The immune system employs extremely specific mechanisms to regulate the circulation of its mobile cell component through each of the lymphoid organs. Each lymphoid organ had its distinct primary function reflected in very different cellular compositions. Regulation of the circulation of cells through these organs plays a role in the coordination of the interactions of the various cell lineages and regulates their exposure to different microenvironments. The expression of receptors for high endothelium contributes to the assortment of cells between these organs. Examining the regulation of these receptors as a function of cell lineage, development and activation is critical to the understanding of the circulation phenotypes of these cells. The objective of this laboratory has been to achieve an understanding of the molecular mechanisms active in the adherence of lymphocytes to the high endothelial venules (HEV) of lymph nodes and to assess the role of this adhesive event in lymphocyte migration, localization and development. The primary goal of the current project has been the isolation of gene sequences encoding the lymphocyte cell surface receptor molecule and the preliminary characterization of the gene structure and organization and the structure of the encoded protein. This goal has been met. The first specific aim of this application is to determine the relationship between the expression of the products of the adhesion receptor gene and the adhesive phenotype. This goal will be met by the examination of gene structure, RNA splicing patterns and protein modification. The gene(s) encoding the HEV receptor appear to define a family of related proteins whose functions in the biology of the immune system are currently obscure. We will define, by immunological and genetic techniques, the regions of the receptor molecule that interact with the endothelial ligand and will assess by direct expression methods the role of the different versions of the adhesion receptor family in adhesion to endothelium. The second specific aim of this project is to examine the regulation of the expression of HEV receptor gene sequence in normal cell populations. We have divided this project into three subsections, each of which concerns the regulation of gene product expression. These sections include the analysis of the expression of the adhesion receptor gene within normal bone marrow derived cell subsets, during the down regulation of adhesion receptor levels observed in normal cell populations during antigen dependent development and the acquisition of receptor expression during the thymic development of T lineage cells.
