| Autor: |
Talal A. Chatila, Mehdi Benamar, Qian Chen, Janet Chou, Amelie Julé, Rafik Boudra, Paola Contini, Elena Crestani, Muyun Wang, Jason Fong, Peggy Lai, 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 Gelmez, Fatma Öktelik, Esin Aktaş Cetin, Yuelin Zhong, Maria Taylor, Katherine Irby, Natasha Halasa, Sara Signa, Ignazia Prigione, Marco Gattorno, Nicola Cotugno, Donato Amodio, Raif Geha, Mary Beth Son, Jane Newburger, Pankaj Agrawal, Stefano Volpi, Paolo Palma, Ayca Kiykim, Adrienne Randolph, Gunnur Deniz, Safa Baris, Raffaele De Palma, Klaus Schmitz-Abe, Louis-Marie Charbonnier, Lauren Henderson |
| Rok vydání: |
2022 |
| Předmět: |
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| Zdroj: |
Research square. |
| Popis: |
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 in association with increased Notch1 expression. Genetic analysis revealed that MIS-C patients were enriched in rare deleterious variant impacting inflammation and autoimmunity pathways, including dominant negative mutations in the Notch1 regulators NUMB and NUMBL. Notch1 signaling in Treg cells induced CD22, leading to their destabilization in an 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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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