FUNCTION OF CD43 IN HEMATOPOIESIS AND T LYMPHOCYTES

CD 43是一种整合的膜唾液酸糖蛋白， 造血细胞以分化和活化特异性的方式。 该分子的缺陷表达与严重的 免疫缺陷综合征，威-艾二氏综合征。本实验室 已经证明HIV感染者会产生自身抗体 抗CD 43抗体体外研究表明，CD 43可能是重要的， 淋巴细胞和其他造血细胞的发育和功能 起源调节造血祖细胞点上CD 43的表达 在这些细胞的谱系特异性发育中的重要性。研究 提示它可能参与胸腺细胞-胸腺上皮细胞的免疫调节 细胞相互作用对成熟淋巴细胞的研究表明， 与抗原呈递细胞上的细胞间粘附分子（ICAM-1） 并为T细胞活化传递共刺激信号。与此相反， 我们自己的研究表明，破坏淋巴细胞中的CD 43基因， 它们的粘附，表明抗粘附功能。这些看似 相反的数据可能表明CD 43是一种多功能分子， 在不同的情况下协调不同的功能。毛 细胞外结构域上的负电荷（由于唾液酸 残基）在限制细胞相互作用中可能是重要的， 与特异性配体的结合可导致信号转导， 激活细胞。这个建议是通过同源的 重组，缺乏CD 43表达的转基因小鼠，以及小鼠 表达胞质结构域缺陷的CD 43，以研究 CD 43在体内的功能。为此目的，小鼠杂合子为 突变的CD 43等位基因已经产生。转基因动物 将检查血液淋巴细胞的结构和功能变化， 器官、造血前体细胞和血细胞。

CD43 is an integral membrane sialoglycoprotein expressed by virtually all hematopoietic cells in a differentiation and activation specific manner. Defective expression of this molecule has been associated with a severe immunodeficiency syndrome, the Wiskott-AIdrich syndrome. Our laboratory has demonstrated that HIV-infected individuals develop auto-antibodies against CD43. In-vitro studies suggest that CD43 may be important in the development and function of lymphocytes and other cells of hemopoietic origin. Regulated CD43 expression on hemopoietic progenitor cells points to its importance in lineage specific development of these cells. Studies on thymocytes indicate it may be involved in thymic cell-thymic epithelial cell interaction. Studies on mature lymphocytes indicate that it may bind to intercellular adhesion molecule (ICAM-I) on antigen presenting cells and deliver a co-stimulatory signal for T cell activation. In contrast, our own studies show that disrupting CD43 gene in lymphocytes enhances their adhesiveness, suggesting an anti-adhesion function. These seemingly contradictory data might indicate that CD43 is a multifunctional molecule mediating different functions under different circumstances. The gross negative charge on the extracellular domain (because of Sialic acid residues) may be important in limiting cellular interactions while, binding to a specific ligand may lead to signal transduction and activation of cells. This proposal is to generate, by homologous recombination, transgenic mice lacking CD43 expression, as well as mice expressing cytoplasmic domain deficient CD43 in order to study the function of CD43 in vivo. For this purpose, mice heterozygous for a mutated CD43 allele have already been produced. The transgenic animals will be examined for structural and functional changes in hemato-lymphoid organs, hematopoietic precursor cells and blood cells.