T Cells in Multisystem Inflammatory Syndrome in Children (MIS-C) Have a Predominant CD4+ T Helper Response to SARS-CoV-2 Peptides and Numerous Virus-Specific CD4− CD8− Double-Negative T Cells

• Published in: International journal of molecular sciences Vol. 23; no. 13; p. 7219
• Main Authors: Hsieh, Li-En, Song, Jaeyoon, Grifoni, Alba, Shimizu, Chisato, Tremoulet, Adriana H., Dummer, Kirsten B., Burns, Jane C., Sette, Alessandro, Franco, Alessandra
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 29.06.2022; MDPI
• Subjects: CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Chemokines; Child; Coronaviruses; COVID-19; COVID-19 - complications; Cytotoxicity; Disease transmission; Humans; Lymphocytes; Multisystem inflammatory syndrome in children; Pandemics; Pathogenesis; Pediatrics; Peptides; Peptides - metabolism; Proteins; SARS-CoV-2; Severe acute respiratory syndrome coronavirus 2; Systemic Inflammatory Response Syndrome; T cell receptors; Tumor necrosis factor-TNF; MIS-C; SARS-CoV-2; T cell receptor Vβ21.3; T cells; CD4− CD8− double-negative T cells
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms23137219

We studied SARS-CoV-2-specific T cell responses in 22 subacute MIS-C children enrolled in 2021 and 2022 using peptide pools derived from SARS-CoV-2 spike or nonspike proteins. CD4+ and CD8+ SARS-CoV-2-specific T cells were detected in 5 subjects, CD4+ T helper (Th) responses alone were detected in 12 subjects, and CD8+ cytotoxic T cell (CTL) responses alone were documented in 1 subject. Notably, a sizeable subpopulation of CD4− CD8− double-negative (DN) T cells out of total CD3+ T cells was observed in MIS-C (median: 14.5%; IQR 8.65–25.3) and recognized SARS-CoV-2 peptides. T cells bearing the Vβ21.3 T cell receptor (TcRs), previously reported as pathogenic in the context of MIS-C, were detected in high frequencies, namely, in 2.8% and 3.9% of the CD4+ and CD8+ T cells, respectively. However, Vβ21.3 CD8+ T cells that responded to SARS-CoV-2 peptides were detected in only a single subject, suggesting recognition of nonviral antigens in the majority of subjects. Subjects studied 6–14 months after MIS-C showed T cell epitope spreading, meaning the activation of T cells that recognize more SARS-CoV-2 peptides following the initial expansion of T cells that see immunodominant epitopes. For example, subjects that did not recognize nonspike proteins in the subacute phase of MIS-C showed good Th response to nonspike peptides, and/or CD8+ T cell responses not appreciable before arose over time and could be detected in the 6–14 months’ follow-up. The magnitude of the Th and CTL responses also increased over time. In summary, patients with MIS-C associated with acute lymphopenia, a classical feature of MIS-C, showed a physiological response to the virus with a prominent role for virus-specific DN T cells.