Multisystem Inflammatory Syndrome in Children (MIS-C) associated with 
Coronavirus Disease 2019 (COVID-19) is a newly recognized condition in which 
children with recent SARS-CoV-2 infection present with a constellation of 
symptoms including hypotension, multiorgan involvement, and elevated 
inflammatory markers. These symptoms and the associated laboratory values 
strongly resemble toxic shock syndrome, an escalation of the cytotoxic adaptive 
immune response triggered upon the binding of pathogenic superantigens to MHCII 
molecules and T cell receptors (TCRs). Here, we used structure-based 
computational models to demonstrate that the SARS-CoV-2 spike (S) exhibits a 
high-affinity motif for binding TCR, interacting closely with both the α- and 
β-chains variable domains' complementarity-determining regions. The binding 
epitope on S harbors a sequence motif unique to SARS-CoV-2 (not present in any 
other SARS coronavirus), which is highly similar in both sequence and structure 
to bacterial superantigens. Further examination revealed that this interaction 
between the virus and human T cells is strengthened in the context of a recently 
reported rare mutation (D839Y/N/E) from a European strain of SARS-CoV-2. 
Furthermore, the interfacial region includes selected residues from a motif 
shared between the SARS viruses from the 2003 and 2019 pandemics, which has 
intracellular adhesion molecule (ICAM)-like character. These data suggest that 
the SARS-CoV-2 S may act as a superantigen to drive the development of MIS-C as 
well as cytokine storm in adult COVID-19 patients, with important implications 
for the development of therapeutic approaches.