Analysis of adaptor protein (LAT) in TCR signaling

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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.