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

While SARS-CoV-2 infection results in a mild disease course for most children, severe manifestations including respiratory failure and a Multisystem Inflammatory Syndrome in Children (MIS-C) can develop in rare cases. Here, we present a longitudinal immune profiling study of children who developed SARS-CoV-2-associated MIS-C during acute disease and following recovery, relative to children with more typical clinical manifestations of SARS-CoV-2 infection. We demonstrate distinct immune parameters associated with acute MIS-C including elevated levels of pro-inflammatory cytokines in circulation not observed in children with acute COVID-19 (non-MIS-C), aberrant expression of activation and tissue residency signatures by T cells, and expansion of T cells bearing specific TCR chains. Importantly, markers of tissue-derived T cells correlated with clinical measurements of cardiac damage suggesting key roles for T cells in the disease process. While these T cell alterations and the accompanying systemic inflammation resolved during recovery, children with prior MIS-C generated increased frequencies of functionally robust virus-specific T cells compared to children who recovered from mild disease, while both cohorts generated protective, long-lasting SARS-CoV-2-specific antibodies. Together our results reveal that the T cell response in acute MIS-C contributed to disease pathology, while also generating robust memory responses for future immune protection. Overall design: RNA-seq profiling study of children who developed SARS-CoV-2-associated MIS-C during acute disease and following recovery, relative to children with more typical clinical manifestations of SARS-CoV-2 infection.