X-linked lymphoproliferative disease (XLP) is a rare disease in which young boys frequently die of fatal infectious mononucleosis. Although Epstein Barr virus (EBV) is one of the most highly transforming viruses known in any species, it causes no disease in the vast majority of all infected individuals. Only in a small minority a self-limiting disease develops: Infectious Mononucleosis. This is due to the fact that the human immune system has developed an vigorous yet controlled response to the virus. The normal equilibrium can be compromised by infectious (HIV), iatrogenic (transplantation) or in XLP, a congenital impairment of the immune system. In all three instances this may lead to fatal infectious mononucleosis or progressively growing immunoblastoma that may turn into a monoclonal lymphoma. XLP patients who survive the infectious mononucleosis stage often develop a dysgammaglobunemia. We have recently cloned the gene for XLP, termed SAP, and found that it binds to a specific site of the cytoplasmic tail of SLAM (CDw150), a glycoprotein protein that is expressed on the surface of activated B and T cells. Since SAP comprises an SH2 domain with a tail of a mere 26 amino acids, we propose that this molecule is a natural inhibitor of SH2 dependent docking sites. In fact, SAP inhibits the binding of the tyrosine phosphatase SHP-2 to the tyrosine phosphorylated cytoplasmic tail of SLAM. Our long term goal is to understand the role of SAP in T cell physiology and particularly in the immune response to EBV. In this project we plan to examine the molecular underpinnings of the function of SAP in T lymphocyte development and T cell activation. This information will provide us with the basic knowledge that will be necessary to dissect the role of SAP in normal and aberrant T cell responses to EBV infected B lymphocytes. Specifically we propose to: 1 Test the hypothesis that the SAP protein, encoded by the XLP gene, acts as a regulatory switch for SLAM dependent signal transduction pathways in T lymphocytes. 2 Generate a murine model for XLP. 3 Elucidate the molecular mechanisms that govern expression of the XLP gene.
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