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

Zhenguang Zhang, Iain R. L. Kean, Lisa M. Dratva, John A. Clark, Eleni Syrimi, Naeem Khan, Esther Daubney, Deborah White, Lauran O’Neill, Catherine Chisholm, Caroline Payne, Sarah Benkenstein, Klaudia Kupiec, Rachel Galassini, Victoria Wright, Helen Winmill, Ceri Robbins, Katherine Brown, Padmanabhan Ramnarayan, Barnaby Scholefield, Mark Peters, Nigel Klein, Hugh Montgomery, Kerstin B. Meyer, Sarah A. Teichmann, Clare Bryant (), Graham Taylor () and Nazima Pathan ()
Additional contact information
Zhenguang Zhang: University of Cambridge
Iain R. L. Kean: University of Cambridge
Lisa M. Dratva: Wellcome Genome Campus
John A. Clark: University of Cambridge
Eleni Syrimi: University of Birmingham
Naeem Khan: University of Birmingham
Esther Daubney: Addenbrookes Hospital
Deborah White: Addenbrookes Hospital
Lauran O’Neill: Great Ormond Street Hospital
Catherine Chisholm: Great Ormond Street Hospital
Caroline Payne: Great Ormond Street Hospital
Sarah Benkenstein: Great Ormond Street Hospital
Klaudia Kupiec: Great Ormond Street Hospital
Rachel Galassini: Imperial College London
Victoria Wright: Imperial College London
Helen Winmill: Birmingham Children’s Hospital
Ceri Robbins: Birmingham Children’s Hospital
Katherine Brown: Great Ormond Street Hospital
Padmanabhan Ramnarayan: Imperial College London
Barnaby Scholefield: Birmingham Children’s Hospital
Mark Peters: Great Ormond Street Hospital
Nigel Klein: Great Ormond Street Hospital
Hugh Montgomery: University College London
Kerstin B. Meyer: Wellcome Genome Campus
Sarah A. Teichmann: Wellcome Genome Campus
Clare Bryant: University of Cambridge
Graham Taylor: University of Birmingham
Nazima Pathan: University of Cambridge

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-48699-y

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