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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_H2 and T_H17) 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 …