Protection against most gut pathogens requires intestinal secretory IgA responses. Key in this response is the proper uptake of antigens by the intestinal epithelium, which has evolved to restrict the uptake of macromolecules as well as regulate gut immunity. Here, we aim to explore whether signalling through aminopeptidase N (APN) present on small intestinal enterocytes activates these cells to release mediators which can promote secretory IgA responses. APN serves as a receptor for several gut pathogens, such as F4 fimbriated E. coli and certain coronaviruses. We recently showed that APN-specific recombinant antibodies are transported through the small intestinal epithelium upon binding to APN and elicit a potent antigen-specific intestinal immunity. This suggests that targeting to APN can serve as an antigen highway to the small intestinal immune system. This antigen transport through the epithelium is however on itself insufficient to trigger protective immunity. It also requires a shift from a tolerogenic to an immune-inductive micro-environment. This project proposal will unravel whether targeting to APN activates the release of mediators by small intestinal epithelial cells as well as whether the identified molecules enhance intestinal secretory IgA responses to antigens upon oral immunisation in a large animal model.