Multimodal analysis reveals polyclonality and inflammatory programs specific to TRBV11-2+ CD4 T cells in MIS-C

Multisystem inflammatory syndrome in children (MIS-C) is a life-threatening condition presenting with multi-organ dysfunction, whose presentation shares features of other inflammatory syndromes. Expansion of TRBV11-2+ T cells has been suggested to distinguish MIS-C, but mechanisms underlying this phenomenon remain unclear. Contrasting models posit that TRBV11-2+ T cell activation is driven by peptide antigen-specific versus superantigen-induced mechanisms. However, systematic evaluation of these hypotheses has been limited without molecular insight into the relationship between T cell clonality and gene expression states in MIS-C. Here, we present a unique single-cell dataset capturing integrated expression of TCR genes, surface epitopes, and transcriptomes from peripheral blood mononuclear cells of children with MIS-C versus clinically severe COVID-19, mild COVID-19, and healthy controls. Multimodal analyses resolved a proliferative and Th1-polarized CD4 T cell subset in MIS-C with profound TRBV11-2 skewing and polyclonality, both hallmark features of superantigen-mediated expansion. Moreover, known superantigen-induced transcriptional programs were enriched in TRBV11-2+ CD4 T cells from MIS-C patients, but not TRBV11-2− cells nor COVID-19 patients. Together, these data are consistent with nonspecific expansion of TRBV11-2+ and Th1-polarized CD4 T cells in MIS-C. Our findings demonstrate the power of integrated single-cell profiling to resolve pathways of T cell activation in pediatric inflammatory diseases.