Understanding the role of Gpr183 for the development and function of murine lung resident dendritic cells

了解 Gpr183 对小鼠肺常驻树突状细胞发育和功能的作用

• 批准号: 440241727
• 负责人: Professor Dr. Andreas Schlitzer
• 金额: --
• 依托单位: Life and Medical Sciences Institute (LIMES)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2020
• 资助国家: 德国
• 起止时间: 2019-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/440241727?language=en
• 关键词: Understanding; role; Gpr183; development; function

Dendritic cells (DC) are the major antigen presenting cell type in mice and man and provide an essential link between the adaptive and innate immune system. This regulatory link is crucial for the establishment of efficient and timely adaptive T and B-cell responses to provide host defence. DCs develop via a gradually more committed cascade of bone marrow derived hematopoietic progenitors and can be found in all lymphoid and non-lymphoid organs in mice and man. DCs can be subdivided by transcriptomic, phenotypic and functional hallmarks into two subsets, conventional DC1 (cDC1) and conventional DC2 (cDC2). Development of cDC1 and 2 diverts at the level of the bone marrow progenitors where specialized progenitors for cDC1 and 2 arise, pre-cDC1 and pre-cDC2 respectively. Both pre-cDC1 and 2 already harbour their core subset specific transcriptome signature however once in their target tissue undergo tissue specific adaptation processes in order to gain tissue-specific functionalities, such as the ability to induce regulatory T-cells by cDC1 in the intestine or priming of mucosal Th17 responses by cDC2. G-protein coupled receptor 183 (Gpr183) is highly expressed on a variety of immune cells, most notably on B and dendritic cells. In the spleen Gpr183 acts as a chemotactic signal guiding cDC2s towards their correct positioning within the spleen’s microanatomy allowing full functional maturation and survival of cDC2s. However how such microenvironmental guidance and functional imprinting is achieved in non-lymphoid tissues, such as the lung, remains largely elusive. Therefore this proposal aims to elucidate the role of Gpr183 for microenvironmental guidance and functional specialization of cDCs within the lung to understand how lung-resident cDCs adapt to the lung microenvironment in order to gain their tissue-specific functionality. To achieve this we will utilize state of the art cell type specific in vivo knockout systems for cDCs, in vitro and in vivo migration analysis, transcriptomic, developmental and functional profiling alongside in situ tissue niche analysis during homeostasis and house dust mite induced asthma of cDCs. Therefore these analysis will allow us to deconvolute the roles of Gpr183 on the migratory and functional properties of cDCs within the lung microenvironment during health and disease.

树突状细胞（DC）是小鼠和人体内主要的抗原呈递细胞类型，在适应性免疫系统和先天免疫系统之间提供了重要的联系。这种调节联系对于建立有效和及时的适应性T细胞和b细胞反应来提供宿主防御至关重要。树突状细胞通过骨髓衍生的造血祖细胞的级联逐渐发展，可以在小鼠和人的所有淋巴和非淋巴器官中发现。dc可根据转录组学、表型和功能特征细分为两个子集，传统DC1 （cDC1）和传统DC2 （cDC2）。cDC1和cd2的发育在骨髓祖细胞水平上发生转移，在骨髓祖细胞水平上，cDC1和2的特异性祖细胞分别为前cDC1和前cdc2。pre-cDC1和2都已经包含了它们的核心亚群特异性转录组特征，但是一旦进入它们的靶组织，就会经历组织特异性适应过程，以获得组织特异性功能，例如通过cDC1在肠中诱导调节性t细胞或通过cDC2启动粘膜Th17反应的能力。g蛋白偶联受体183 （Gpr183）在多种免疫细胞上高表达，尤其是在B细胞和树突状细胞上。在脾脏中，Gpr183作为趋化信号，引导cDC2s在脾脏微观解剖结构中正确定位，从而使cDC2s完全功能成熟和存活。然而，这种微环境引导和功能印记如何在非淋巴组织（如肺）中实现，在很大程度上仍然是难以捉摸的。因此，本研究旨在阐明Gpr183在肺内cdc微环境引导和功能特化中的作用，以了解肺内驻留cdc如何适应肺微环境以获得其组织特异性功能。为了实现这一目标，我们将利用最先进的cDCs细胞类型特异性体内敲除系统，体外和体内迁移分析，转录组学，发育和功能分析以及在稳态和室内尘螨诱导的cdc哮喘期间的原位组织生态位分析。因此，这些分析将使我们能够解开Gpr183在健康和疾病期间肺微环境中cdc的迁移和功能特性中的作用。