(A) Binding of TCR (with Vβ chain sequentially identical to that of TRBV11-2 gene product) to the SAg-like region of SARS-CoV-2 spike (E661 to R685; colored yellow). The TCR α and β chains are shown in magenta and cyan, respectively. The spike subunits are colored dark red, beige, and gray, and the neurotoxin motif (299–356), green. (B and C) Overall and close-up view of the interactions between the SAg-like region and the TCR. Two basic residues, R682 and R683, on the SAg-like region of spike interact with 2 acidic residues, D67 and D68 in the Vβ domain, and D2 in the Vα domain. (D) Multiple sequence alignment (MSA) of the TCR Vβ chains distinguished by Vβ skewing in MIS-C (protein products of TRBV11-2, TRBV11-3, and TRBV24-1 with their corresponding UniProt IDs) and severe adult COVID-19 patients (protein products of TRBV24-1, TRBV14, and TRBV5-6). The MSA was generated by Clustal Omega (76). CDR1, CDR2, and CDR3 are indicated by orange shades. The regions enclosed in blue boxes indicate the highly conserved paratopes in Vβ chains corresponding to TRBV11-2 and TRBV14. See more extended MSA in Supplemental Figure 6.