title: 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.
  
  
  CONCLUSIONS
  IL-25 and CD4(+) TH2 cells induced by ingested antigens enhance ILC2-derived IL-13 production, thereby promoting IgE-mediated experimental food allergy.
authors.affiliation: Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Jee-Boong
authors.initials: JB
authors.lastname: Lee
authors.affiliation: Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Chun-Yu
authors.initials: CY
authors.lastname: Chen
authors.affiliation: Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Bo
authors.initials: B
authors.lastname: Liu
authors.affiliation: Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Luke
authors.initials: L
authors.lastname: Mugge
authors.affiliation: Department of Medical Technology, Faculty of Allied Health Sciences, Thammasat University, Bangkok, Thailand.
authors.forename: Pornpimon
authors.initials: P
authors.lastname: Angkasekwinai
authors.affiliation: Department of Immunology, University of Texas and MD Anderson Cancer Center, Houston, Tex.
authors.forename: Valeria
authors.initials: V
authors.lastname: Facchinetti
authors.affiliation: Department of Immunology, University of Texas and MD Anderson Cancer Center, Houston, Tex.
authors.forename: Chen
authors.initials: C
authors.lastname: Dong
authors.affiliation: Medimmune, Gaithersburg, Md.
authors.forename: Yong-Jun
authors.initials: YJ
authors.lastname: Liu
authors.affiliation: Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Marc E
authors.initials: ME
authors.lastname: Rothenberg
authors.affiliation: Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Simon P
authors.initials: SP
authors.lastname: Hogan
authors.affiliation: Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Medicine, Cincinnati Veterans Affairs Medical Center, Cincinnati, Ohio; Division of Immunology, Allergy and Rheumatology, University of Cincinnati College of Medicine, Cincinnati, Ohio.
authors.forename: Fred D
authors.initials: FD
authors.lastname: Finkelman
authors.affiliation: Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. Electronic address: yui_hsi.wang@cchmc.org.
authors.forename: Yui-Hsi
authors.initials: YH
authors.lastname: Wang
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D021181:Egg Hypersensitivity / Q000276:immunology*; D007073:Immunoglobulin E / Q000276:immunology*; D018793:Interleukin-13 / Q000276:immunology*; D007378:Interleukins / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology*
chemical_list: D015415:Biomarkers; D018793:Interleukin-13; D007378:Interleukins; C442281:Mydgf protein, mouse; D007073:Immunoglobulin E; D010047:Ovalbumin
keywords: CD4(+) T(H)2 cells; IL-13; IL-25; food allergy; type 2 innate lymphoid cells