Characterization of Allergen-Specific Immunoglubulin E Development in a Food Allergy Model and Its Regulation by T Follicular Helper and T Follicular Regulatory Cells

Abstract

Food allergy is a highly prevalent and serious disease regulated by immunoglobin E (IgE) antibodies specific for food allergens.The development of IgE is regulated by T follicular helper cells (TFH) and T follicular regulatorycells (TFR) in the germinal center (GC). We aimed to understandthe regulation of IgEin the GC by TFH and TFR cellsusinga mouse food allergy model. We found that the dosage and timingof allergen delivery into thegut is criticalfor allergen-specific IgE development, in part because the timing of allergen delivery affected the expression of regulatory factors by TFH and TFR cells. We studied FGL2, an inhibitory factor, and found that down-regulation of FGL2 in TFH cells was important for the allergic IgEresponse. Apart from inhibitory factors, TFH cell-derived IL-4 is required for IgE responses. We unexpectedlyfound that TFR cells in food allergy produce comparable amountsof IL-4 to TFH cellsand IL-4–expressing TFR cells promoteallergen-specific IgEin food allergy. The IgE response is highly sensitive to IL-4 levels, suggesting the need for extra IL-4 from TFR cells. However,TFR cells have distinct functionsdepending on the immune environment, since TFR cells repress IgEinanairway inflammation model. We found that TFR cells in airway inflammation have a different gene expression profile from TFR cells in food allergy, whichmay explain their distinct functions. Lastly, previous studies showed that high-affinity IgE driving anaphylactic reactions is produced via IgG1-switchedintermediate B cells. We challenged this paradigm by showing that high-affinity IgE develops in the absence ofIgG1-switchedB cellsin our food allergy model.Overall, our studies reveal that IgE is regulated by novel pathways in food allergy. We hope to exploit these new pathways to develop new specific therapies for food allergy.