Superantigens: Just Like Peptides Only Different

T he exotoxins produced by Staphylococcus aureus and Streptococcus pyogenes are prototype molecules for the larger family of superantigens (SAGs). This family now includes many structurally unrelated molecules of disparate origins reflecting a wide evolutionary convergence towards the common goal of subverting T cell antigen recognition. SAGs bind simultaneously to MHC class II molecules and TCRs, bringing them together in such a way as to induce profound T cell activation. How SAGs, and in particular the staphylococcal enterotoxins do this, has been the subject of intense interest over the last nine years. It's the subject of an elegant paper from Leder et al. at the Center for Advanced Research at the University of Maryland published in this issue of the Journal of Experimental Medicine (1). This paper examines the thermodynamics of staphylo-coccal enterotoxin (SE) B and C3 binding to TCR and ultimately raises questions about how similar peptides and SAGs are in their engagement and triggering of T cells. Much is now known about the fine structure of the sta-phylococcal and streptococcal exotoxins. They are small, single chain proteins constructed from two globular domains. In all toxins except streptococcal pyrogenic exo-toxin C (SPEC), the variable NH 2-terminal domain contains a generic binding site for the invariant ␣ 1 domain of MHC class II. In a subset of toxins including SEA, SED, SEE, and SPEC, an additional zinc-dependent site is located in the larger more conserved COOH-terminal domain that binds to the highly polymorphic ␤ 1 domain of MHC class II. The TCR binding site is located in a shallow groove between the two toxin domains (except in toxic shock syndrome toxin [TSST] and probably also SPEC). In the paper by Leder et al. (1) the energetic contribution of individual residues within the TCR binding site of SEC3 and SEB to a soluble form of mV ␤ 8.2 TCR have been determined using a combination of sedimentation equilibrium and real-time bio-sensing techniques. A previous three-dimensional crystal structure of SEC3/V ␤ 8.2 is used as a guide to mutate all those residues that make contact with V ␤ 8.2 (2). The authors generate a thermodynamic map of the TCR site of SEC3 that shows that overall binding energy is shared fairly evenly among all residues but there are five that are clustered in the center of the binding site that make significantly more energy contributions than the others. Two residues, an asparagine …