Notch4 signaling limits regulatory T-cell-mediated tissue repair and promotes severe lung inflammation in viral infections

Hani Harb, Mehdi Benamar, Peggy S. Lai, Paola Contini, Jason W. Griffith, Elena Crestani, Klaus Schmitz-Abe, Qian Chen, Jason Fong, Luca Marri, Gilberto Filaci, Genny Del Zotto, Novalia Pishesha, Stephen Kolifrath, Achille Broggi, Sreya Ghosh, Metin Yusuf Gelmez, Fatma Betul Oktelik, Esin Aktas Cetin, Ayca KiykimMurat Kose, Ziwei Wang, Ye Cui, Xu G. Yu, Jonathan Z. Li, Lorenzo Berra, Emmanuel Stephen-Victor, Louis Marie Charbonnier, Ivan Zanoni, Hidde Ploegh, Gunnur Deniz, Raffaele De Palma, Talal A. Chatila

Research output: Contribution to journalArticlepeer-review


A cardinal feature of COVID-19 is lung inflammation and respiratory failure. In a prospective multi-country cohort of COVID-19 patients, we found that increased Notch4 expression on circulating regulatory T (Treg) cells was associated with disease severity, predicted mortality, and declined upon recovery. Deletion of Notch4 in Treg cells or therapy with anti-Notch4 antibodies in conventional and humanized mice normalized the dysregulated innate immunity and rescued disease morbidity and mortality induced by a synthetic analog of viral RNA or by influenza H1N1 virus. Mechanistically, Notch4 suppressed the induction by interleukin-18 of amphiregulin, a cytokine necessary for tissue repair. Protection by Notch4 inhibition was recapitulated by therapy with Amphiregulin and, reciprocally, abrogated by its antagonism. Amphiregulin declined in COVID-19 subjects as a function of disease severity and Notch4 expression. Thus, Notch4 expression on Treg cells dynamically restrains amphiregulin-dependent tissue repair to promote severe lung inflammation, with therapeutic implications for COVID-19 and related infections.

Original languageEnglish
Pages (from-to)1186-1199
Number of pages14
Issue number6
Publication statusPublished - Jun 8 2021


  • amphiregulin
  • COVID-19
  • IL-18
  • IL-6
  • influenza
  • Notch4
  • regulatory T cells
  • SARS-CoV-2

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases


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