: 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.

Benamar, M., Chen, Q., Chou, J., Julé, A.m., Boudra, R., Contini, P., et al. (2023). The Notch1/CD22 signaling axis disrupts Treg cell function in SARS-CoV2-associated multisystem inflammatory syndrome in children. THE JOURNAL OF CLINICAL INVESTIGATION, 133(1) [10.1172/JCI163235].

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

Cotugno, Nicola
Membro del Collaboration Group
;
Amodio, Donato;Palma, Paolo;
2023-10-25

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 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.
25-ott-2023
Pubblicato
Rilevanza internazionale
Articolo
Esperti anonimi
Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA
Settore MEDS-20/A - Pediatria generale e specialistica
English
Adaptive immunity
COVID-19
Immunology
T cells
Tolerance
Benamar, M., Chen, Q., Chou, J., Julé, A.m., Boudra, R., Contini, P., et al. (2023). The Notch1/CD22 signaling axis disrupts Treg cell function in SARS-CoV2-associated multisystem inflammatory syndrome in children. THE JOURNAL OF CLINICAL INVESTIGATION, 133(1) [10.1172/JCI163235].
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, Tmf; Altun, Ez; Ke...espandi
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/311190
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