Myeloid dendritic cells and lymphoid dendritic cells

骨髓树突状细胞和淋巴树突状细胞

基本信息

批准号：
11470085
负责人：
INABA Kayo
金额：
$ 9.22万
依托单位：
KYOTO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2001
项目状态：
已结题

项目摘要

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 … More 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

树突状细胞（DC）由异质种群在表型和功能方面组成。这种异质性不仅在成熟阶段，而且是前体细胞的起源。在这项研究中，我们进行了实验，以阐明树突状细胞的分化和成熟，相对于它们作为潜在的抗原呈递细胞的功能，并获得以下结果。1）当注入荧光烯酰化的微球时，单核细胞会诱导到入口位点吞噬微壳中。它们中的大多数变成了巨噬细胞，但其中约25％迁移到排水的YMPH节点中，并显示出未成熟的树突状细胞表型。微球传输细胞与居民皮肤DC不同，在单核细胞缺乏的OP/OP小鼠中，这种转运降低了85％以上。2）CD11C^+ CD1^+细胞在人类外周血单核细胞中的谱系群体中，发现了Expedermal langersin and the e and expermal langersin and the e and e e and e e and the e and e e and the e and e and e and e and e and e and e and e and e and e and e and e and e and e and and and langerser and and and and and。 Birbeck颗粒在TGF-β1相对于单核细胞衍生的树突状细胞中。3）I型IFN（IFN-α/β）产生的Cd11c^ - 浆细胞类动物树突状细胞是一种潜在的抑制剂，它是对静脉细胞的自发成熟的ifn-ifn-ifn-ifn-ifn-ifn-ifn-ifn-ifn-ifn-ifn-ifn-ifn-ifn-ifn-ifn-ifn-ifn-ifn-ifn-ifn-ifn-ifn-ifn-ifn-ifn-ifn-ifn-ifn-ifn-ifn-ifn-ifn。 MHC II类和CD11C^+ DC上的各种共刺激分子，IFN-α/β不会诱导IL-12的产生，而是促进IL-10产生。此外，IFN-α/β阻止了IFN-γ的作用，并使树突状细胞对Th0和/或Th2.4）与MHC II一致的抗原表现偏向于Th0和/或Th2.4）严格取决于成熟刺激。将内吞蛋白抗原提供信息后期内体/溶酶体室（MIIC），但是除非DC暴露于炎症介质，否则MHC肽复合物不会形成。然而，一旦刺激，MHC肽复合物通过MHC I类和共刺激分子通过CIIV运输到细胞表面上，MHC和共刺激分子仍然聚集。成熟DC的能力提高了用抗原货物加载MHC II类分子的能力，有助于将随后在培养物和族中的免疫邻接中进行比较时观察到的随后的原发性免疫反应的增强> 100倍。5）在培养物和族中的免疫接头。通过使用MGF-或HGF-转基因小鼠在表皮和真皮中吞噬角蛋白粒子的吞噬细胞。6）在稳态中，通过使用抗原特异性T细胞的抗原特异性T型抗血症抗精管抗体，证明了从周围组织中连续迁移的T区域树突状细胞被证明可诱导抗原特异性T细胞。耐受性诱导是由于IL-2瞬时增殖后未经IFN-γ产生的特定T细胞的缺失。抗CD40 mAb伴随着抗原刺激树突状细胞，阻止了此步骤。较少的