FUNCTION OF CD43 IN HEMATOPOIESIS AND T LYMPHOCYTES

CD43是一种完整的膜唾液酸糖蛋白，几乎所有的 造血细胞以一种分化和激活的特定方式。 这种分子的表达缺陷与严重的 免疫缺陷综合征，即Wiskott-AIdrich综合征。我们的实验室 已经证明艾滋病毒感染者会产生自身抗体 抗CD43。体外研究表明，CD43可能在血管生成中起重要作用。 淋巴细胞和其他造血细胞的发育和功能 起源。造血祖细胞点CD43的表达调控 它在这些细胞的谱系特异性发育中的重要性。研究 提示它可能参与了胸腺细胞--胸腺上皮 细胞相互作用。对成熟淋巴细胞的研究表明，它可能与 对抗原提呈细胞表面细胞间黏附分子(ICAM-I)的影响 并传递T细胞激活的共刺激信号。相比之下， 我们自己的研究表明，扰乱淋巴细胞中的CD43基因可以增强 它们的粘附性，表明具有防粘连功能。这些看似 相互矛盾的数据可能表明CD43是一种多功能分子 在不同的情况下调解不同的职能。毛利率 胞外区域上的负电荷(由于唾液酸 残基)可能在限制细胞相互作用方面很重要， 与特定配体的结合可能导致信号转导和 激活细胞。这项建议是由同源产生的 重组、CD43表达缺失的转基因小鼠以及小鼠 表达胞浆结构域缺陷的CD43以研究其生物学行为 CD43在体内的功能。为此目的，杂合的小鼠 突变的CD43等位基因已经产生。转基因动物 将检查血液淋巴系统的结构和功能变化 器官、造血祖细胞和血细胞。

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.