Clinical resolution is associated with recovery of type II IFN signature and contraction of CD16+ monocytes and TIM3+ T cells. (A) Bar chart depicting ratios of routine laboratory values, serum proteins, and UMAP cell populations measured at sampling time points T2 and T1. Ratios were calculated from normalized values (fold changes to the median of HCs). Bars are ordered on the median and represent the top 25 most negative (blue) and top 10 most positive (red) differences, with whiskers denoting the range. Significant differences between T2 and T1 were calculated by Wilcoxon matched-pairs signed-rank test, indicated by *, P < 0.05; **, P < 0.01; ***, P < 0.001; and ****, P < 0.0001. (B) Heatmap separated by condition (T1 and T2) displaying hierarchical clustered normalized biomarkers (cytokines and tissue marker fold change relative to median of HCs) for individual MIS-C patients. CS, corticosteroids. (C) Dot plot showing type I and type II IFN and downstream chemokines (CXCL9 and CXCL10) concentrations from patients collected at sampling time points T2 and T1. (D) Principal component (PC) analysis of all UMAP clusters (B, T/NK, innate cells), identified by flow cytometry. (E) UMAP representation of innate leukocytes (within PBMCs) with density plots stratified per time point of sampling in MIS-C (n = 9 on T1 and n = 10 on T2). Numbers show percentage of clusters of interest. (F) Evolution of the proportions of innate UMAP clusters by pairing samples from identical patients on both time points. (G) UMAP representation of T lymphocytes, NK cells, and iNKT/MAIT cells (within PBMCs) and density plots for both time points of sampling in MIS-C, similar to E. (H and I) Evolution of the proportions of T lymphocytes as determined by manual gating of FCM data, pairing samples from identical patients on both time points. Significances between T2 and T1 were calculated by Wilcoxon matched-pairs signed-rank test, indicated by *, P < 0.05; **, P < 0.01; and ***, P < 0.001. Values for individual patients are displayed with MIS-C (red), severe adult COVID-19 (orange), and age-matched HCs (blue). Distinct symbols depict patients with severe MIS-C with (inverted triangle) or without treatment (triangle) and moderate disease (circle).