Journal Article

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

Harb, Hani, Geha, Raif S., Crestani, Elena, Leyva-Castillo, Juan Manuel, Phipatanakul, Wanda, Chatila, Talal A., Stephen-Victor, Emmanuel, Baris, Safa, Cui, Ye, Mousavi, Amirhosein J., Benamar, Mehdi, Schmitz-Abe, Klaus, Cunnigham, Amparito, Arbag, Sena, Massoud, Amir, Charbonnier, Louis-Marie, Guennewig, Boris, Sioutas, Constantinos

2020

Overview

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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/250/2152/569/2495 / 631/250/2504/2506 / 692/699/249/2510/31 / Allergens / Allergens - immunology / Analysis of Variance / Asthma / Asthma - diagnosis / Asthma - etiology / Asthma - metabolism / Biomarkers / Biomedical and Life Sciences / Biomedicine / Care and treatment / Development and progression / Disease Susceptibility / Effector cells / Gene Expression / Genetic aspects / Genetic regulation / Growth Differentiation Factor 15 - metabolism / Health aspects / Helper cells / Hippo Signaling Pathway / Humans / Immune Tolerance / Immunological tolerance / Immunology / Immunophenotyping / Infectious Diseases / Inflammation / Interleukin 6 / Lungs / Lymphocytes T / Lymphoid cells / Particulate matter / Pollutants / Protein Serine-Threonine Kinases - metabolism / Receptor, Notch4 - metabolism / Respiratory tract diseases / Severity of Illness Index / Stat3 protein / T-Lymphocyte Subsets - immunology / T-Lymphocyte Subsets - metabolism / T-Lymphocytes, Regulatory - immunology / T-Lymphocytes, Regulatory - metabolism / Transforming growth factors / Wnt protein / Wnt Signaling Pathway