Keratinizing epithelia comprise many important tissues of the body and have been the subject of cell-biologic, genetic and biochemical investigation for most of this century. In recent years, development of techniques for in vitro propagation of nontransformed epidermal keratinocytes has stimulated their use as models for the study of regulation of cell differentiation. This proposal is designed to take advantage of epidermal culture techniques to investigate in parallel the regulation of differentiation of normal human epidermis, a tissue in which the in vivo differentiation program is known, and thymic epithelium, a tissue in which less is known about the program of differentiation. Epithelial specific monoclonal antibodies which in vivo define distinct compartments of both epidermis and thymic epithelium, will be used to establish the pathway of differentiation within the epithelial component of the thymus. Regulation of differentiation of both epidermis and thymic epithelium by calcium, epidermal growth factor, steroids, vitamin A, and other agents will be studied. Evidence suggests that epidermis and thymus share a special relationship with T lymphocytes. Epidermis has been postulated as a site of extra-thymic T cell maturation. This possibility will be examined in cocultivation experiments. Immunoincompetent T cell precursors will be cultured with human epidermal keratinocytes and also with supernatants from epidermal cultures and examined for changes in cell surface phenotype, expression of markers of T cell activation (4F2, transferrin receptor, Ia-like antigens), and acquisition of functional capability (response to mitogens and to foreign histocompatibility antigens). Patients with autoimmune disease often show abnormalities in immunoregulatory T cells which may be due to aberrant epithelial-T cell interaction. Sera from patients with autoimmune diseases also often show cross reactive binding on thymus and skin. In the autoimmune disease pemphigus, skin lesions are the result of a loss of cell-cell adhesion mediated by plasminogen activator stimulated by autoantibody. The potential role for plasminogen activator in aberrant function of thymic epithelium by disruption of cell-cell interaction will be examined. It is expected that these studies will provide insight into the basic processes of regulation of cellular differentiation and cell-cell interaction between epidermal and lymphoid cells, as well as aberrant interaction in pathologic states particularly autoimmune disorders.
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