Project Summary The U.S. Center for Disease Control and Prevention estimates of up to 6 million American children with food allergies (roughly 2 in every classroom) at an economic cost of ~$25 billion per year. Currently, there are limited FDA-approved treatment options for food allergy, with food avoidance remaining the only safe option. A better understanding of the immune mechanisms and signaling pathways underlying food allergy is clearly warranted to permit development of new effective and safe therapies8. Over the last funded period our team identified “canonical” goblet cell antigen passages (GAPs) that act to deliver dietary antigens to discrete immunological niches and imprint antigen presenting cells (APCs) with tolerogenic properties to promote immune tolerance. Furthermore, we showed that the food allergic condition was associated with altered gut antigen passage patterning and landscape. These IL-13/IL-4R-dependent “non-canonical” antigen passages were required for induction of IgE-MC reactions. In preliminary studies we demonstrate that systemic activation of the IL-13/IL-4R-signaling pathway is sufficient to promote the outgrowth of SI pro-type-2 GC subpopulation, which express genes associated with dietary antigen recognition and a distinct pro-type-2 inflammatory phenotype and form antigen passages. Strikingly, we provide a link between disruption of skin barrier and pro-Type 2 cytokine production with increased gut IL-13-producing ILC2 cells and a shift in gastrointestinal antigen passage landscape from the “canonical” to “non-canonical” antigen passages. The current gap in knowledge is the requirement of pro-type-2 GCs to food allergen passage and directing the allergic inflammatory response to the gut (allergic gut tropism) and priming for food reactivity. We hypothesize that SI pro-type 2 GCs act as non-canonical antigen passages, drive allergic gut tropism and clinical reactivity to foods. To test our hypothesis, we propose three specific Aims (SA); SA1) Define the role of systemic Type-2 signals in GI pro-type 2 GC-antigen passage formation; SA2) Define the role of GI pro-type 2 GC antigen passages in allergic gut tropism and SA3) Define the requirement of GI pro-type 2 GC antigen passage-induced allergic gut tropism in food reactivity. With respect to the expected outcomes, the studies proposed in SA1 are expected to demonstrate GI pro-type 2 GC antigen passages; SA2 demonstrate that GI pro-type 2 GCs direct antigens to sensitizing LP-DC populations and recruit the food antigen-specific CD4+ Th2 cell response to GI tract and SA3) identify the requirement for GI pro-type 2 GCs in allergic gut tropism and clinical reactivity. Successfully completing the proposed studies will provide a new and substantive departure from our current understanding of the underlying molecular mechanisms of dietary food allergen passage across the intestinal epithelium underpinning a critical role for GI pro-type 2 GCs in allergic gut trop...