Physiological and cell biological studies on dendritic cells

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Antigen uptake, processing and presentation by dendritic cells (DCs) have become amenable to cell biological approaches. The critical events occur in DCs that are undergoing development and maturation in response to inflammatory stimuli. The aim of this project is to define developmental stages and to elucidate regulatory mechanisms of antigen processing in immunostimulatory dendritic cells. The following results are obtained.1) DCs ate unusually efficient at forming MHC-peptide complexes from phagocytosed cells, some 1-10 thousand times more efficiently than an exposure to preprocessed peptide. A comparable phenomenon is observed in vivo when short-lived migratory DCs migrate via afferent lymphatics to the T cell areas of the lymph nodes.2) After phagocytosing injected microspheres, about 25% of inflammatory monocytes migrated to the T area of draining node, where they expressed dendritic cell-restricted markers and high levels of costimulatory molecules.3) Fractalkine/neurotactin and … More MDC are isolated from mouse bone marrow-derived DC cDNA libraries by the signal sequence trap method. Both chemokines are expressed by DC differentiated from bone marrow precursors cells in vitro and mature DCs from tissues, and constitutively produced by DCs in T area to attract T cells.4) Based on the relative expression of CD11c and CD1a, we have identified three fractions of DCs in human peripheral blood. A major population expressing CD1a and CD11c is demonstrated to be immediate precursors of epidermal Langerhans cells. A minor fraction (CD1a-CD11c-) is identified as plasmacytoid T cells, which are supposed to be lymphoid-lineage DCs.5) Immature dendritic cells internalize antigens into lysosomal compartments rich in MHC II molecules. The capacity of MHC-rich lysosomes to mediate the formation of MHC II-peptide complexes is strictly controlled during dendritic cell differentiation, helping to coordinate antigen acquisition and inflammatory stimuli with formation of ligands for the T cell receptor. Less