| Research Abstract |
Dendiritic cells (DCs) consist of heterogeneous populations in terms of phenotype and function. Such heterogeneity is ascribed to the difference not only in maturation stage but also in origin of precursor cells. In this study, we conducted experiments to clarify differentiation and maturation of dendritic cell in relation to their functions as a potent antigen presenting cells and obtained the following results.
1) When fluorescenated microspheres were injected, monocytic cells induced into the injection site engulfed microspheres. Most of them became macrophages, but about 25% of them migrated into the draining ymph nodes and showed immature dendritic cells phenotype. Microsphere-transporting cells were distinct from resident skin DCs, and this transport was reduced by more than 85% in monocyte-deficient op/op mice.
2) CD11c^+ CD1^+ cells in lineage- population of human peripheral blood mononuclear cells was found to be the direct precursors of epidermal Langerhans cells, because of th
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e rapid expression of E-cadherin, Langerin and Birbeck granules in the presence of TGF-β1 relative to monocyte-derived dendritic cells.
3) Type I IFN (IFN-α/β) produced from CD11c^- plasmacytoid dendritic cells was a potent inhibitor for he spontaneous maturation of plasmacytoid dendritic cells. Although IFN-α/β as well as IFN-γ induced the upregulation of MHC class II and various costimulatory molecules on CD11c^+ DCs, IFN-α/β did not induce IL-12 production and rather promote IL-10 production. In addition, IFN-α/β blocked the effect of IFN-γ and rendered dendritic cells to skew T cell activation towards Th0 and/or Th2.
4) Antigen presentation in concert with MHC class II was strictly dependent on maturation stimuli. Endocytosed protein antigen was delivered info late endosome/lysosome compartment (MIIC), but MHC-peptide complex did not form unless the DCs are exposed to inflammatory mediators. Once stimulated, however, and MHC-peptide complexes are transported onto cell surface via CIIV with MHC class I and costimulatory molecules, and the MHC and costimulatory molecules remained clustered. The increased ability of maturing DCs to load MHC class II molecules with antigenic cargo contributed to the >100-fold enhancement of the subsequent primary immune response observed when immature and mature DCs are compared as immune adjuvants in culture and in mice.
5) Epidermal Langerhans cells, which is one of the most long-lived dendritic cells in situ, was found to keep migrating to the draining lymph node by phagocytosing keratin-particles in epidermis and dermis using mgf- or hgf-transgenic mice.
6) In steady state, T area dendritic cells that were continuously migrated from peripheral tissues were shown to induce immunological tolerance of antigen-specific T cells by targeting antigen using DEC-205 antibody. Tolerance induction was due to the deletion of specific T cells after transient proliferation by IL-2 without IFN-γ production. This step was blocked by the concomitant administration of anti-CD40 mAb to stimulate dendritic cells with antigen. Less
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