The Role of HS1 in T Cell Activation

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DESCRIPTION (provided by applicant): Actin dynamics play a key role in nearly all aspects of T cell function. Though the regulation of T cell actin responses are poorly understood, one key player is HS1, an actin regulatory protein with genetic links to Lupus. We have recently discovered that HS1 is required for actin polymerization at the immune synapse, and for signaling events leading to IL2 promoter activation. Here, I will test the mechanisms by which HS1 facilitates T cell activation. In Aim 1, the T cell compartment of HS1-deficient mice will be analyzed using flow cytometry for subset and activation markers. Cell biological aspects of T cell function will be tested, including actin responses, immune synapse formation, signaling events, cytokine production, and cytotoxicity. In Aim 2, structure-function analysis will be conducted to more fully understand the role of HS1 on a molecular level. HS1-/- T cells will be retrovirally transduced with various domain or point mutants and analyzed for hallmarks of T cell activation. In addition, the role of phosphorylation-dependent association of HS1 with key signaling molecules such as Vav1 and PLCgamma will be analyzed.