IL-25 and CD4(+) TH2 cells enhance type 2 innate lymphoid cell-derived IL-13 production, which promotes IgE-mediated experimental food allergy

Abstract

Background: Food-mediated allergic reactions have emerged as a major health problem. The underlying mechanisms that promote uncontrolled type 2 immune responses to dietary allergens in the gastrointestinal tract remain elusive.

Objective: We investigated whether altering IL-25 signaling enhances or attenuates allergic responses to food allergens.

Methods: Mice of an IL-25 transgenic mouse line (iIL-25Tg mice), which constitutively overexpress intestinal IL-25, and Il17rb(-/-) mice, in which Il17rb gene expression is disrupted, were sensitized and gavage fed with ovalbumin (OVA). We assessed symptomatic characteristics of experimental food allergy, including incidence of diarrhea, incidence of hypothermia, intestinal TH2 immune response, and serum OVA-specific IgE and mast cell protease 1 production.

Results: Rapid induction of Il25 expression in the intestinal epithelium preceded onset of the anaphylactic response to ingested OVA antigen. iIL-25Tg mice were more prone and Il17rb(-/-) mice were more resistant to experimental food allergy. Resident intestinal type 2 innate lymphoid cells (ILC2s) were identified as the major producers of IL-5 and IL-13 in response to IL-25. Reconstituting irradiated wild-type mice with Rora(-/-) or Il17rb(-/-) bone marrow resulted in a deficiency or dysfunction of the ILC2 compartment, respectively, and resistance to experimental food allergy. Repeated intragastric antigen challenge induced a significant increase in numbers of CD4(+) TH2 cells, which enhance IL-25-stimulated IL-13 production by ILC2s ex vivo and in vivo. Finally, reconstituted IL-13-deficient ILC2s had reduced capability to promote allergic inflammation, resulting in increased resistance to experimental food allergy.

Conclusion: IL-25 and CD4(+) TH2 cells induced by ingested antigens enhance ILC2-derived IL-13 production, thereby promoting IgE-mediated experimental food allergy.

Keywords: CD4(+) T(H)2 cells; IL-13; IL-25; food allergy; type 2 innate lymphoid cells.