Summary Oral immunotherapy has had limited success in establishing tolerance in food allergy, reflecting failure to elicit an effective regulatory T (Treg) cell response. We show that disease-susceptible mice (Il4raF709) with enhanced IL-4 receptor (IL-4R) signaling exhibited STAT6-dependent impaired generation and function of mucosal allergen-specific Treg cells. This failure was associated with the acquisition by Treg cells of T helper 2 (Th2) cell-like phenotype, also found in peripheral blood allergen-specific Treg cells of food allergic children. Selective augmentation of IL-4R signaling in Treg cells induced their reprogramming into Th2-like cells and disease susceptibility, whereas Treg cell lineage-specific deletion of Il4 and Il13 was protective. IL-4R signaling impaired the capacity of Treg cells to suppress mast cell activation and expansion, which in turn drove Treg cell Th2 cell reprogramming. Interruption of Treg cell Th2 cell reprogramming may thus provide novel therapeutic strategies in food allergy.

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