Amphiregulin-Producing Pathogenic Memory T Helper 2 Cells Instruct Eosinophils to Secrete Osteopontin and Facilitate Airway Fibrosis

Immunity. 2018 Jul 17;49(1):134-150.e6. doi: 10.1016/j.immuni.2018.04.023. Epub 2018 Jun 26.


Memory T cells provide long-lasting protective immunity, and distinct subpopulations of memory T cells drive chronic inflammatory diseases such as asthma. Asthma is a chronic allergic inflammatory disease with airway remodeling including fibrotic changes. The immunological mechanisms that induce airway fibrotic changes remain unknown. We found that interleukin-33 (IL-33) enhanced amphiregulin production by the IL-33 receptor, ST2hi memory T helper 2 (Th2) cells. Amphiregulin-epidermal growth factor receptor (EGFR)-mediated signaling directly reprogramed eosinophils to an inflammatory state with enhanced production of osteopontin, a key profibrotic immunomodulatory protein. IL-5-producing memory Th2 cells and amphiregulin-producing memory Th2 cells appeared to cooperate to establish lung fibrosis. The analysis of polyps from patients with eosinophilic chronic rhinosinusitis revealed fibrosis with accumulation of amphiregulin-producing CRTH2hiCD161hiCD45RO+CD4+ Th2 cells and osteopontin-producing eosinophils. Thus, the IL-33-amphiregulin-osteopontin axis directs fibrotic responses in eosinophilic airway inflammation and is a potential target for the treatment of fibrosis induced by chronic allergic disorders.

Keywords: ECRS; EGFR; IL-33; airway fibrosis; amphiregulin; eosinophil; osteopontin; pathogenic memory Th2 cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amphiregulin / biosynthesis
  • Amphiregulin / immunology*
  • Amphiregulin / metabolism
  • Amphiregulin / pharmacology
  • Animals
  • Disease Models, Animal
  • Eosinophils / immunology*
  • ErbB Receptors / metabolism
  • Female
  • Immunologic Memory / immunology
  • Immunomodulation
  • Interleukin-33 / metabolism
  • Mice
  • Osteopontin / metabolism*
  • Pulmonary Fibrosis / immunology*
  • Rhinitis / immunology
  • Rhinitis / pathology
  • Signal Transduction / immunology*
  • Sinusitis / immunology
  • Sinusitis / pathology
  • Th2 Cells / immunology*
  • Transcription, Genetic / drug effects


  • Amphiregulin
  • Areg protein, mouse
  • Il33 protein, mouse
  • Interleukin-33
  • Spp1 protein, mouse
  • Osteopontin
  • EGFR protein, mouse
  • ErbB Receptors