节T细胞增殖和细胞因子产生方面的基本理解。此外，这些研究将为我们提供了解和更好地治疗自身免疫性疾病所必需的知识。

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.