A regulatory T cell Notch4–GDF15 axis licenses tissue inflammation in asthma
Authors: Elena Crestani
Ye Cui
Amparito Cunnigham
Hani Harb
Constantinos Sioutas
Talal A Chatila
Amir Massoud
Mehdi Benamar
Sena Arbag
Juan Manuel Leyva-Castillo
Klaus Schmitz-Abe
Boris Guennewig
Safa Baris
Wanda Phipatanakul
Emmanuel Stephen-Victor
Louis-Marie Charbonnier
Amirhosein J Mousavi
Raif S Geha
Journal: Nature Immunology (2020)
Discipline: IMMUNOLOGY
Keywords: asthmatic inflammation; interleukin-6; STAT3 transcription factor; Notch4 receptor; lung tissue
Affiliations: Division of Immunology, Boston Children's Hospital, Boston, MA, USA., Department of Pediatrics, Harvard Medical School, Boston, MA, USA., Division of Pediatric Allergy/Immunology, Marmara University Faculty of Medicine, Istanbul, Turkey., Department of Civil and Environmental Engineering, University of Southern California, Los Angles, CA, USA., Brain and Mind Centre, School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Camperdown, Sydney, NSW, Australia., Division of Newborn Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA., Division of Immunology, Boston Children's Hospital, Boston, MA, USA. ., Department of Pediatrics, Harvard Medical School, Boston, MA, USA. .

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 (Treg) cells is necessary for allergens and particulate matter pollutants to promote airway inflammation. Notch4 subverted Treg cells into the type 2 and type 17 helper (TH2 and TH17) effector T cells by Wnt and Hippo pathway-dependent mechanisms. Wnt activation induced growth and differentiation factor 15 expression in Treg 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 Treg cells of individuals with asthma 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. 

Retracted: No

PubPeer comments:
 Two images in Figure Extended Data Fig. 5 appear unexpectedly similar if, as I understand it, these mice are from different groups. *** ![file] ![file] , 
 Thank you for bringing my attention to this These photomicrographs have not been generated in my Laboratory I will bring it to the attention of the senior author , 
 Thank you for bringing to our attention this inadvertent error. We have worked with the editors of Nature Immunology to issue an author correction in which the photomicrographs shown in Extended Data Figure 5, panel a were replaced with new representative pictures. The correction can be accessed at the following weblink: https: www.nature.com articles s41590-021-00929-x , 
 #3 Thank you for the update and making the correction. Could the authors explain why all of the images in this figure needed to be replaced? I only saw one duplication in the original. Correction reads:  In the version of this article initially published, in Extended Data Fig. 5a, the microscopy images from the OVA-treated Foxp3YFPCre mouse and the OVA+UFP-treated Foxp3YFPCreStat3u0394 u0394 mouse were almost identical due to an inadvertent duplication. New images were taken for all of the samples in the panel to ensure all of the images are correct, and these are shown below. The data in the other figure panels are correct and are therefore unchanged. The error has been corrected in the HTML and PDF versions of the article. ![file] ,