TLR3-driven IFN-β antagonizes STAT5-activating cytokines and suppresses innate type 2 response in the lung

Rinna Tei, Koji Iijima, Koji Matsumoto, Takao Kobayashi, Jyoti Lama, Elizabeth A. Jacobsen, Hirohito Kita

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Group 2 innate lymphoid cells (ILC2s) are involved in type 2 immune responses in mucosal organs and are associated with various allergic diseases in humans. Studies are needed to understand the molecules and pathways that control ILC2s. Objective: The aims of this study were to develop a mouse model that limits the innate type 2 immune response in the lung and to investigate the immunologic mechanisms involved in regulation of lung ILC2s. Methods: Naive BALB/c mice were administered various Toll-like receptor agonists and exposed intranasally to the fungal allergen Alternaria alternata. The mechanisms were investigated using gene knockout mice as well as cultures of lung cells and isolated lung ILC2s. Results: Polyinosinic–polycytidylic acid, or poly (I:C), effectively inhibited innate type 2 response to A alternata. Poly (I:C) promoted production of IFNα, -β, and -γ, and its inhibitory effects were dependent on the IFN-α/β receptor pathway. IFN-β was 100 times more potent than IFN-α at inhibiting type 2 cytokine production by lung ILC2s. Signal transducer and activator of transcription 5 (STAT5)-activating cytokines, including IL-2, IL-7, and thymic stromal lymphopoietin, but not IL-33, promoted survival and proliferation of lung ILC2s in vitro, while IFN-β blocked these effects. Expression of the transcription factor GATA3, which is critical for differentiation and maintenance of ILC2s, was inhibited by IFN-β. Conclusions: IFN-β blocks the effects of STAT5-activating cytokines on lung ILC2s and inhibits their survival and effector functions. Administration of IFN-β may provide a new strategy to treat diseases involving ILC2s.

Original languageEnglish (US)
JournalJournal of Allergy and Clinical Immunology
DOIs
StateAccepted/In press - 2021

Keywords

  • Group 2 innate lymphoid cell
  • IFN-β
  • IL-13
  • IL-33
  • IL-5
  • IL-7
  • lung
  • poly (I:C)
  • TSLP

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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