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

通过类维生素A梯度调节屏障组织中树突状细胞的发育

• 批准号: 10092940
• 负责人: CHANG H KIM
• 金额: $ 18.76万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10092940
• 关键词: Cells; Cues; Data; Dendritic Cells; Dermal; Development; Disease; Drug or chemical Tissue Distribution; Embryo; Epidermis; Epithelial; Frequencies; Generations; Goals; HIV; Immune; Immune Tolerance; Immune response; Immune system; Immunity; Immunologics; In Vitro; Inflammatory; Inflammatory Response; Intestines; Langerhans cell; Location; Lung; Lymphoid; Maps; Mediating; Morphogenesis; Mucous Membrane; Oral; Organ; Outcome; Pathogenesis; Pathway interactions; Play; Population; Regulation; Research; Retinoid Receptor; Retinoids; Role; Sentinel; Signal Transduction; Skin; Skin Tissue; T cell differentiation; T cell response; Testing; Tissues; Tretinoin; Vagina; Vitamin A; base; effector T cell; immunoregulation; insight; langerin; neoplastic cell; novel; pathogen; precursor cell; prevent; progenitor; receptor; retinoic acid receptor alpha; tissue tropism; transcription factor; transcriptome

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.

项目摘要 表达Langerin的树突状细胞（DC）亚群起免疫哨兵的作用，并且激活或 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，通过朗格汉斯细胞（LC）在阻断HIV发病机制中的作用以及 langerin+ DCs在增加效应T细胞对其他病原体的应答中的作用。Langerin+ DC具有 独特的组织向性或分布：LC存在于皮肤和粘膜的上皮层中 组织，如口腔、肺、阴道和肠组织中，而其他langerin+ DC被发现在 真皮层和整个淋巴和非淋巴组织在低频率。存在显著 我们对这些特化DC亚群的发育机制的理解存在差距， 以组织依赖的方式调节。我们假设维生素A、视黄酸及其受体 是大多数表达langerin的DCs的发育和组织向性的关键调节因子， 这种作用类似于它们在调节胚胎形态发生中的作用， 前体细胞发育的线索本项目的总体目标是确定视黄酸的作用- RAR β轴在langerin+ DC群体的调节中的作用。为了验证这一假设， 为了达到这一目的，我们将确定RAR β作为组织特异性转录因子所必需的作用。 发展langerin表达的DC亚群，并将研究视黄酸作为阴性对照的功能。 调节子限制表达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亚群。这些结果有望提供有关组织的新信息- 表达朗格兰的DC亚群的特异性发育。这些结果将为以下方面提供新的思路： 维持有效的免疫力并控制由特化DC介导的炎症反应 子集