Mast cells link immune sensing to antigen-avoidance behaviour

The physiological functions of mast cells remain largely an enigma. In the context of barrier damage, mast cells are integrated in type 2 immunity and, together with immunoglobulin E (IgE), promote allergic diseases. Allergic symptoms may, however, facilitate expulsion of allergens, toxins and parasites and trigger future antigen avoidance(1-3). Here, we show that antigen-specific avoidance behaviour in inbred mice(4,5) is critically dependent on mast cells; hence, we identify the immunological sensor cell linking antigen recognition to avoidance behaviour. Avoidance prevented antigen-driven adaptive, innate and mucosal immune activation and inflammation in the stomach and small intestine. Avoidance was IgE dependent, promoted by Th2 cytokines in the immunization phase and by IgE in the execution phase. Mucosal mast cells lining the stomach and small intestine rapidly sensed antigen ingestion. We interrogated potential signalling routes between mast cells and the brain using mutant mice, pharmacological inhibition, neural activity recordings and vagotomy. Inhibition of leukotriene synthesis impaired avoidance, but overall no single pathway interruption completely abrogated avoidance, indicating complex regulation. Collectively, the stage for antigen avoidance is set when adaptive immunity equips mast cells with IgE as a telltale of past immune responses. On subsequent antigen ingestion, mast cells signal termination of antigen intake. Prevention of immunopathology-causing, continuous and futile responses against per se innocuous antigens or of repeated ingestion of toxins through mast-cell-mediated antigen-avoidance behaviour may be an important arm of immunity.

Automated summary

The physiological functions of mast cells are not well understood. Mast cells are involved in type 2 immunity and promote allergic diseases through the interaction with immunoglobulin E (IgE). However, allergic symptoms may also facilitate the elimination of allergens, toxins, and parasites and trigger future antigen avoidance. In this study, mast cells were found to be crucial for antigen-specific avoidance behavior in inbred mice. This behavior prevented immune activation and inflammation in the stomach and small intestine. Antigen avoidance was dependent on IgE and regulated by Th2 cytokines in the immunization phase and by IgE in the execution phase. Mucosal mast cells quickly detected the ingestion of antigens. Multiple signaling pathways between mast cells and the brain were identified. Inhibition of leukotriene synthesis impaired avoidance, but no single pathway interruption completely abolished it, suggesting complex regulation. Overall, antigen avoidance mediated by mast cells may play an important role in preventing immunopathology and repeated ingestion of toxins.