A Treg 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-dependent upregulation of Notch4 on Iung tissue regulatory T (Treg) cells is necessary for allergens and particulate matter pollutants to promote airway inflammation. Notch4 subverted Treg cells into TH2 and TH17 effector T (Teff) cells by Wnt and Hippo pathway-dependent mechanisms. Wnt activation induced GDF15 expression in Treg 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 Treg cells of asthmatics 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. The mice were sensitized twice at days 0 and 14 with OVA i.p. The mice were then challenged with OVA+UFP on days 27, 28 and 29. There is two groups, the Foxp3YFPCre mice vs. Foxp3YFPCrexNotch4fl/fl group. The mice were sacked and the lungs were digested to sort the cells out for analysis.