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_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 tolerance subversion as a fundamental mechanism that licenses tissue inflammation in asthma.

SUBMITTER: Harb H 

PROVIDER: S-EPMC7578174 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature