title: IL-33 dysregulates regulatory T cells and impairs established immunologic tolerance in the lungs.
abstract: BACKGROUND
  Airway exposure to environmental antigens generally leads to immunologic tolerance. A fundamental question remains: Why is airway tolerance compromised in patients with allergic airway diseases? IL-33 promotes innate and adaptive type 2 immunity and might provide the answer to this question.
  
  
  OBJECTIVE
  The goal of this study was to investigate the roles played by IL-33 in altering regulatory T (Treg) cells in the lungs and in affecting previously established airway immunologic tolerance.
  
  
  METHODS
  We analyzed CD4+forkhead box P3 (Foxp3)+Treg cells that were isolated from the lungs of naive BALB/c mice and those treated with IL-33. Airway tolerance and allergen-induced airway inflammation models in mice were used to investigate how IL-33 affects established immunologic tolerance in vivo.
  
  
  RESULTS
  CD4+Foxp3+Treg cells in the lungs expressed the IL-33 receptor ST2. When exposed to IL-33, Treg cells upregulated their expression of the canonical TH2 transcription factor GATA3, as well as ST2, and produced type 2 cytokines. Treg cells lost their ability to suppress effector T cells in the presence of IL-33. Airway administration of IL-33 with an antigen impaired immunologic tolerance in the lungs that had been established by prior exposure to the antigen. Dysregulated Foxp3+Treg cells with distinct characteristics of TH2 cells increased in the lungs of mice undergoing IL-33-dependent allergen-driven airway inflammation.
  
  
  CONCLUSIONS
  IL-33 dysregulated lung Treg cells and impaired immunologic tolerance to inhaled antigens. Established airway tolerance might not be sustained in the presence of an innate immunologic stimulus, such as IL-33.
authors.affiliation: Department of Immunology, Mayo Clinic Rochester, Minn.
authors.forename: Chien-Chang
authors.initials: CC
authors.lastname: Chen
authors.affiliation: Department of Medicine, Mayo Clinic Rochester, Minn.
authors.forename: Takao
authors.initials: T
authors.lastname: Kobayashi
authors.affiliation: Department of Medicine, Mayo Clinic Rochester, Minn.
authors.forename: Koji
authors.initials: K
authors.lastname: Iijima
authors.affiliation: Department of Immunology, Mayo Clinic Rochester, Minn.
authors.forename: Fan-Chi
authors.initials: FC
authors.lastname: Hsu
authors.affiliation: Department of Immunology, Mayo Clinic Rochester, Minn; Department of Medicine, Mayo Clinic Rochester, Minn. Electronic address: kita.hirohito@mayo.edu.
authors.forename: Hirohito
authors.initials: H
authors.lastname: Kita
mesh_terms: D056704:Adaptive Immunity; D000485:Allergens / Q000276:immunology; D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006801:Humans; D006967:Hypersensitivity / Q000276:immunology*; D007108:Immune Tolerance; D007113:Immunity, Innate; D000072179:Interleukin-1 Receptor-Like 1 Protein / Q000235:genetics; D000067596:Interleukin-33 / Q000378:metabolism*; D008168:Lung / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology*
chemical_list: D000485:Allergens; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C486189:Il1rl1 protein, mouse; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33
keywords: IL-33; Regulatory T cells; T(H)2 cells; allergy; asthma; lung