IL-25 and CD4⁺ T_H2 cells enhance type 2 innate lymphoid cell-derived IL-13 production, which promotes IgE-mediated experimental food allergy

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• 作者：Jee-Boong Lee ; PhD^a ; Chun-Yu Chen ; PhD^a ; Bo Liu ; PhD^a ; Luke Mugge ; MSc^a ; Pornpimon Angkasekwinai ; PhD^b ; Valeria Facchinetti ; PhD^c ; Chen Dong ; PhD^c ; Yong-Jun Liu ; MD ; PhD^d ; Marc E. Rothenberg ; MD ; PhD^a ; Simon P. Hogan ; PhD^a ; Fred D. Finkelman ; MD^e ; ^f ; ^g ; Yui-Hsi Wang ; PhD^a ; ^{yui_hsi.wang@cchmc.org" class="auth_mail" title="E-mail the corresponding author}
• 关键词：IL-25 ; type 2 innate lymphoid cells ; CD4+ TH2 cells ; IL-13 ; food allergy
• 刊名：Journal of Allergy and Clinical Immunology
• 出版年：2016
• 出版时间：April 2016
• 年：2016
• 卷：137
• 期：4
• 页码：1216-1225.e5
• 全文大小：4102 K

文摘

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 T_H2 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⁺ T_H2 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⁺ T_H2 cells induced by ingested antigens enhance ILC2-derived IL-13 production, thereby promoting IgE-mediated experimental food allergy.