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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. Dysregulation of lung T reg cell function contributes to asthma development. Chatila and colleagues find that allergens upregulate Notch4–Hippo–Wnt signaling in T reg cells, triggering their release of GDF15 growth factor, which drives type 2 innate lymphoid cell activity and asthma.

A Correction to this paper has been published: https://doi.org/10.1038/s41590-021-00929-x.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.