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

• Published in: Nature communications Vol. 15; no. 1; p. 4227
• Main Authors: Zhang, Zhenguang, Kean, Iain R L, Dratva, Lisa M, Clark, John A, Syrimi, Eleni, Khan, Naeem, Daubney, Esther, White, Deborah, O'Neill, Lauran, Chisholm, Catherine, Payne, Caroline, Benkenstein, Sarah, Kupiec, Klaudia, Galassini, Rachel, Wright, Victoria, Winmill, Helen, Robbins, Ceri, Brown, Katherine, Ramnarayan, Padmanabhan, Scholefield, Barnaby, Peters, Mark, Klein, Nigel, Montgomery, Hugh, Meyer, Kerstin B, Teichmann, Sarah A, Bryant, Clare, Taylor, Graham, Pathan, Nazima
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 18.05.2024; Nature Publishing Group UK; Nature Portfolio
• Subjects: Adolescent; Caspase-8; CD16 antigen; CD28 antigen; CD28 Antigens - metabolism; CD4 antigen; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; CD95 antigen; Cell activation; Cell differentiation; Cells; Child; Child, Preschool; Children; COVID-19; COVID-19 - complications; COVID-19 - immunology; COVID-19 - metabolism; COVID-19 - virology; Cytokines; fas Receptor - genetics; fas Receptor - metabolism; Female; Gene expression; Gene sequencing; Humans; Immunoregulation; Inflammasomes; Inflammasomes - immunology; Inflammasomes - metabolism; Inflammation; Interleukin 18; Interleukin-18 - metabolism; Interleukins; Killer Cells, Natural - immunology; Killer Cells, Natural - metabolism; Lymphocyte Activation - immunology; Lymphocytes; Lymphocytes T; Male; Monocytes; Monocytes - immunology; Monocytes - metabolism; Multisystem inflammatory syndrome in children; Natural killer cells; NLR Family, Pyrin Domain-Containing 3 Protein - genetics; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; Receptors; Receptors, Antigen, T-Cell, alpha-beta - genetics; Receptors, Antigen, T-Cell, alpha-beta - metabolism; Receptors, Interleukin-18 - genetics; Receptors, Interleukin-18 - immunology; Receptors, Interleukin-18 - metabolism; RNA sequencing; SARS-CoV-2 - immunology; Sequence analysis; Severe acute respiratory syndrome coronavirus 2; Signal Transduction; Single-Cell Analysis; Subgroups; Systemic Inflammatory Response Syndrome - immunology; Systemic Inflammatory Response Syndrome - metabolism; T cell receptors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-48699-y

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.