FUNCTION OF CD43 IN HEMATOPOIESIS AND T LYMPHOCYTES

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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.