(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.