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

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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.