Physiological and cell biological studies on dendritic cells

树突状细胞（DC）的抗原摄取、加工和呈递已经变得适合于细胞生物学方法。关键事件发生在响应于炎症刺激而正在经历发育和成熟的DC中。本项目的目的是确定免疫刺激性树突细胞的发育阶段和阐明抗原加工的调节机制。获得了以下结果：1）DC在从吞噬的细胞形成MHC-肽复合物方面异常有效，比暴露于预处理的肽的效率高约1- 1万倍。当短寿命的迁移性DC通过传入神经迁移到淋巴结的T细胞区时，在体内观察到类似的现象。2）在吞噬注射的微球后，约25%的炎性单核细胞迁移到引流结的T细胞区，在那里它们表达树突状细胞限制性标志物和高水平的共刺激分子。 ...更多信息 通过信号序列捕获法从小鼠骨髓来源的DC cDNA文库中分离MDC。这两种趋化因子均由骨髓前体细胞体外分化的DC和组织来源的成熟DC表达，并由T区的DC组成性产生以吸引T细胞。4）根据CD 11 c和CD 1a的相对表达，我们鉴定了人外周血中的三种DC组分。表达CD 1a和CD 11 c的主要群体被证明是表皮朗格汉斯细胞的直接前体。一小部分（CD 1a-CD 11 c-）被鉴定为浆细胞样T细胞，其被认为是淋巴系DC。5）未成熟树突状细胞将抗原内化到富含MHC II分子的溶酶体区室中。富含MHC的溶酶体介导MHC II-肽复合物形成的能力在树突状细胞分化过程中受到严格控制，有助于协调抗原获得和炎症刺激与T细胞受体配体的形成。少

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