IL-33 dysregulates regulatory T cells and impairs established immunologic tolerance in the lungs

Chien Chang Chen, Takao Kobayashi, Koji Iijima, Fan Chi Hsu, Hirohito Kita

Research output: Contribution to journalArticlepeer-review

59 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1351-1363.e7
JournalJournal of Allergy and Clinical Immunology
Issue number5
StatePublished - Nov 2017


  • IL-33
  • Regulatory T cells
  • T2 cells
  • allergy
  • asthma
  • lung

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


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