Elucidating the mechanisms that sustain asthmatic inflammation is critical for precision therapies. We found that IL-6 and STAT3 transcription factor-dependent upregulation of Notch4 receptor on Iung tissue regulatory T (T reg ) cells is necessary for allergens and particulate matter pollutants to promote airway inflammation. Notch4 subverted T reg cells into T H 2 and T H 17 effector T (T eff ) cells by Wnt and Hippo pathway-dependent mechanisms. Wnt activation induced growth and differentiation factor 15 (GDF15) expression in T reg cells, which activated group 2 innate lymphoid cells (ILC2) to provide a feed-forward mechanism for aggravated inflammation. Notch4, Wnt and Hippo were upregulated on circulating T reg cells of asthmatics 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.

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