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Enhanced CD95 and interleukin 18 signalling accompany T cell receptor Vβ21.3+ activation in multi-inflammatory syndrome in children.

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Multisystem inflammatory syndrome in children is a post-infectious presentation SARS-CoV-2 associated with expansion of the T cell receptor Vβ21.3+ T-cell subgroup. Here we apply muti-single cell omics to compare the inflammatory process in children with acute respiratory COVID-19 and those presenting with non SARS-CoV-2 infections in children. Here we show that in Multi-Inflammatory Syndrome in Children (MIS-C), the natural killer cell and monocyte population demonstrate heightened CD95 (Fas) and Interleuking 18 receptor expression. Additionally, TCR Vβ21.3+ CD4+ T-cells exhibit skewed differentiation towards T helper 1, 17 and regulatory T cells, with increased expression of the co-stimulation receptors ICOS, CD28 and interleukin 18 receptor. We observe no functional evidence for NLRP3 inflammasome pathway overactivation, though MIS-C monocytes show elevated active caspase 8. This, coupled with raised IL18 mRNA expression in CD16- NK cells on single cell RNA sequencing analysis, suggests interleukin 18 and CD95 signalling may trigger activation of TCR Vβ21.3+ T-cells in MIS-C, driven by increased IL-18 production from activated monocytes and CD16- Natural Killer cells.



Humans, Interleukin-18, Child, Signal Transduction, Killer Cells, Natural, fas Receptor, Monocytes, Systemic Inflammatory Response Syndrome, COVID-19, Inflammasomes, SARS-CoV-2, Adolescent, Male, Receptors, Antigen, T-Cell, alpha-beta, Female, Child, Preschool, Single-Cell Analysis, NLR Family, Pyrin Domain-Containing 3 Protein, CD4-Positive T-Lymphocytes, CD28 Antigens, Lymphocyte Activation, Receptors, Interleukin-18

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Nat Commun

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Springer Science and Business Media LLC
Action Medical Research (GN2903)
Addenbrooke's Charitable Trust (ACT) (900240)
Action Medical Research Addenbrookes Charitable Trust Gates Foundation NIHR BRC