The purpose of the present studies is to identify cells bearing Ia antigens encoded in the I region of the murine major histocompatibility complex (MHC) which influence the development and function of self Ia recognizing Lyt-1+ helper T cells. We anticipate studying four such cells: Veto cells, which are involved in clonal deletion of autoreactive T cells; Thymic epithelial cells, which are involved in expansion of self Ia recognizing Ly1 T cell precursors; Antigen presenting cells, which are involved in antigen-specific expansion of self Ia recognizing T cells in the periphery; and B cells, which are activated to proliferate and to secrete antibody in the presence of Ly1 helper T cells. We will identify and determine the functional activity of these cells with cloned T cell lines of known self and non-self Ia recognition capabilities, with monoclonal anti-Ia antibodies, and with monoclonal antibodies to other differentiation antigens, such as surface Ig on B cells. We will also test the interactions of each Ia bearing cell type with pre-T cells, with thymocytes, and with mature peripheral T cells. The importance of Ia antigen density on the surface of each cell type will be analyzed using F1 hybrid mice that express Ia antigen alleles unequally, allowing us to manipulate the density of Ia on cell surfaces in a defined fashion. We will examine the induction of tolerance in mature Ly1 T cells and suppressor T cells activated by interaction with such cloned helper T cell lines. From this study, a clear understanding of self tolerance and of the selective activation of self Ia recognizing helper T cells should emerge. This, in turn, should clarify the mechanism of action of Immune response genes (Ir genes), which in many instances appear to reflect tolerance to self antigens in the context of self Ia glycoproteins. Information about Ia antigen functions in mice should give insight into the influence of HLA antigens on disease susceptibility in man.
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