Why do superantigens care about peptides?

Superantigen (SAg)-mediated activation of T cells is enhanced by the ability of the SAg to bind to major histocompatibility complex (MHC) class II molecules outside the peptide-binding groove, thereby bypassing the normal constraints of MHC restriction. However, recent studies have shown that SAg binding is acutely sensitive to the MHC class II-associated peptide. Here, David Woodland, Renren Wen and Marcia Blackman argue that this feature has evolved to optimize T-cell responses by more closely mimicking conventional antigen recognition.