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Description: The pathways responsible for the emergence of IgE antibodies that drive food allergy remains poorly understood. Using a model of the early stages of food allergy, Koenig et al. found that a single gavage of allergen with cholera toxin adjuvant failed to sensitize mice, but re-exposure to the allergen alone even 1 year later caused sensitization and anaphylaxis upon allergen challenge. The first intragastric exposure induced CD44hi lineage-ambiguous CD4+ T cells but failed to activate B cells. Allergen re-exposure drove Tfh differentiation and IgE production de novo through naïve B cells dependent on IL-4 and CD40/CD40L ligation. Koenig's data implicated memory CD4+ T cells in initiating IgE production and holding IgE memory.