A Regulatory T Cell Notch4 Switch Governs Lung Inflammation in Viral Infections

Coronavirus disease 2019 (Covid19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is associated with lung inflammation and respiratory failure. In a prospective multi-country cohort of Covid19 patients, we found that increased Notch4 expression on circulating Treg cells was associated with increased 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 suppressed the dysregulated innate immune response and rescued disease morbidity and mortality induced by a synthetic analogue of viral RNA or by the influenza H1N1 virus in an amphiregulin-dependent manner. Notably, amphiregulin production declined in Covid19 subjects as a function of disease severity and Notch4 expression. These results identify Notch4 as an immune regulatory switch that licenses virus-induced lung inflammation by altering Treg cell-mediated tissue repair. They also suggest Notch4 as a therapeutic target in Covid19 and other respiratory viral infections.