Superantigen Architecture: Functional Decoration on a Conserved Scaffold

This chapter outlines the details of the core three-dimensional structure of the superantigens (SAgs) and discusses precisely what is conserved among the family along with the evolutionary reasons for conservation. It then discusses the variation that has been grafted onto the conserved structure, allowing different members of the family to bind to major histocompatibility class II molecules (MHC-II) and the T-cell receptors (TCRs) in many different configurations, with different affinities and, in the case of TCR binding, different specificities. The interactions between SAgs and their target MHC-II molecules and TCRs cover virtually all permutations of the following binding modes: MHC-II α-chain binding; MHC-II β-chain binding; TCR Vα binding and restriction; TCR Vβ binding and restriction; SAg oligomerization; MHC-II cross-linking. For the purposes of discussion these variations are loosely divide into MHC-II α-chain binding and its associated TCR interactions, MHC-II α-chain binding and its associated TCR interactions, and SAg oligomerization and MHC-II cross-linking. As secreted proteins from two highly adapted human pathogens, S. aureus and S. pyogenes, SAgs and the related staphylococcal superantigen-like proteins (SSLs) must be subject to severe immune pressure due to their potent effects. Despite their notoriety, it is likely that, for the most part, the effects of SAg and SSL secretion are relatively benign, and that only when local concentrations rise, or synergistic relationships with other factors apply, do they trigger the severe invasive disease with which they are associated.