The ability of lymphocytes to recirculate and to localize at sites of antigen deposition is important for both the induction and expression of normal immune and inflammatory responses. Leukocyte migration is controlled by a series of surface adhesion molecules which mediate the recognition of complementary ligands on vascular endothelial cells (EC). The homing of lymphocytes to lymph nodes (LN) and Peyer's patches is regulated by surface homing receptors that mediate lymphocyte adhesion to specialized high endothelial venules (HEV) within these organs. We have shown that antigen-driven activation and differentiation of murine T lymphocytes in LN results in the down regulation of the LN-specific homing receptor gp9O-MEL-14 (gp90) and an increase in expression of several other adhesion molecules, including VLA-4, LFA-1, and Pgp-l. Although alteration of the pattern of lymphocyte endothelial cell receptor (ECR) expression would likely have a profound effect on the migration properties of T cells, our current understanding of the role of receptor modulation in the immune response is incomplete. The objectives of the proposed research are: (1) To test the hypothesis that down regulation of gp90-MEL-14, Coordinated with changes in other adhesion molecules, serves to direct the migration of effector T cells away from lymphoid tissue and to target them to peripheral sites of antigen deposition and inflammation. We will examine several model immune responses in vivo for changes in the expression of gp9O and other adhesion molecules during the activation and differentiation of T lymphocytes and correlate such changes with the type of antigenic stimulation and activity of the responding T cells. The effects of ECR modulation on the traffic of antigen-specific T cells will be determined. (2) To examine the regulation of gp9O and other surface adhesion molecules at the RNA level. Northern and slot blot analyses will be used to measure RNA levels. (3) To examine the mechanism of protein kinase C-induced proteolytic cleavage and shedding of gp9O and its human homolog, LAM-1, from the surface of lymphocytes, monocytes, and neutrophils. We will use PCR technology to create deletions and site-directed mutants of gp9O cDNA, and will also use protein sequencing of the shed gp9O fragment to determine the precise site at which cleavage occurs.
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