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

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• 作者：Magali Noval Rivas ; PhD^a ; ^b ; ^&lowast ; ; ^§ ; ; Oliver T. Burton ; PhD^a ; ^b ; ^&lowast ; ; Hans C. Oettgen ; MD ; PhD^a ; ^b ; ^&Dagger ; ; Talal Chatila ; MD ; MSc^a ; ^b ; ^&Dagger ; ; ^{talal.chatila@childrens.harvard.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Anaphylaxis ; food allergy ; IL-4 ; IL-13 ; IL-33 ; group 2 innate lymphoid cells ; innate lymphoid cells ; nuocytes ; mast cells ; regulatory T cells ; oral tolerance
• 刊名：Journal of Allergy and Clinical Immunology
• 出版年：2016
• 出版时间：September 2016
• 年：2016
• 卷：138
• 期：3
• 页码：801-811.e9
• 全文大小：8229 K

文摘

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 using Il4raF709, IL-33 receptor–deficient (Il1rl1^−/−), IL-13–deficient (Il13^−/−), and IL-4–deficient (Il4^−/−) mice and by adoptive transfer of in 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 assessed in vitro and in vivo.

Results

Il4raF709 mice 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 in Il4raF709 Il1rl1^−/− mice protects against allergen sensitization and anaphylaxis while reducing ILC2 induction. Adoptive transfer of wild-type and Il13^−/− but not Il4^−/− ILC2s restored sensitization in Il4raF709 Il1rl1^−/− mice. Treg cells suppress ILC2s in vitro and in 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.