Journal Article

The Notch1/CD22 signaling axis disrupts Treg function in SARS-CoV-2–associated multisystem inflammatory syndrome in children

Palma, Paolo, Aygun, Fatih, Amodio, Donato, Taylor, Maria Lucia, Lee, Pui, Cokugras, Haluk, Fong, Jason, Ozen, Ahmet, Chen, Qian, Julé, Amélie M., Deniz, Gunnur, Benamar, Mehdi, Contini, Paola, Cotugno, Nicola, Onal, Pinar, Halasa, Natasha B., Henderson, Lauren A., Son, Mary Beth, Mack, Elizabeth H., Newburger, Jane, Crestani, Elena, Boran, Perran, Karakoc-Aydiner, Elif, Baris, Safa, Chan, Tsz Man Fion, Agrawal, Pankaj B., Boudra, Rafik, Sakalli, Ayse Ayzit Kilinc, Wang, Muyun, Oktelik, Fatma Betul, Prigione, Ignazia, Irby, Katherine, Chatila, Talal A., Volpi, Stefano, Chou, Janet, Lai, Peggy S., Kepenekli, Eda, Gattorno, Marco, Rockwitz, Shira, Randolph, Adrienne G., Kiykim, Ayca, Charbonnier, Louis-Marie, Zhong, Yuelin, De Palma, Raffaele, Geha, Raif S., Altun, Ekin Zeynep, Gelmez, Metin Yusuf, Schmitz-Abe, Klaus, Cetin, Esin Aktas, Signa, Sara

2023

Overview

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.

• Publisher: American Society for Clinical Investigation
• Subject: Analysis / Autoimmunity / Biomedical research / CD22 antigen / Cellular signal transduction / Child / Children / Coronaviruses / COVID-19 / COVID-19 - genetics / Cytokines / Gene expression / Genetic analysis / Health aspects / Humans / Immune checkpoint / Immunology / Infection / Infections / Inflammation / Inflammation - genetics / Lymphocytes / Lymphocytes T / Monte Carlo simulation / Multisystem inflammatory syndrome in children / Mutation / Notch1 protein / Notch4 protein / Numbl protein / Patients / Pediatric research / Pediatrics / Physiological aspects / Pneumonia / Receptor, Notch1 - genetics / SARS-CoV-2 / Severe acute respiratory syndrome coronavirus 2 / Sialic Acid Binding Ig-like Lectin 2 / Suppressor cells / T cell receptors / T-Lymphocytes, Regulatory / Viral infections