Development of allergen-specific IgE in a food-allergy model requires precisely timed B cell stimulation and is inhibited by Fgl2

Immunoglobulin E (IgE) responses are a central feature of allergic disease. Using a well-established food-allergy model in mice, we show that two sensitizations with cognate B cell antigen (Ag) and adjuvant 7 days apart promotes optimal development of IgE+ germinal center (GC) B cells and high-affinity IgE production. Intervals of 3 or 14 days between Ag sensitizations lead to loss of IgE+ GC B cells and an undetectable IgE response. The immunosuppressive factors Fgl2 and CD39 are down-regulated in T follicular helper (TFH) cells under optimal IgE-sensitization conditions. Deletion of Fgl2 in TFH and T follicular regulatory (TFR) cells, but not from TFR cells alone, increase Ag-specific IgE levels and IgE-mediated anaphylactic responses. Overall, we find that Ag-specific IgE responses require precisely timed stimulation of IgE+ GC B cells by Ag. Furthermore, we show that Fgl2 is expressed by TFH cells and represses IgE. This work has implications for the development and treatment of food allergies.