While food allergy has emerged as a major health issue, treatment options are quite limited. There is an urgent need to identify the specific environmental and endogenous factors that prime and then sustain allergic responses to foods so that new mechanism-based therapies can be developed. We have found that, IgE- activated mast cells, best known for causing immediate hypersensitivity reactions including food anaphylaxis, actually play a separate but critical role as food allergen sensors and adjuvants for Type 2 immune responses and that the activating effects of food-specific IgE on mast cells can be countered by IgG antibodies of corresponding specificity. Important questions remain unanswered, however: 1) What specific aspects of Type 2 immunity (Th2, ILC2, IgE+ B cells) are enhanced by IgE-activated mast cells?, 2) Are these effects mediated by mast cell cytokines?, 3) Is the protective effect of IgG antibodies in vivo, suppressing Th2 and enhancing Treg responses, mediated by their negative signals, delivered via FcgR2b, specifically in mast cells and can responses to food allergens be attenuated by using specific monoclonal IgG antibodies to activate this suppressive pathway? These questions will be answered in this project under the following aims: AIM 1: Establish how IgE-activated mast cells promote food allergy: 1.1 Test the impact of IgE-activated mast cells in vivo on emergence of Th2, Tfh and IgE+ B cells and evaluate the contributions of mast cell derived Th2 cytokines 1.2 Examine mast cell effects on emerging effector RORgt+ vs. pathogenic GATA-3+, IRF-4+, IL-4+ Treg 1.3 Evaluate reciprocal TGFb-mediated inhibitory effects of Treg on mast cell functions 1.4 Examine the influence of IgE-activated mast cells on ILC2 induction in vivo: Roles of mast cell- vs. gut epithelial cell-derived cytokines AIM 2: Determine how IgG:FcgR2b signals can reset the immune response in food allergy: 2.1 Evaluate the direct role of IgG inhibitory signals in mast cells in suppression of Type 2 and restoration of functional Treg responses in food allergy 2.2 Evaluate the effects of high-affinity human monoclonal peanut specific IgG antibodies (and their IgG subclass swap variants) cloned from single B cells transcriptomes on IgE-mediated basophil activation 2.3 Use our humanized mouse model of peanut allergy to test the effects of monoclonal peanut-specific IgE on immediate hypersensitivity responses (systemic anaphylaxis). 2.4 Test IgG effects on Th, Tfh and Treg responses in the humanized mice