Superantigens (SAgs) are a class of bacterial or viral proteins that aberrantly alter immune system function through simultaneous interaction with lateral surfaces of major histocompatibility (MHC) class II molecules on antigen presenting cells, and to particular variable regions of the T-cell antigen receptor (TCR) β-chain. Among the secreted virulence factors from group A streptococci are the streptococcal pyrogenic exotoxins (SPEs), also commonly known as erythrogenic toxins or scarlet fever toxins. Together with the enterotoxins and toxic shock syndrome toxin-1 (TSST-1) from Staphylococcus aureus , the SPEs belong to a larger family of related exotoxins collectively known as the “pyrogenic toxin” class of superantigens, which share functional activities, similar amino acid sequences, and conserved three-dimensional structures (1 ,2 ). Due to their notable association with scarlet fever and streptococcal toxic shock syndrome (TSS), SPE A (3 ,4 ) and SPE C (5 ) are generally considered to be the prototypical streptococcal superantigens.