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

树突状细胞(DC)是小鼠和人体内的主要抗原提呈细胞类型，是连接适应性免疫系统和天然免疫系统的重要纽带。这一调节环节对于建立高效和及时的适应性T和B细胞反应以提供宿主防御至关重要。DC通过骨髓来源的造血祖细胞的级联逐渐发展，在小鼠和人的所有淋巴和非淋巴器官中都可以找到。根据转录、表型和功能特征，DCs可细分为常规DC1(CDC1)和常规DC2(CDC2)两个亚集。CDC1和2的发育在骨髓祖细胞水平上发生转移，其中cDC1和2的特异性祖细胞分别出现在cDC1和cDC2之前。Pre-cDC1和2都已经拥有其核心亚集的特定转录组特征，然而一旦在他们的目标组织中经历组织特异性的适应过程，以获得组织特异性的功能，例如由cDC1在肠道中诱导调节性T细胞的能力或由cDC2启动粘膜Th17反应的能力。G蛋白偶联受体183(GPR183)高表达于多种免疫细胞，尤其是B细胞和树突状细胞。在脾中，GPR183起着趋化信号的作用，引导cDC2在脾的显微解剖结构中正确定位，使cDC2充分功能成熟和存活。然而，这种微环境引导和功能印迹是如何在非淋巴组织中实现的，例如肺，在很大程度上仍然难以捉摸。因此，本研究旨在阐明GPR183在肺内CDC的微环境指导和功能特化中的作用，以了解常驻肺的CDC如何适应肺微环境以获得其组织特异性功能。为了实现这一点，我们将利用最先进的CDCs体内细胞类型特异性敲除系统、体外和体内迁移分析、转录、发育和功能图谱，以及动态平衡期间的原位组织生态位分析和室内尘螨诱导的CDCs哮喘。因此，这些分析将使我们能够解开GPR183在健康和疾病期间对肺微环境中CDC迁移和功能特性的作用。

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.