The intestinal tissue is continuously exposed to large amounts of microbe– and food–derived molecules that can stimulate immune responses. We study how the intestine generates protective responses against invading pathogens (resistance) while absorbing beneficial microbe– and food–derived molecules (tolerance). Several cellular and molecular mechanisms exist to ensure robust tolerance induction in the mucosal surfaces, and disruption of such processes often leads to severe chronic inflammatory pathologies such as colitis, Celiac disease and food allergies, and colorectal cancer.
The regulation of immune activation is of particular relevance at the intestinal epithelium, directly exposed to luminal stimulation and the first line of defense against invading pathogens, but also an essential site for nutrient absorption and exposure to beneficial microbial metabolites. We demonstrated that gut-epithelium imprinting on lymphocytes is an essential process for this balance. We defined molecular mechanisms and tissue cues responsible for lymphocyte differentiation and function to maintain gut barrier integrity.
RESISTANCE AND TOLERANCE
We are interested in defining mechanisms by which luminal stimulation influences systemic immunity, and the consequences when these mechanisms are disrupted. In this line, we have defined stromal, innate and adaptive immune cells that modulate local and systemic responses towards intestinal antigens. Our studies also revealed that compartmentalization of intestinal lymphatic drainage to functionally distinct lymphnodes facilitates the simultaneous induction of tolerogenic and effector immune responses in the gut.
In addition to immune cells, the intestine also hosts a large number of enteric-associated neurons (EANs), which extend projections towards the villi to control a variety of functions within the gastrointestinal tract. We described neuro-immune interactions that modulate intestinal physiology and response to microbes. Our studies revealed microbiota-tuned EAN circuits, and a role for EANs in sensing luminal perturbations and providing signals that direct the function of surrounding immune cells. Reciprocally, we described that immune cells nearby EANs play an important role in regulating local neuronal death and repair.