Notch1 signaling impairs regulatory T cells during multisystem inflammatory syndrome in children

Abstract

Multisystem inflammatory syndrome in children (MIS-C) is a rare pediatric inflammatory disorder characterized by immune cell hyperactivation, cytokine storm, and the production of autoantibodies. The mechanisms underlying such immune dysregulation still need to be unraveled. In this issue of the JCI, Benamar et al. demonstrated the critical role of the Notch receptor 1/CD22 (Notch1/CD22) axis in Tregs, which, when activated, impairs Treg functions and promotes inflammation. They showed that the Notch1/CD22 axis contributed to dysregulated immune responses in MIS-C. These findings may have implications for MIS-C and many other inflammatory diseases.

Figure 1. Immune responses are dysregulated during MIS-C.

(A) MIS-C develops in children two to five weeks after SARS-CoV-2 infection or exposure. Patients present with fever and elevated markers of inflammation associated with gastrointestinal (GI), cardiovascular, and neurological manifestations. (B) MIS-C is characterized by increased activation of neutrophils, monocytes, and NK cells. Decreased proportions of naive T cells (CD4⁺ Tconv and Tregs) and increased proportions of activated cells are also reported during MIS-C. Furthermore, TCR repertoire skewing and an expansion of TRBV11-2 T cell clonotypes, increased frequencies of plasmablasts, and the presence of autoantibodies have also been reported during MIS-C. In this issue of the JCI, Benamar et al. show that MIS-C was also associated with dysregulated Treg responses. In the presence of IL-1β and IL-6, Tregs from patients with MIS-C upregulated the expression of Notch1, CD22, and the gut-homing integrin α4β7. Activation of the Notch1/CD22 pathway in Tregs resulted in their instability, decreased Foxp3 expression, and subversion toward IFN-γ–producing effector cells, further propagating the MIS-C hyperinflammatory response. Blocking CD22 or using rapamycin, an mTORC1 inhibitor, inhibited the Notch1/CD22-triggered dysregulation of Tregs (18). CRP, C-reactive protein; LV, left ventricular; NT-proBNP, N-terminal pro-brain natriuretic peptide.