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Enhanced CD95 and interleukin 18 signalling accompany T cell receptor Vβ21.3+ activation in multi-inflammatory
Zhenguang Zhang1, Iain R L Kean1, Lisa M Dratva2
1Departments of Paediatrics, University of Cambridge, Cambridge, UK.
Insights
Multisystem inflammatory syndrome in children (MIS-C) involves specific T-cell changes. Interleukin-18 and CD95 signaling, driven by monocytes and natural killer cells, may activate T cells in MIS-C.
Area of Science:
- Immunology
- Pediatrics
- Virology
Background:
- Multisystem inflammatory syndrome in children (MIS-C) is a post-infectious condition linked to SARS-CoV-2.
- It is characterized by an expansion of the T cell receptor Vβ21.3+ T-cell subgroup.
Purpose of the Study:
- To compare the inflammatory processes in children with acute COVID-19 versus MIS-C.
- To investigate the specific immune cell populations and signaling pathways involved in MIS-C.
Main Methods:
- Multi-single cell omics techniques were employed.
- Comparative analysis of immune cells from children with COVID-19 and MIS-C.
Main Results:
- In MIS-C, natural killer cells and monocytes showed increased CD95 (Fas) and Interleukin-18 receptor expression.
- TCR Vβ21.3+ CD4+ T-cells displayed skewed differentiation and increased co-stimulation receptor expression (ICOS, CD28, IL-18 receptor).
- Elevated active caspase 8 in MIS-C monocytes and increased IL18 mRNA in CD16- NK cells were observed, without NLRP3 inflammasome overactivation.
Conclusions:
- Interleukin-18 and CD95 signaling may activate TCR Vβ21.3+ T-cells in MIS-C.
- This activation appears to be driven by increased IL-18 production from monocytes and CD16- Natural Killer cells.
Abstract:
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.
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