Open AccessA regulatory T cell Notch4–GDF15 axis licenses tissue inflammation in asthma
Author(s) -
Hani Harb,
Emmanuel Stephen-Victor,
Elena Crestani,
Mehdi Benamar,
Amir Hossein Massoud,
Ye Cui,
Louis-Marie Charbonnier,
Sena Arbag,
Safa Barış,
Amparito Cunnigham,
Juan Manuel Leyva-Castillo,
Amirhosein Mousavi,
Boris Guennewig,
Klaus SchmitzAbe,
Constantinos Sioutas,
Wanda Phipatanakul,
Talal Chatila
Publication year - 2020
Publication title -
nature immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 9.074
H-Index - 388
eISSN - 1529-2916
pISSN - 1529-2908
DOI - 10.1038/s41590-020-0777-3
Subject(s) - inflammation , immunology , wnt signaling pathway , innate lymphoid cell , biology , downregulation and upregulation , microbiology and biotechnology , allergic inflammation , interleukin 23 , immune system , innate immune system , cancer research , signal transduction , interleukin 17 , biochemistry , gene
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 (T reg ) cells is necessary for allergens and particulate matter pollutants to promote airway inflammation. Notch4 subverted T reg cells into the type 2 and type 17 helper (T H 2 and T H 17) effector T cells by Wnt and Hippo pathway-dependent mechanisms. Wnt activation induced growth and differentiation factor 15 expression in T reg 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 T reg cells of individuals with asthma as a function of disease severity, in association with reduced T reg cell-mediated suppression. Our studies thus identify Notch4-mediated immune tolerance subversion as a fundamental mechanism that licenses tissue inflammation in asthma.