CHEMOKINES IN DENDRITIC CELL TRAFFICKING AND FUNCTION

树突状细胞运输和功能中的趋化因子

• 批准号: 6123763
• 负责人: S T HWANG
• 金额: --
• 依托单位: DIVISION OF CLINICAL SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6123763
• 关键词: CD40 molecule; antigen presentation; chemokine; chemotaxis; clinical research; cytokine receptors; dendritic cells; fluorescence microscopy; human subject; inflammation; polymerase chain reaction; skin disorder; tissue /cell culture

"Dendritic cells (DCs) in skin and other tissues play major roles in the presentation of antigen to T cells. Chemokines are small molecules produced by a variety of cells and induce migration in cells expressing appropriate receptors. We wish to understand the role chemokines and chemokine receptors in biology of DC trafficking and function. Most of our studies are conducted with bona fide DCs derived after culturing mouse skin for several days. DCs spontaneously migrate from skin and into media where they can be collected. We perform a variety of assays including: chemotaxis assays, RT-PCR gene expression analysis, and fluorescence microscopy. We have found that CC chemokine receptor 7 (CCR7) is strongly upregulated in skin DC following exposure to inflammatory cytokines. Secondary lymphoid-tissue chemokine (SLC), a ligand of CCR7, was found to be constitutively expressed by dermal lymphatic endothelium and was highly potent in stimulating mature DC migration in vitro. Using antibodies directed against SLC, we found that DC trafficking from peripheral tissue to regional lymph nodes could be significantly inhibited in a murine model of DC trafficking, thus providing evidence the SLC and CCR7 play a functional role in the trafficking of DC to secondary lymphoid organs. We have also found that maturing DCs produce a variety of chemokines including fractalkine, the lone member of the CX3C family of chemokine. Expression of fractalkine was enhanced by ligation of CD40 on DC, suggesting a mechanism by which CD40 ligation primes DC to become better antigen presenting cells. Although initially expressed in a surface bound form, fractalkine can be cleaved from the cell surface, and the cleaved form induces migration of IL-2 stimulated T cells. Because of the unique surface bound stucture of fractalkine on the DC, it is possible that fractalkine acts as a cell surface adhesion molecule in addition to possibly acting as a T cell chemoattractant for the DC."

“皮肤和其他组织中的树突状细胞 (DC) 发挥着重要作用 在将抗原呈递给 T 细胞方面发挥着重要作用。趋化因子 是由多种细胞产生的小分子，并诱导 表达适当受体的细胞中的迁移。我们希望 了解趋化因子和趋化因子受体在生物学中的作用 DC 贩运和功能。我们的大部分研究都是在 含有经过数次培养小鼠皮肤后获得的真正 DC 天。 DC 自发地从皮肤迁移到介质中 它们可以被收集。我们进行各种检测，包括： 趋化性测定、RT-PCR 基因表达分析，以及 荧光显微镜。我们发现CC趋化因子 受体 7 (CCR7) 在皮肤 DC 中强烈上调 暴露于炎症细胞因子。次级淋巴组织 趋化因子 (SLC) 是 CCR7 的配体，被发现是组成型 由真皮淋巴内皮表达，并且非常有效 刺激成熟 DC 体外迁移。使用抗体 针对SLC，我们发现来自外围的DC贩运 组织到区域淋巴结的作用可以被显着抑制 DC贩运的小鼠模型，从而为SLC提供证据 和 CCR7 在 DC 贩运中发挥功能性作用 次级淋巴器官。我们还发现，成熟的 DC 产生多种趋化因子，包括 fractalkine（唯一的趋化因子） 趋化因子 CX3C 家族的成员。表达 fractalkine 通过在 DC 上连接 CD40 得到增强，这表明 CD40 连接促使 DC 变得更好的机制 抗原呈递细胞。尽管最初以表面形式表达 结合形式，fractalkine可以从细胞表面裂解，并且 裂解形式诱导 IL-2 刺激的 T 细胞迁移。 由于分形体独特的表面束缚结构 DC，fractalkine 可能充当细胞表面粘附剂 该分子除了可能充当 T 细胞化学引诱剂之外 对于华盛顿特区。”