Myeloid dendritic cells and lymphoid dendritic cells

骨髓树突状细胞和淋巴树突状细胞

• 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
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-11470085/
• 关键词: Dendritic cells; Development; Maturation; T cell activation; Antigen presentation; Subsets; Phenotype; サブセット; ランゲルハンス細胞; ランゲリン; 接触過敏応答; IL-12; 食作用; アポトーシス; 腫瘍細胞; TH1; TH2; 免疫制御; 単球; MHCクラスII分子; 抗原プロセッシング; 細胞間相互作用

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（Dendritic cells，DCs）是一种表型和功能均不均一的细胞群。这种异质性不仅归因于成熟阶段的差异，而且归因于前体细胞来源的差异。本研究通过实验阐明树突状细胞分化成熟与其作为强有力的抗原提呈细胞功能的关系，并获得以下结果：1）注射荧光微球后，单核细胞被诱导进入注射部位吞噬微球。其中大部分转化为巨噬细胞，但约25%迁移至引流淋巴结，表现为未成熟树突状细胞表型。微球转运细胞与皮肤DCs不同，在单核细胞缺乏的op/op小鼠中，这种转运减少了85%以上。2）人外周血单核细胞谱系群中的CD 11 c ^+ CD 1 ^+细胞被发现是表皮朗格汉斯细胞的直接前体，因为它们是表皮朗格汉斯细胞的直接前体。 ...更多信息 3）CD 11 c ~+-浆细胞样树突状细胞产生的I型干扰素（IFN-α/β）是浆细胞样树突状细胞自发成熟的有效抑制剂。尽管IFN-α/β和IFN-γ可诱导CD 11 c ^+ DC上MHC II类分子和各种共刺激分子的表达上调，但IFN-α/β并不诱导IL-12的产生，而是促进IL-10的产生。此外，IFN-α/β阻断IFN-γ的作用，并使树突状细胞将T细胞活化偏向Th 0和/或Th 2。4）与MHC II类一致的抗原呈递严格依赖于成熟刺激。内吞的蛋白抗原被递送到晚期内体/溶酶体区室（MIIC），但除非DC暴露于炎性介质，否则MHC-肽复合物不形成。然而，一旦受到刺激，MHC-肽复合物就会通过CIIV与MHC I类分子和共刺激分子一起转运到细胞表面，并且MHC和共刺激分子保持聚集。当在培养物和小鼠中比较未成熟和成熟DC作为免疫佐剂时，成熟DC用抗原货物装载MHC II类分子的能力增加，导致随后的初级免疫应答增强>100倍。5）表皮朗格汉斯细胞，其是原位最长寿的树突细胞之一，发现通过吞噬表皮和真皮中的角蛋白颗粒，持续迁移到引流淋巴结。6）在稳定状态下，从外周组织连续迁移的T区树突状细胞显示通过使用DEC靶向抗原诱导抗原特异性T细胞的免疫耐受。205抗体。耐受性诱导是由于IL-2短暂增殖后特异性T细胞的缺失而不产生IFN-γ。通过同时给予抗CD 40 mAb以用抗原刺激树突状细胞来阻断该步骤。少

项目成果

Hemmi, H.: "Skin antigens in steady state are trafficked to regional lymph nodes by transforming growth factor-β1-dependent cells"Int. Immunol.. 13(5). 695-704 (2001)

Hemmi, H.：“稳定状态的皮肤抗原通过转化生长因子-β1 依赖性细胞运输至区域淋巴结”Int.Immunol.. 695-704 (2001)。

Steinman, R.M.: "Myeloid dendritic cells"J.Leukocyte Biol. 66 2). 205-208 (1999)

Steinman，R.M.：“骨髓树突状细胞”J.Leukcyto Biol。

Steinman, R.M.: "Can the capture of apoptoic cells by dendritic cells lead to tolerance?"J.Exp.Med. 191(2). 411-416 (2000)

Steinman, R.M.：“树突状细胞捕获凋亡细胞能否导致耐受？”J.Exp.Med。

Steinman R.: "Myeloid dendritic cells"J. Leukocyte Biol.. 66. 205-208 (1999)

Steinman R.：“骨髓树突状细胞”J。

Ito.T.: "Regulation of myeloid and lymphoid dendritic cell functions by interferons and relevant cytokines"J. Immunol.. 166(5). 2961-2969 (2001)

Ito.T.：“干扰素和相关细胞因子调节骨髓和淋巴树突状细胞功能”J.