The general aim of this proposal is to characterize the biological role played by CD4 and CD8 in T cell activation and to further define the biological effects of HIV binding to CD4. The approaches planned rely on recent methodological developments in cell biology, protein chemistry, and molecular biology. In order to accomplish these aims we have developed a model system in which cDNAs encoding human T cell surface molecules can be readily expressed in murine T cell hybridomas that are specifically stimulated by human class I or Class II MHC antigens. This system enables us to analyse the functional effects of various mutations of the cDNAs encoding CD4 and CD8 expressed in an antigne reactive T cell. Detailed structure/function studies can then be performed. The specific aims of the proposal are as follows: (1) Determine whether the ligands for CD4 and CD8 are the class II and class I MHC antigens, respectively; (2) Determine the role of CD4 and CD8 in cell adhesion; (3) Determine the role of CD4 and CD8 in antigen-activated signal transduction; (4) Determine the role of MAbs directed against CD4 and CD8 in signal transduction; (5) Determine the role of anti-CD4 and anti-CD8 MAb in negative signaling; (6) Use CD4 and CD8 mutants to define the relationship between structure and function; (7) Determine the effects ofthe binding of HIV gp120 to CD4.