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

Hani Harb, Emmanuel Stephen-Victor, Elena Crestani, Mehdi Benamar, Amir Massoud, Ye Cui, Louis-Marie Charbonnier, Sena Arbag, Safa Baris, Amparito Cunnigham, Juan Manuel Leyva-Castillo, Raif S Geha, Amirhosein J Mousavi, Boris Guennewig, Klaus Schmitz-Abe, Constantinos Sioutas, Wanda Phipatanakul, Talal A Chatila
Nature Immunology 2020 September 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 (TH 2 and TH 17) 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.

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