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Updated: Aug 24, 2025

Stimulation of Notch Signaling in Mouse Osteoclast Precursors
Published on: February 28, 2017
The Notch1/CD22 signaling axis disrupts Treg function in SARS-CoV-2-associated multisystem inflammatory syndrome in
Mehdi Benamar1,2, Qian Chen1,2, Janet Chou1,2
1Division of Immunology, Boston Children's Hospital, Boston, Massachusetts, USA.
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.
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