Bibliographic Details
| Title: |
The Notch1/CD22 signaling axis disrupts Treg function in SARS-CoV-2–associated multisystem inflammatory syndrome in children |
| Authors: |
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) |
| Publisher Information: |
American Society for Clinical Investigation, 2023. |
| Publication Year: |
2023 |
| Collection: |
LCC:Medicine |
| Subject Terms: |
COVID-19, Immunology, Medicine |
| More Details: |
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. |
| Document Type: |
article |
| File Description: |
electronic resource |
| Language: |
English |
| ISSN: |
1558-8238 |
| Relation: |
https://doaj.org/toc/1558-8238 |
| DOI: |
10.1172/JCI163235 |
| Access URL: |
https://doaj.org/article/a39c807bcee64be782682857c935eead |
| Accession Number: |
edsdoj.39c807bcee64be782682857c935eead |
| Database: |
Directory of Open Access Journals |
