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

树突状细胞（DC）是小鼠和人类中主要的抗原呈递细胞类型，并且在适应性免疫系统和先天性免疫系统之间提供必要的联系。这种调节联系对于建立有效和及时的适应性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逐渐更定型的级联而发育，并且可以在小鼠和人的所有淋巴和非淋巴器官中发现。DC可以通过转录组学、表型和功能标志被细分为两个子集，常规DC 1（cDC 1）和常规DC 2（cDC 2）。cDC 1和2的发育在骨髓祖细胞水平转向，其中产生cDC 1和2的特化祖细胞，分别为前cDC 1和前cDC 2。前cDC 1和前cDC 2都已经具有其核心亚群特异性转录组特征，然而一旦在其靶组织中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cDC 1在肠中诱导调节性T细胞的能力或通过cDC 2引发粘膜Th17应答的能力。G蛋白偶联受体183（Gpr183）在多种免疫细胞上高度表达，最显著的是在B和树突细胞上。在脾脏中，Gpr183作为趋化信号引导cDC2朝向它们在脾脏的显微解剖结构内的正确定位，允许cDC2的完全功能成熟和存活。然而，如何在非淋巴组织（如肺）中实现这种微环境引导和功能印记，在很大程度上仍然是难以捉摸的。因此，本提案旨在阐明Gpr183在肺内cDC的微环境指导和功能特化中的作用，以了解肺驻留cDC如何适应肺微环境以获得其组织特异性功能。为了实现这一点，我们将利用最先进的cDC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cDC稳态和屋尘螨诱导的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卷积Gpr183对健康和疾病期间肺微环境内cDC的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.