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

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

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.