학술논문
The Notch1/CD22 signaling axis disrupts Treg function in SARS-CoV-2–associated multisystem inflammatory syndrome in children
Document Type
article
Author
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 Lee; Tsz Man Fion Chan; Ekin Zeynep Altun; Eda Kepenekli; Elif Karakoc-Aydiner; Ahmet Ozen; Perran Boran; Fatih Aygun; Pinar Onal; Ayse Ayzit Kilinc Sakalli; Haluk Cokugras; Metin Yusuf Gelmez; Fatma Betul Oktelik; Esin Aktas Cetin; Yuelin Zhong; Maria Lucia Taylor; Katherine Irby; Natasha B. Halasa; Elizabeth H. Mack; Overcoming COVID-19 Investigators; Sara Signa; Ignazia Prigione; Marco Gattorno; Nicola Cotugno; Donato Amodio; Raif S. Geha; Mary Beth Son; Jane Newburger; Pankaj B. Agrawal; Stefano Volpi; Paolo Palma; Ayca Kiykim; Adrienne G. Randolph; Gunnur Deniz; Safa Baris; Raffaele De Palma; Klaus Schmitz-Abe; Louis-Marie Charbonnier; Lauren A. Henderson; Talal A. Chatila
Source
The Journal of Clinical Investigation, Vol 133, Iss 1 (2023)
Subject
Language
English
ISSN
1558-8238
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.