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Master of Public Health

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

AUTHORS

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 , Kepenekli E , Karakoc-Aydiner E , Ozen A , Boran P , Aygun F , Önal P , Kilinc Sakalli AA , Cokugras H , Gelmez MY , Oktelik FB , Cetin Aktas E , Zhong Y , Taylor ML , Irby K , Halasa NB , Mack EH , Signa S , Prigione I , Gattorno M , Cotugno N , Amodio D , Geha RS , Son MB , Newburger JW , Agrawal PB , Volpi S , Palma P , Kiykim A , Randolph A , Deniz G , Baris S , De Palma R , Schmitz-Abe K , Charbonnier LM , Henderson LA , Chatila TA , . The Journal of clinical investigation. 2022 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.

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