Grant: Project Grant

The gastrointestinal tract is the body's largest mucosal surface. The number of microorganisms seeding this environment vastly outnumber the body's own cell numbers. The intestinal epithelium, a single layer of tightly connected cells, is the first physical barrier to these microbes, while the inner and outer mucus layer serve as chemical barriers and contain antibodies and anti-microbial peptides. Breaching of these barriers by microbes results in inflammation, tissue damage, organ failure and death. It is thus an obvious task to maintain the intestinal barrier function whilst avoiding overriding immune activation. This task demands about 60% of the body's total immune cell mass and further emphasizes the importance of maintaining the homeostasis of the intestinal tract. Macrophages (MP) and Dendritic cells (DC), also termed mononuclear phagocytes (MNP) are the body's major sentinel cells. Their key function is the phagocytosis of foreign antigens, its processing and presentation to T cells as an MHC-peptide complex. This process requires contextual interpretation of the local microenvironment to initiate an inflammatory response against pathogens, or immunologic tolerance towards commensals and food. The molecular cues required to interpret the intestinal microbial composition are poorly defined. It is further completely enigmatic how immunologic tolerance to this vastly great number of bacterial antigens is achieved. The quest for the molecules and mechanisms initiating this process are of great importance, as a growing number of autoimmune pathologies are associated with alterations in the intestinal microbial community. This proposal aims to understand the fundamental signals and mechanisms that are required to initiate the crosstalk of innate immune cells of the intestine, to ultimately control immunity to luminal antigens.