The adhesion of leukocytes to vascular endothelial cells is an important initial event controlling the migration and tissue localization of all leukocytes. Lymphocyte binding to specialized endothelial cells, high endothelial venules (HEV), of lymph nodes and Peyer's patches, mediated by specific lymphocyte surface receptors (homing receptors), is required for the homing of lymphocytes to these organs. Activation of murine T lymphocytes in vitro results in a down-regulation of these receptors, as detected by the lack of binding of a monoclonal antibody (MEL-14) specific for this receptor. Human lymphocytes, neutrophils, and monocytes express a series of analogous proteins recognized by the 515 antibody, implying that they are also involved in leukocyte- endothelial adhesion. The objective of this research is two-fold: (1) to examine the distribution and regulation of expression of leukocyte receptors for endothelial cells (ECR). Mouse T lymphocytes will be examined to determine if activation by antigen in vivo results in alteration of cell migration and localization in host tissues, mediated by changes in cell surface receptors for HEV. MEL-14 will be used in three color FACS analysis to determine what cells undergo down-regulation of homing receptors, (2) to test the hypothesis that multiple ECRs on human leukocytes, and related antigens on fibroblasts and keratinocytes, constitute a diverse family os structurally related but distinct polypeptides. ECR- related antigens will be biochemically characterized to determine whether these receptors are composed of different polypeptides or if receptor specificity is conferred by post-translational modification. These experiments will describe the cellular control and biochemical characteristics of a series of important cell surface proteins involved in lymphocyte recirculation and inflammation. They may also define a novel aspect of antigen-driven T cell differentiation in which cells activated in situ undergo changes in surface protein expression, become nonrecirculating, and remain localized at the site of activation. Understanding this family of endothelial cell receptors will provide insights into mechanisms controlling leukocyte function in such diverse processes as immunity, inflammation, atherosclerosis.
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