SARS-CoV-2 infection and recovery in children: Distinct T cell responses in MIS-C compared to COVID-19

Abstract

SARS-CoV-2 infection for most children results in mild or minimal symptoms, though in rare cases severe disease can develop, including a multisystem inflammatory syndrome (MIS-C) with myocarditis. Here, we present longitudinal profiling of immune responses during acute disease and following recovery in children who developed MIS-C, relative to children who experienced more typical symptoms of COVID-19. T cells in acute MIS-C exhibited transient signatures of activation, inflammation, and tissue residency which correlated with cardiac disease severity, while T cells in acute COVID-19 upregulated markers of follicular helper T cells for promoting antibody production. The resultant memory immune response in recovery showed increased frequencies of virus-specific memory T cells with pro-inflammatory functions in children with prior MIS-C compared to COVID-19 while both cohorts generated comparable antibody responses. Together our results reveal distinct effector and memory T cell responses in pediatric SARS-CoV-2 infection delineated by clinical syndrome, and a potential role for tissue-derived T cells in the immune pathology of systemic disease.

Antibody-mediated cellular responses are dysregulated in Multisystem Inflammatory Syndrome in Children (MIS-C)

“…Children with MIS-C exhibit a unique cytokine and chemokine profile in the plasma, with higher levels of the pro-inflammatory cytokines, consistent with previous reports of cytokines in MIS-C serum (Butters et al, 2023;Consiglio et al, 2020;Gurlevik et al, 2022;Hoste et al, 2022;Rybkina et al, 2023;Sacco et al, 2022). Interestingly, we found high amounts of IL-32 in MIS-C, suggesting that IL-32 may be a new biomarker of MIS-C.…”

“…Here, we present antibody and innate immune profiling of children who developed MIS-C compared to other control children and adults with a spectrum of COVID-19 disease severity. We found that children with MIS-C displayed a substantial neutralizing antibody response and a highly inflammatory and distinct cytokine milieu, consistent with what has been shown previously (Rybkina et al, 2023). These observations led us to the hypothesis that even though there are neutralizing antibodies, there is lingering SARS-CoV-2 infection in children with MIS-C because of a dysfunctional antibodymediated cellular response.…”

“…This enabled the comparison of Fc-mediated antibody functions across ages and clinical symptoms. We found that children with MIS-C had a neutralizing antibody response and a highly inflammatory cytokine milieu, consistent with previous studies (Consiglio et al, 2020;Gurlevik et al, 2022;Ravichandran et al, 2021;Rybkina et al, 2023;Thiriard et al, 2023). Leveraging the PBMC samples collected, we performed flow cytometric immunophenotyping and ex vivo functional assays with leukocytes expressing Fc receptors.…”

“…A key hallmark of MIS-C and severe COVID-19 in adults is the elevation of proinflammatory cytokines (Consiglio et al, 2020;Diorio et al, 2021;Rybkina et al, 2023;Szabo et al, 2021). We therefore compared cytokine and chemokine profiles as measured by multiplex analysis at the group and individual subject level (Fig.…”

“…The heatmap was drawn using R (v.4.3.0) package heatmap (v.1.0.12) and clustering was done using Euclidean distance and complete linkage Kolde, 2018). (Rybkina et al, 2023).…”