Notch1-CD22-Dependent Immune Dysregulation in the SARS-CoV2-Associated Multisystem Inflammatory Syndrome in Children

Area of Science:

• Immunology
• Pediatric infectious diseases
• Molecular biology

Background:

• Multisystem inflammatory syndrome in children (MIS-C) is a post-SARS-CoV-2 complication with unknown mechanisms.
• Regulatory T (Treg) cell Notch4 expression correlated with acute COVID-19 severity, but MIS-C Treg cell function is altered.

Approach:

• Investigated Treg cell Notch signaling pathways in MIS-C patients.
• Performed genetic analysis to identify variants in Notch1 regulators (NUMB, NUMBL) in MIS-C patients.
• Examined the role of Notch1-induced CD22 expression and mTORC1 signaling in Treg cell destabilization.

Key Points:

• Treg cells in MIS-C patients exhibit destabilization associated with elevated Notch1 expression.
• Genetic analysis revealed deleterious variants in NUMB and NUMBL, Notch1 regulators, in MIS-C patients.
• Notch1 signaling in Treg cells upregulates CD22, leading to destabilization via mTORC1 and promoting systemic inflammation.

Conclusions:

• A novel Notch1-CD22 signaling axis disrupts Treg cell function in MIS-C.
• Distinct Treg cell Notch receptors control immune checkpoints influencing SARS-CoV-2 inflammatory outcomes.
• Identified potential therapeutic targets for managing MIS-C-associated inflammation.