Major histocompatibility complex (MHC)-restricted, antigen- specific recognition by T cells is mediated by a receptor complex composed of CD3 associated with the antigen receptor alpha beta heterodimer. It has been recently demonstrated that the thymus and spleen of mice and humans of contain a small subpopulation of cells that express an alternative CD3-associated receptor composed of the products of the antigen receptor gamma and delta genes. The existence of cells that express these alternative forms of receptor raises important questions concerning their relationship in thymic differentiation. In addition, while it is known that gamma delta cells can mediated cytotoxic reactions, little is known of the role of the gamma delta receptor in the process, or of the capacity of the cells for antigen-specific recognition. We have recently demonstrated that the major component of T cells in the epidermis mice, Thy-1+ dEC cells, express gamma delta receptors that have a very restricted repertoire of V-gene expression. These cells offer an excellent and accessible model in which to address several of the important questions concerning gamma delta cells. Specifically, we propose to: (1) Produce monoclonal antibodies to epitopes of the gamma delta receptor. (2) To use the antibodies in multicolor immunofluorescence flow cytometry to directly determine the distribution of gamma delta cells in the thymus, spleen, lymph nodes, and skin of mice. (3) To assess the relationship between gamma delta and alpha beta cells in thymic differentiation by administration of the antibodies to developing mouse thymus in vivo and in vitro. (4) To use thymic grafting in nude mice to determine the role of the thymus in the development of dEC cells. (5) To assess the degree and origin of diversity in the gamma and delta chains of dEC cells by analysis at the DNA, RNA, and protein levels. (6) To construct receptor loss mutants of dEC cells in order to determine the role of the gamma delta receptor in functional activity of the cells. (7) To analyze dEC cells obtained following specific immunization in order to determine whether the gamma delta receptor is capable of antigen-specific immunization in order to determine whether the gamma delta receptor is capable of antigen-specific recognition. These studies will provide important insight into our understanding of thymic differentiation and important information concerning the origin, diversity, and functional capacity of the major T cell component in the skin.
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