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      IL-4 Production by Group 2 Innate Lymphoid cells Promotes Food Allergy by Blocking Regulatory T cell Function

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          Abstract

          Background

          Food allergy is a major health issue, but its pathogenesis remains obscure. Group 2 innate lymphoid cells (ILC2) promote allergic inflammation. However their role in food allergy is largely unknown.

          Objective

          We sought to investigate the role of ILC2 in food allergy.

          Methods

          Food allergy-prone mice with a gain of function mutation in the IL-4 receptor a chain ( Il4raF709) were orally sensitized with food allergens and the ILC2 compartment was analyzed. The requirement for ILC2 in food allergy was investigated using Il4raF709, IL-33 receptor deficient ( Il1rl1 −/− ), IL-13 ( Il13 −/− ) and IL-4 ( Il4 −/− ) deficient mice and by adoptive transfers of in vitro-expanded ILC2. Direct effects of ILC2 on regulatory T (Treg) cells and mast cells were analyzed in co-culture experiments. Treg cell control of ILC2 was assessed in vitro and in vivo.

          Results

          Food allergic Il4raF709 mice exhibit increased numbers of ILC2. IL-4 secretion by ILC2 contributes to the allergic response by reducing allergen-specific Treg cells and activating mast cells. IL-33 receptor deficiency in Il4raF709Il1rl1 −/− mice protects against allergen sensitization and anaphylaxis while reducing ILC2 induction. Adoptive transfer of WT and Il13 −/− but not Il4 −/− ILC2 restored sensitization in Il4raF709 Il1rl1 −/− mice. Treg cells suppress ILC2 in vitro and in vivo.

          Conclusion

          IL-4 production by IL-33-stimulated ILC2 blocks the generation of allergen-specific Treg cells and favors food allergy. Strategies to block ILC2 activation or the IL-33:IL-33R pathway may lead to innovative therapies in food allergy.

          Graphical Abstract

          Capsule summary

          IL-4 production by ILC2 plays a crucial role in enabling sensitization to food allergens.

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          Author and article information

          Journal
          1275002
          4431
          J Allergy Clin Immunol
          J. Allergy Clin. Immunol.
          The Journal of allergy and clinical immunology
          0091-6749
          1097-6825
          19 April 2016
          18 April 2016
          September 2016
          01 September 2017
          : 138
          : 3
          : 801-811.e9
          Affiliations
          [a ]Division of Immunology, Boston Children’s Hospital, Boston, MA, USA
          [b ]Department of Pediatrics, Harvard Medical School, Boston, MA, USA
          Author notes
          Corresponding Author: Talal A. Chatila at the Division of Immunology, Boston Children’s Hospital and the Department of Pediatrics, Harvard Medical School. Address: Karp Family Building, Room 10-214. 1 Blackfan Street, Boston, MA 02115, talal.chatila@ 123456childrens.harvard.edu , Phone number: 617/919-3529
          [§]

          Current address: Division of Pediatric Infectious Diseases and Immunology, Department of Pediatric, Infectious and Immunologic Diseases Research Center, Cedars-Sinai Medical Center, Los Angeles, CA

          [*]

          These authors contributed equally to this work.

          [‡]

          These authors contributed equally to this work

          Article
          PMC5014699 PMC5014699 5014699 nihpa779517
          10.1016/j.jaci.2016.02.030
          5014699
          27177780
          Categories
          Article

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