The Notch1/CD22 signaling axis disrupts Treg function in SARS-CoV-2–associated multisystem inflammatory syndrome in children
Mehdi Benamar, Qian Chen, Janet Chou, Amélie M. Julé, Rafik Boudra, Paola Contini, Elena Crestani, Peggy S. Lai, Muyun Wang, Jason Fong, Shira Rockwitz, Pui Y. Lee, Tsz Man Fion Chan, Ekin Zeynep Altun, Eda Kepenekli, Elif Karakoç-Aydıner, Ahmet Ozen, Perran Boran, Fatih Aygün, Pınar Önal, Ayşe Ayzıt Kılınç Sakallı, Haluk Çokuğraş, Metin Yusuf Gelmez, Fatma Betül Öktelik, Esin Aktaş Çetin, Yuelin Zhong, Mária Lucía Taylor, Katherine Irby, Natasha Halasa, Elizabeth H. Mack, Sara Signa, Ignazia Prigione, Marco Gattorno, Nicola Cotugno, Donato Amodio, Raif S. Geha, Mary Beth F. Son, Jane W. Newburger, Pankaj B. Agrawal, Stefano Volpi, Paolo Palma, Ayça Kıykım, Adrienne G. Randolph, Günnur Deniz, Safa Barış, Raffaele De Palma, Klaus Schmitz‐Abe, Louis‐Marie Charbonnier, Lauren A. Henderson, Talal A. Chatila
Abstract
Multisystem inflammatory syndrome in children (MIS-C) evolves in some pediatric patients following acute infection with SARS-CoV-2 by hitherto unknown mechanisms. Whereas acute-COVID-19 severity and outcomes were previously correlated with Notch4 expression on Tregs, here, we show that Tregs in MIS-C were destabilized through a Notch1-dependent mechanism. Genetic analysis revealed that patients with MIS-C had enrichment of rare deleterious variants affecting inflammation and autoimmunity pathways, including dominant-negative mutations in the Notch1 regulators NUMB and NUMBL leading to Notch1 upregulation. Notch1 signaling in Tregs induced CD22, leading to their destabilization in a mTORC1-dependent manner and to the promotion of systemic inflammation. These results identify a Notch1/CD22 signaling axis that disrupts Treg function in MIS-C and point to distinct immune checkpoints controlled by individual Treg Notch receptors that shape the inflammatory outcome in SARS-CoV-2 infection.