Role of SLP-76 in Naive and Memory T Cell Function

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DESCRIPTION (provided by applicant): Mature T lymphocytes can be divided into at least three groups based on previous encounter with antigen. In contrast to naive cells, effector and memory T lymphocytes have previously encountered and been activated by interaction with an antigen presenting cell expressing a specific antigen in the groove of an appropriate MHC molecule. It has become clear that the signal generated by stimulation through the T cell receptor of these sub-populations of T cells is quantitatively and qualitatively different. Adaptor proteins are known to be critical for integration of signals in all cells. The SH2 domain containing Leukocyte Protein of 76 kilodaltons (SLP-76) is essential for both thymocyte development and mature T cell function. Unfortunately, because of the absolute dependence of SLP-76 expression during thymic development, there are no genetic models to study the function of SLP-76 in normally selected mature T cells; neither naive, effector, nor memory phenotype. Studies in primary murine T cells have shown that the level of SLP-76 protein expression is different in naive, effector and memory T cells suggesting the hypothesis that the requirements for SLP-76 expression and the specific molecular interactions differ in mature T cells of different functional phenotypes. To address this hypothesis, I propose to generate mice in which expression of SLP-76 is controlled by the administration of exogenous drugs. These mice will be utilized in in vivo infection models to evaluate the requirements for SLP-76 at different maturational stages. Mice conditionally expressing SLP-76 will be mated to mice with mutant forms of the protein to evaluate structure/function in vivo. This proposal describes a five-year training program with the goal of becoming an independent investigator in an academic setting. The principal investigator has completed clinical training in Internal Medicine and Nephrology and graduate training in immunology. Dr. Gary Koretzky will mentor the scientific and career development of the principal investigator. Dr. Koretzky is a leader in the fields of Immunology and signal transduction. He is director of the Signal Transduction Program at the University of Pennsylvania and has mentored numerous students and post-doctoral fellows. In addition to Dr. Koretzky, an advisory committee of physician-scientists has been formed to oversee scientific and career development.