ROLE OF THE XLP GENE, SAP, IN T CELL FUNCTIONS

x连锁淋巴细胞增生性疾病（XLP）是一种罕见的疾病，年轻男孩经常死于致命的传染性单核细胞增多症。尽管爱泼斯坦·巴尔病毒（EBV）是所有物种中已知的转化能力最强的病毒之一，但在绝大多数受感染的个体中，它不会引起疾病。只有少数会发展为自限性疾病：传染性单核细胞增多症。这是由于人体免疫系统对病毒产生了强烈而可控的反应。正常的平衡可被感染性（HIV）、医源性（移植）或先天性免疫系统缺陷（XLP）所破坏。在所有三种情况下，这可能导致致命的传染性单核细胞增多症或逐渐生长的免疫母细胞瘤，可能转变为单克隆淋巴瘤。在传染性单核细胞增多症阶段存活下来的XLP患者通常会出现异常γ -球蛋白血症。我们最近克隆了XLP的基因，称为SAP，并发现它与SLAM （CDw150）的细胞质尾部的特定位点结合，CDw150是一种在活化的B细胞和T细胞表面表达的糖蛋白蛋白。由于SAP包含一个仅由26个氨基酸组成的SH2结构域，因此我们认为该分子是SH2依赖性对接位点的天然抑制剂。事实上，SAP抑制酪氨酸磷酸酶SHP-2与酪氨酸磷酸化的SLAM细胞质尾部的结合。我们的长期目标是了解SAP在T细胞生理学中的作用，特别是在对EBV的免疫反应中。在这个项目中，我们计划研究SAP在T淋巴细胞发育和T细胞活化中的功能的分子基础。这些信息将为我们提供必要的基本知识，以解剖SAP在正常和异常T细胞对EBV感染的B淋巴细胞的反应中的作用。具体而言，我们提出：1 .验证由XLP基因编码的SAP蛋白在T淋巴细胞中作为SLAM依赖信号转导通路的调节开关的假设。2生成XLP的小鼠模型。阐明调控XLP基因表达的分子机制。

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.