Immunity requires the random assembly of a diverse repertoire of immune receptors during lymphocytedevelopment, many of which are self-reactive. To prevent autoimmunity, self-reactive lymphocytes areeliminated in central lymphoid organs during development. However, central tolerance mechanisms are notsufficient to veto all of the autoreactivity. In the first funding period of this program project award wedeveloped a means to specifically target antigens to a subset of dendritic cells (DCs) that express the DEC-205 antigen (CD8+DEC205+DCs) in vivo and showed that the steady state function of these cells is tomaintain tolerance by inducing T cell deletion, or anergy or by facilitating the development of regulatory Tcells. In preliminary experiments we have extended this antigen delivery method to a second group of DCs(CD8-33D1+DCs) that represent most of the DCs in mouse spleen. We find a novel form of regulation ofantigen processing and presentation by DCs in vivo not anticipated by in vitro studies. CD8+DEC205+DCsare specialized for intracellular retention of immunologically intact antigen and presentation on MHCI,whereas CD8-33D1+DCs rapidly process the same antigen for presentation by MHCIL The long-rangegoals of this proposal are to determine how the two DC subsets contribute to maintaining self-tolerance andto exploit differences between the subsets in the prevention and therapy of autoimmunity. To accomplishthese goals we propose to determine the cellular and molecular basis for the observed differences in antigenprocessing and presentation by the two subsets and to compare the two DC subsets in induction of T celldeletion, anergy and regulatory T cells. The working hypothesis is that the two DCsubsets will have uniqueand complementary functions in maintaining tolerance in vivo.
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