A regulatory T cell Notch4-GDF15 axis licenses tissue inflammation in asthma

Nat Immunol. 2020 Nov;21(11):1359-1370. doi: 10.1038/s41590-020-0777-3. Epub 2020 Sep 14.


Elucidating the mechanisms that sustain asthmatic inflammation is critical for precision therapies. We found that interleukin-6- and STAT3 transcription factor-dependent upregulation of Notch4 receptor on lung tissue regulatory T (Treg) cells is necessary for allergens and particulate matter pollutants to promote airway inflammation. Notch4 subverted Treg cells into the type 2 and type 17 helper (TH2 and TH17) effector T cells by Wnt and Hippo pathway-dependent mechanisms. Wnt activation induced growth and differentiation factor 15 expression in Treg cells, which activated group 2 innate lymphoid cells to provide a feed-forward mechanism for aggravated inflammation. Notch4, Wnt and Hippo were upregulated in circulating Treg cells of individuals with asthma as a function of disease severity, in association with reduced Treg cell-mediated suppression. Our studies thus identify Notch4-mediated immune tolerance subversion as a fundamental mechanism that licenses tissue inflammation in asthma.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allergens / immunology
  • Analysis of Variance
  • Asthma / diagnosis
  • Asthma / etiology*
  • Asthma / metabolism*
  • Biomarkers
  • Disease Susceptibility
  • Gene Expression
  • Growth Differentiation Factor 15 / metabolism*
  • Humans
  • Immune Tolerance
  • Immunophenotyping
  • Protein-Serine-Threonine Kinases / metabolism
  • Receptor, Notch4 / metabolism*
  • Severity of Illness Index
  • T-Lymphocyte Subsets / immunology
  • T-Lymphocyte Subsets / metabolism
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / metabolism*
  • Wnt Signaling Pathway


  • Allergens
  • Biomarkers
  • GDF15 protein, human
  • Growth Differentiation Factor 15
  • NOTCH4 protein, human
  • Receptor, Notch4
  • Hippo protein, human
  • Protein-Serine-Threonine Kinases