CD43 Regulation of Immune Responses

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DESCRIPTION (provided by applicant): CD43 is unarguably one of the most abundant proteins on the T cell surface. Recently, it has been implicated in p53 regulation and tumor survival (1), in microbial adhesion to inflammatory cells (2-6), in HIV pathogenesis (7-10) and in CDS effector T cell apoptosis (11). Yet our fundamental knowledge about the function of CD43 is still sorely lacking. In fact, the literature is full of seemingly contradictory findings on the function of this molecule. In various studies over the years, CD43 has been defined as a costimulatory molecule, a death receptor, an adhesion receptor, an anti-adhesion molecule, and a negative regulator of T cell activation and IL-2 production (12). In the past granting period, we have used structure/function techniques to characterize the parameters of CD43 function in clearly defined systems. In the current application, we propose to determine the intracellular mechanisms by which CD43 functions in these systems, and thereby elucidate the true functions of the widely expressed surface molecule. This fundamental knowledge is essential to finally begin to understand the role of this molecule in the above pathologies as well as normal immune responses. Although our previous findings showed no role for the extracellular domain of CD43, we now propose a novel function for the role of CD43 that may depend on the ECD: regulation of T cell trafficking. We have now identified two phosphorylation sites within the CD43-ICD one of which regulates T cell trafficking to the lymph node. We have also developed an antibody that specifically detects phosphorylation at these sites. Further, we have identified PKD and PKA as kinases that either co-immunoprecipitates and/or phosphorylates CD43-ICD in vitro at these specific sites. The overall hypothesis of this proposal is that CD43 regulates T cell function through phosphorylation of unique sites in its cytoplasmic tail. Therefore, the goal of this grant is to determine the molecular interactions and signal transduction events by which phosphorylation of CD43 regulates T cell trafficking, adhesion, and activation.