(A) Superantigen and conventional antigen activate T cells to expand in a polyclonal or clonal manner. Because superantigens classically activate T cells by binding to the Vβ region (blue) without interacting with the CDR3 loops (red, green, purple), the expanded polyclonal T cell population demonstrates shared Vβ usage but diversity in CDR3 sequences and lengths. In contrast, T cells activated by conventional antigens depend on interactions of the CDR3 loop with the peptide-MHC complex. Thus, T cells expanded by conventional antigens demonstrate clonal expansion with shared CDR3 loops as well as Vβ usage. The findings in Porritt, Paschold, et al. (9) suggest that superantigens drive T cell expansion in MIS-C. (B) The two-hit model for MIS-C posits that the first hit occurs from nonspecific superantigen activation of a polyclonal T cell population by SARS-CoV-2. The second hit occurs following infection with a second virus, leading to robust reactivation of a previously expanded T cell subgroup from the first hit. This subgroup of T cells may also cross-react with self-antigens, leading to tissue injury.