Grant: Project Grant

The intestinal track is the body's largest mucosal surface. Our body dedicates a tremendous number of immune cells to this organ, sustaining its appropriate function, defense and repair. These critical processes rely on the strategical positioning of immune cells within diverse micro-anatomic regions of the gut. Tissue-resident innate immune cells, like macrophages (MP) and innate lymphoid cells (ILC), are permanent inhabitants of these environments. Their functions feed into antimicrobial defense, tissue repair and homeostasis through fairly well understood mechanisms, however, our understanding on how tissue-resident innate immune cells instruct their surroundings to provide signals that support their maintenance within the intestinal tract remains poor. MP and ILCs co-localize with mesenchymal tissue cells like fibroblasts during early and adult life. Morphogens, a group of proteins known for their critical role in regulating the development and differentiation of tissue cells are expressed by MP and ILCs, suggesting a possible mode of communication between tissue-resident innate immune cells and morphogen-responsive fibroblasts. Indeed, macrophages and ILCs both express high levels of Bone Morphogenic Protein (BMP) 2, inspiring the hypothesize that innate immune cell-derived BMP2 instructs fibroblasts to provide growth and survival factors for the maintenance of innate immune cells within the intestinal tract. To unravel this intricate interaction between MP, ILCs and tissue cells, conditional deletion systems of Bmp2 will be used to abrogate BMP2 production by MP or ILCs. We will further delete the BMP receptor in fibroblast populations and knock out MP and ILC growth and survival factors expressed by fibroblasts to probe the presence of a BMP2-fibroblast axis that maintains innate immune cell homeostasis in the intestine.