The human immune response is generated and regulated by a complex set of cellular interactions between subsets of T cells, B cells and antigen-presenting macrophages. The molecules which govern these interactions are surface membrane glycoproteins which become expressed during differentiation. Many of these molecules define unique subsets of cells and are also intimately involved in the function of the cells they define. During the last several years, our laboratory has been particularly concerned with the CD4 and CD8 molecules which are simultaneously expressed on the majority of thymocytes, but during terminal differentiation become expressed on the surface of the mutually exclusive subsets of T cells. Mounting evidence suggests that these molecules have dual functions. First, they are thought to be receptor structures for conserved regions of MHC molecules (CD4 recognizing class II and CD8 recognizing class I MHC). Second, they are involved in transmitting regulatory signals to T cells during antigen activation. In order to more precisely define the immunobiology of these molecules, we have isolated and sequenced the genes and cDNA's encoding these molecules. A major thrust of this renewal proposal will be to continue to employ recombinant DNA technology to create mutant CD4 and CD8 molecules and, following gene transfer to relevant cells and clones, define the structure function relationships of these molecules. In addition, we will extend these studies to other known functionally interesting differentiation antigens on immunocompetent cells, including CD5 which is expressed on T cells and a subset of B cells. Finally, we will employ the monoclonal antibody and gene isolation technologies which have been used successful to date in the analysis of DC 4 and CD8 in order to define new cell surface molecules important in the control of human T cell functions. Because T cells are known to be intimately involved in the immunopathology of most immunologic diseases of man, including AIDS, we believe our studies will contribute basic data that my be essential to further understanding of these diseases.
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