The Journal of Clinical Investigation (Jan 2023)
The Notch1/CD22 signaling axis disrupts Treg function in SARS-CoV-2–associated multisystem inflammatory syndrome in children
- 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
Affiliations
- 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
- Journal volume & issue
-
Vol. 133,
no. 1
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.
