PROJECT SUMMARY: IgE-mediated food allergy affects approximately 1 in 13 children in the USA and has continued to grow in prevalence in recent decades. For many, current immunotherapies are ineffective, making this is a lifelong disease with significant impairment in quality of life. Although IgE is central to the pathophysiology of food allergy, the mechanisms maintaining high affinity (pathogenic) IgE are not well understood. Previous work from our laboratory has shown that IgE memory in mice is contained within a population of antigen-specific IgG memory B cells (MBC) that can undergo class switching to IgE. However, strategies targeting a broad subset of IgG-expressing cells for treatment of food allergy is complicated by the need to retain protective immunity against pathogens. Therefore, it is important to identify the specific IgG MBC that have the ability to generate high affinity IgE responses. This proposal seeks to use mouse models of peanut allergy to identify immunophenotypic markers that can distinguish IgG MBC subsets with the ability to produce high affinity IgE plasma cells (PC). In addition, this application will address the plasticity of this cell fate and the external signals that are required for IgG MBC differentiation into IgE PC. Ultimately, we want to understand what it takes for an IgG MBC to become a pathogenic-IgE producing plasma cell and reveal targets that could be amenable to therapeutic intervention to improve the quality of life of patients who suffer from food allergies.