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

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.