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

J Allergy Clin Immunol. 2016 Sep;138(3):801-811.e9. doi: 10.1016/j.jaci.2016.02.030. Epub 2016 Apr 18.

Abstract

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 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.

Keywords: Anaphylaxis; IL-13; IL-33; IL-4; food allergy; group 2 innate lymphoid cells; innate lymphoid cells; mast cells; nuocytes; oral tolerance; regulatory T cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Coculture Techniques
  • Food Hypersensitivity / immunology*
  • Immunity, Innate
  • Interleukin-4 / genetics
  • Interleukin-4 / immunology*
  • Lymphocytes / immunology*
  • Mast Cells / immunology*
  • Mice, Transgenic

Substances

  • Interleukin-4