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

Immunity. 2021 Jun 8;54(6):1186-1199.e7. doi: 10.1016/j.immuni.2021.04.002. Epub 2021 Apr 28.


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.

Keywords: COVID-19; IL-18; IL-6; Notch4; SARS-CoV-2; amphiregulin; influenza; regulatory T cells.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amphiregulin / pharmacology
  • Animals
  • Biomarkers
  • Cytokines / metabolism
  • Disease Models, Animal
  • Disease Susceptibility
  • Host-Pathogen Interactions* / immunology
  • Humans
  • Immunity, Cellular*
  • Immunohistochemistry
  • Immunomodulation / drug effects
  • Inflammation Mediators / metabolism
  • Influenza A virus / physiology
  • Lung / immunology
  • Lung / metabolism
  • Lung / pathology
  • Lung / virology
  • Mice
  • Mice, Transgenic
  • Pneumonia, Viral / etiology*
  • Pneumonia, Viral / metabolism*
  • Pneumonia, Viral / pathology
  • Receptor, Notch4 / antagonists & inhibitors
  • Receptor, Notch4 / genetics
  • Receptor, Notch4 / metabolism*
  • Severity of Illness Index
  • Signal Transduction*
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / metabolism*


  • Amphiregulin
  • Biomarkers
  • Cytokines
  • Inflammation Mediators
  • Receptor, Notch4