PROJECT ABSTRACT The immune system at mucosal sites must be tightly regulated to mediate rapid immunity to invading pathogens, while limiting over-reactive responses that drive chronic inflammation. In particular, type 2 immune responses in the airway or gastrointestinal tract are essential to protect from helminth parasites, but if dysregulated, drive asthma and allergic inflammation. Despite this knowledge, we do not yet fully appreciate the complexity of cellular and molecular signals that control these responses, which will be critical for developing the next generation of preventative, therapeutic or curative treatments. The fundamental focus of this renewal application for the Mucosal Immunology Studies Team is to define novel pathways by which the type 2 immune response harnesses signals associated with the nervous system to regulate rapid mucosal immunity and inflammation. In this context, we will define: (i) the pathways that induce and regulate these neuronal signals, (ii) the functional significance of these pathways in type 2 mucosal immunity and inflammation, and (iii) whether it is possible to therapeutically target these signals to boost immunity to helminth infection or reduced chronic allergic inflammation. We will employ innovative approaches and develop new tools to address these fundamental gaps in knowledge, and where possible, translate our findings from mice into human samples. Results from these studies will significantly advance our understanding of the pathways that are essential to mediate rapid type 2 immunity and inflammation at mucosal sites and could provoke the next generation of preventative, therapeutic and curative treatment strategies.