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

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

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

Description

: 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.

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

Description

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