Regulation of the development of dendritic cells in barrier tissues by retinoid gradients

项目总结 表达Langerin的树突状细胞(DC)亚群作为免疫哨兵发挥作用，激活或 调节对病原体和肿瘤细胞的免疫反应。它们在免疫系统中的重要性 例如，朗格汉斯细胞(LCS)在阻止HIV发病中的作用和 Langerin+DC在提高效应T细胞对其他病原体反应中的作用。Langerin+DC拥有 独特的组织取向或分布：LC存在于皮肤和粘膜的上皮层 组织，如口腔、肺、阴道和肠道组织，而其他langerin+DC存在于 真皮层及淋巴组织和非淋巴组织中均有低频率表达。有一个重要的 我们对这些专门化DC亚集的形成机制的理解存在差距 以组织依赖的方式进行调节。我们假设维生素A、维甲酸及其受体 是大多数表达langerin的DC的发育和组织趋向性的关键调节因子，调节 以类似于其通过提供空间来调节胚胎形态发生的角色的方式来特化DC 提示发育中的前体细胞。该项目的总体目标是确定维甲酸的作用- RAR轴在调节Langerin+DC群体中的作用。要检验这一假设并实现已定义的 目的：我们将确定RAR作为组织特异性转录因子的作用。 表达Langerin的DC亚群的研究进展及视黄酸的负性功能研究 调节以限制表达langerin的DC亚群的异位发育。拟议的研究将 确定维生素A代谢物及其受体在调节Langerin中的基本功能 表达DC子集。这些结果有望提供有关组织的新信息-- 表达langerin的DC亚群的特异性发展。研究结果将为 维持有效免疫，控制树突状细胞介导的炎症反应 子集。

PROJECT SUMMARY Langerin-expressing dendritic cell (DC) subsets function as immunological sentinels and either activate or regulate immune responses to pathogens and tumor cells. Their importance in the immune system has been established, for example, by the role of Langerhans cells (LCs) in blocking HIV pathogenesis and the role of langerin+ DCs in mounting effector T cell responses to other pathogens. Langerin+ DCs have unique tissue tropism or distribution: LCs are present in the epithelial layer of the skin and mucosal tissues, such as oral, lung, vaginal and intestinal tissues, while other langerin+ DCs are found in the dermal layer and throughout lymphoid and non-lymphoid tissues at low frequencies. There is a significant gap in our understanding of the mechanisms by which the development of these specialized DC subsets is regulated in a tissue-dependent manner. We hypothesize that vitamin A, retinoic acid, and their receptors are key regulators of the development and tissue tropism of most langerin-expressing DCs, regulating the specialized DCs in a manner similar to their roles in regulating embryo morphogenesis by providing spatial cues to developing precursor cells. The overall goal of this project is to establish the roles of retinoic acid- RAR axis in the regulation of langerin+ DC populations. To test this hypothesis and attain the defined goal, we will determine the role of RAR as a transcription factor necessary for tissue-specific development of langerin-expressing DC subsets and will study the function of retinoic acid as a negative regulator to limit ectopic development of langerin-expressing DC subsets. The proposed research will identify fundamental functions of vitamin A metabolites and their receptors in regulating langerin- expressing DC subsets. The outcomes are expected to provide novel information regarding the tissue- specific development of langerin-expressing DC subsets. The outcomes will provide novel ideas to maintain effective immunity and to control inflammatory responses mediated by the specialized DC subsets.