Superantigens —remnants of a past process?

Superantigens (SAg) bind simultaneously to T-cell receptors (TcR) and major histocompatibility complex (MHC) class II molecules to activate up to 20% of all peripheral T cells via the TcR V beta region. Their action defines an extremely potent form of TcR triggering in which the vast amino acid diversity between TcR, MHC and foreign peptide that normally determines specificity is largely overcome in favour of a SAg/TcR V beta interaction. The findings question the need for at least the "classical" TcR/MHC class II contacts in SAg activation. We have performed mutational analyses on the bacterial superantigen staphylococcal enterotoxin A (SEA) in order to identify functional residues important to both MHC class II and TCR V beta binding. The recent publication of the crystal structure of staphylococcal enterotoxin B (SEB) has allowed the unequivocal location of these binding sites on the toxin structure, which in turn provides a spatial arrangement of the TcR and MHC class II molecule with respect to SEA. One important outcome from these studies is the suggestion that SAg employ (or induce) a different TcR/MHC class II orientation to that used in normal peptide recognition. In this article, we speculate on these findings and their evolutionary significance.