We plan continued studies of the cellular and molecular biology of lymphocytes utilizing the approaches of cellular immunology, immunochemistry, and molecular genetics. The role of IL-4 in the immune response will be further evaluated with particular emphasis on the molecular mechanisms underlying the IL-4 induction of isotype switching to IgG1. Thus, after defining the critical biological parameters, these studies will involve analysis of changes in chromatin structure, sterile RNA transcripts, determination of promoter and enhancer sequences important in the switch, cloning of such sequences and characterization of the proteins that bind specifically to such sequences. The development of the antibody repertoire in humans will be analyzed by examining the usage of different VH subgroups in different types of lymphoid tissues. This will extend recent findings of a major difference in VH usage between blood and myeloma cells. The organization of human VH genes will be further analyzed because it differs significantly from that of the mouse. The role of T cell-T cell interactions in the generation of cytotoxic T lymphocytes will also be analyzed. The regulation of the generation of CTLs will be studied with particular emphasis on the role of CD4 positive cells as """"""""veto"""""""" cells. The maturation of T cells in epithelial tumors of the thymus and transplantable epithelial tumors of the salivary gland will allow analysis of in vitro and in vivo microenvironments and their impact on T cells with regard to induction of tolerance and immune responsiveness.
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