TIM3+ TRBV11-2 T cells and IFNγ signature in patrolling monocytes and CD16+ NK cells delineate MIS-C

In rare instances, pediatric SARS-CoV-2 infection results in a novel immunodysregulation syndrome termed multisystem inflammatory syndrome in children (MIS-C). We compared MIS-C immunopathology with severe COVID-19 in adults. MIS-C does not result in pneumocyte damage but is associated with vascular endotheliitis and gastrointestinal epithelial injury. In MIS-C, the cytokine release syndrome is characterized by IFN gamma and not type I interferon. Persistence of patrolling monocytes differentiates MIS-C from severe COVID-19, which is dominated by HLA-DRlo classical monocytes. IFN gamma levels correlate with granzyme B production in CD16(+) NK cells and TIM3 expression on CD38(+)/HLA-DR+ T cells. Single-cell TCR profiling reveals a skewed TCR beta repertoire enriched for TRBV11-2 and a superantigenic signature in TIM3(+)/CD38(+)/HLA-DR+ T cells. Using NicheNet, we confirm IFN gamma as a central cytokine in the communication between TIM3(+)/CD38(+)/HLA-DR+ T cells, CD16(+) NK cells, and patrolling monocytes. Normalization of IFN gamma, loss of TIM3, quiescence of CD16(+) NK cells, and contraction of patrolling monocytes upon clinical resolution highlight their potential role in MIS-C immunopathogenesis. MIS-C is a novel immunodysregulation syndrome in children with a history of SARS-CoV-2 infection. This study employs a multi-omics approach to explore its immunopathogenesis. The authors show that IFN gamma-mediated interactions between T cells, monocytes, and NK cells reside at the heart of the disease