Dendritic cells (DCs) play a central role in the immune response due to their capacity for presenting antigens to present antigens to naive T-lymphocytes. Despite their importance, relatively little is known concerning the cell biology, development, or functions of this highly specialized cell type. Recent evidence has demonstrated that DCs can be induced by inflammatory stimuli to exhibit a remarkable developmental pattern accompanied by striking changes in cell morphology, surface expression of MHC class II, endocytosis, and the capacity for antigen presentation. These changes reflect the functional states characteristic of DCs at different stages of their life cycle, during which DCs first reside in peripheral tissues where they act as sentinels that accumulate but are unable to present foreign antigens, and then migrate to lymphoid organs where they can present their accumulated antigens to T-cells. We now plan to determine the cellular and molecular mechanisms responsible for DC maturation, and to elucidate how these alterations result in the conversion of DCs form cells actively engaged in antigen accumulation to cells uniquely well adapted for antigen presentation. The application proposes four Specific Aims: 1. To characterize in detail the three distinct stages in dendritic cell development in mouse bone marrow-derived DCs, and to extend these results to human DCs cultured from CD34+ precursors both to generalize our conclusions and to provide sufficient material for biochemical analysis. 2. To characterize the features and biogenesis of novel MHC class II-containing compartments in DCs, including compartment likely to be involved in antigen processing as well as unique, DC-specific compartments of no known function (e.g., Birbeck granules). 3. To elucidate the mechanisms controlling the surface expression of MHC class II molecules and various accessory proteins during DC development. In the case of class II molecules, initial suggest that the developmentally regulated cleavage of invariant chain plays a key role in controlling class II expression by controlling the intracellular transport of class II. 4. To correlate alterations in DC development with the regulation of antigen processing and presentation by DCs. The application will investigate how the regulation of class II transport, endocytosis, and accessory molecule expression determine antigen processing and presentation activities.
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