CRC 1009 A12 - Interaction of macrophages with cell matrix niches in lymphoid organs

Basic data for this project

Description

With this project we aim to analyze how the communication between macrophages and the extracellular matrix (ECM) in lymphoid tissues impacts lymphoid barrier integrity and B cell function. In particular, we will focus on the role of CD169+ macrophages in lymphoid tissue remodeling and immune responses during infection. CD169 expressing macrophages localize at the interfaces between lymphoid tissue and circulating fluids in secondary lymphoid organs: the subcapsular sinus of the lymph nodes and the marginal zone of the spleen. These environmental niches are sustained by specialized endothelial cells, the so-called sinus lining cells. We have previously demonstrated that the communication between marginal zone macrophages and B cells in the spleen is essential for the immune response against blood-borne antigens. In addition, recent data from our lab show altered expression of certain ECM proteins of the sinus lining cells in spleen (MadCAM-1 and Laminin) and lymph nodes (ColagenIV and Laminin) after transient depletion of CD169+ macrophages, using an inducible knock-out mouse model. In this project we will characterize the molecular pathways defining cell-cell and cell-matrix interactions in these lymphoid barrier niches using diverse reporter and gene deficient mouse models. We plan to elucidate the mechanisms by which macrophages modulate the adhesive interactions with the ECM of sinus lining cells. We will also evaluate how these interactions impact the specific immune responses to blood- and lymph-borne pathogens. To that end, we will combine models of bacterial and virus infections with our inducible knock-out mice for CD169 macrophages. In addition, using fate mapping approaches with inducible transgenic mouse models and in vitro 3D structures, we will explore the importance of cell-matrix interactions during lymphoid organ development. With this study we will define organ-specific effects of ECM on macrophages at barriers between circulating fluids and lymphoid structures and how this influences specific immune responses against blood- and lymph- borne pathogens.