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

Abstract

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.