SARS-CoV-2 as a superantigen in multisystem inflammatory syndrome in children

Abstract

Multisystem inflammatory syndrome in children (MIS-C) is a rare but deadly new disease in children that rapidly progresses to hyperinflammation and shock, and can lead to multiple organ failure if unrecognized. It has been found to be temporally associated with the COVID-19 pandemic and is often associated with SARS-CoV-2 exposure in children. In this issue of the JCI, Porritt, Paschold, et al. identify restricted T cell receptor (TCR) β-chain variable domain (Vβ) usage in patients with severe MIS-C, indicating a potential role for SARS-CoV-2 as a superantigen. These findings suggest that a blood test that determines the presence of specific TCRβ variable gene (TRBV) segments may identify patients at risk for severe MIS-C.

Figure 1. Potential mechanisms for T cell activation in MIS-C.

(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.