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Papers of the Week

2022 Oct 25

J Clin Invest

The Notch1/CD22 signaling axis disrupts Treg cell function in SARS-CoV2-associated multisystem inflammatory syndrome in children.


Benamar M, Chen Q, Chou J, Julé AM, Boudra R, Contini P, Crestani E, Lai PS, Wang M, Fong J, Rockwitz S, Lee PY, Chan T M F, Altun E Z, Kepenekli E, Karakoc-Aydiner E, Ozen A, Boran P, Aygun F, Önal P, et al.
J Clin Invest. 2022 Oct 25.
PMID: 36282598.


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 outcome were previously correlated with Notch4 expression on regulatory T (Treg) cells, here we show that the Treg cells in MIS-C are destabilized through a Notch1-dependent mechanism. Genetic analysis revealed that MIS-C patients were enriched in rare deleterious variants impacting inflammation and autoimmunity pathways, including dominant-negative mutations in the Notch1 regulators NUMB and NUMBL leading to Notch1 upregulation. Notch1 signaling in Treg cells induced CD22, leading to their destabilization in a mTORC1-dependent manner and to the promotion of systemic inflammation. These results establish a Notch1-CD22 signaling axis that disrupts Treg cell function in MIS-C and point to distinct immune checkpoints controlled by individual Treg cell Notch receptors that shape the inflammatory outcome in SARS-CoV-2 infection.