Mls proteins act as superantigens because they have a distinctive mode of binding to both MHC and T-cell receptor molecules that enables them to stimulate very large numbers of T cells. Superantigens are unlike other protein antigens, in that they are recognized by T cells without being processed into peptides that are captured by MHC molecules. Indeed, fragmentation of a superantigen destroys its biological activity, which depends on binding as an intact protein to the outside surface of an MHC class II molecule that has already bound peptide. In addition to binding MHC class II molecules, superantigens are able to bind the Vβ region of many T-cell receptors (Fig. 6.25). Bacterial superantigens bind mainly to the Vβ CDR2 loop, and, to a smaller extent, to the Vβ CDR1 loop and an additional loop called the hypervariable 4 or HV4 loop. The HV4 loop is the predominant binding site for viral superantigens, at least for the Mls antigens encoded by the endogenous mouse mammary tumor viruses.
Fig. 6.25 Superantigens bind directly to T-cell receptors and to MHC molecules.
Superantigens can bind independently to MHC class II molecules and to T-cell receptors. As shown in the top panels, the superantigens (red bars) can bind to the Vβ domain of the T-cell receptor (TCR), away from the complementarity-determining regions, and to the outer faces of the MHC class II molecule, outside the peptide-binding site. In the bottom panel, a reconstruction of the interaction between a T-cell receptor, an MHC class II molecule, and a staphylococcal enterotoxin (SE) superantigen is shown by superimposing separate structures of an enterotoxin:MHC class II complex onto an enterotoxin:T-cell receptor complex. The two enterotoxin molecules (actually SEC3 and SEB) are shown in turquoise and blue, binding to the α chain of the MHC class II molecule (yellow) and to the β chain of the T-cell receptor (colored gray for the Vβ domain and pink for the Cβ domain). Molecular model courtesy of
H.M. Li, B.A. Fields, and R.A. Mariuzza.
Thus, the α-chain V region and the CDR3 of the β chain of the T-cell receptor have little effect on superantigen recognition, which is determined largely by the germline-encoded V gene segments that encode the expressed Vβ chain. Each superantigen is specific for one or a few of the different Vβ gene products, of which there are 20–50 in mice and humans; a superantigen can thus stimulate 2–20% of all T cells.
This mode of stimulation does not prime an adaptive immune response specific for the pathogen. Instead, it causes a massive production of cytokines by CD4 T cells, the predominant responding population of T cells. These cytokines have two effects on the host: systemic toxicity and suppression of the adaptive immune response. Both these effects contribute to microbial pathogenicity. Among the bacterial superantigens are the staphylococcal enterotoxins (SEs), which cause food poisoning, and the toxic shock syndrome toxin-1 (TSST-1) of Staphylococcus aureus, the etiologic principle in toxic shock syndrome, which can be caused by a localized infection with toxin-producing strains of the bacterium. The role of viral superantigens in human disease is less clear.
6-15 MHC polymorphism extends the range of antigens to which the immune system can respond.