IL-4 production by group 2 innate lymphoid cells promotes food allergy by blocking regulatory T-cell function

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Background:Food allergy is a major health issue, but its pathogenesis remains obscure. Group 2 innate lymphoid cells (ILC2s) promote allergic inflammation. However their role in food allergy is largely unknown.Objective:We sought to investigate the role of ILC2s in food allergy.Methods:Food allergy–prone mice with a gain-of-function mutation in the IL-4 receptor α chain(Il4raF709)were orally sensitized with food allergens, and the ILC2 compartment was analyzed. The requirement for ILC2s in food allergy was investigated by usingIl4raF709, IL-33 receptor–deficient(Il1rl1−/−), IL-13–deficient(Il13−/−), and IL-4–deficient(Il4−/−)mice and by adoptive transfer ofin vitro–expanded ILC2s. Direct effects of ILC2s on regulatory T (Treg) cells and mast cells were analyzed in coculture experiments. Treg cell control of ILC2s was assessedin vitroandin vivo.Results:Il4raF709mice with food allergy exhibit increased numbers of ILC2s. IL-4 secretion by ILC2s contributes to the allergic response by reducing allergen-specific Treg cell and activating mast cell counts. IL-33 receptor deficiency inIl4raF709 Il1rl1−/−mice protects against allergen sensitization and anaphylaxis while reducing ILC2 induction. Adoptive transfer of wild-typeand Il13−/−but notIl4−/−ILC2s restored sensitization inIl4raF709 Il1rl1−/−mice. Treg cells suppress ILC2sin vitroandin vivo.Conclusion:IL-4 production by IL-33–stimulated ILC2s blocks the generation of allergen-specific Treg cells and favors food allergy. Strategies to block ILC2 activation or the IL-33/IL-33 receptor pathway can lead to innovative therapies in the treatment of food allergy.Graphical abstract:

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