The vital importance of the immune and inflammatory responses against microbial infections is underlined by the many bacterial toxins active against cells involved in body defense. Several toxins, such as mellitin and membrane-perturbing toxins and pertussis toxin, manifest their effects primarily, but not uniquely, on inflammatory and immune cells. More specific are the 22- to 28-kDa protein superantigent toxins involved in staphylococcal food poisoning and toxic shock syndromes, which are produced by different species of Streptococci and Staphylococci (1, 2). It is likely that similar protein toxins are produced by several other bacteria. These toxins share various degrees of primary structure similarities, but are structurally and functionally very similar (3). The protein molecules have two lobes: One is organized as a beta-sheet and the other as a b-barrel, with hydrophobic residues lining the inner surface of the cylinder. a-Helices are concentrated in the region connecting the two domains, with a key role played by a central long a-helix. Two major grooves are present on the opposite sides of this helix, one of them appears to be involved in binding major histocompatibility complex (MHC) class II (MHC-II) and is adjacent to the T-cell receptor (TCR) binding site.
The most relevant aspect of their superantigen toxin action appears to be the stimulation of T-cell proliferation, which has led to their general classification as superantigens . This stimulation is quite different from that of most other mittens like lectins (eg, concanavalin A). Superantigen toxins are capable of a double interaction: with MHC-II molecules and with the TCR (Fig. 1). A ternary complex forms upon antigen presentation to T-cells by an antigen-presenting cell in the presence of a superantigen toxin, which stimulates T-cell proliferation and the release of cytokines. However, at variance from normal antigens, which are processed intracellularly and presented on a groove on the MHC-II surface, superantigen toxins bind to a different site of the MHC-II molecule, with dissociation constants in the 10-5 to 10-8 M range. One group of superantigen toxins binds MHC-II molecules via an atom of Zn , which bridges three toxin histidine residues, one located on the B chain of MHC-II; other superantigen toxins bind directly to different sites on the class II molecule.
Figure 1. Stimulation of T-cell proliferation by conventional antigens (left) and bacterial superantigens (right). Both antigens are recognized only when presented to the T-cell antigen receptor (TCR) by a class II molecule of the major histocompatibility complex (MHC-II). Antigens are processed intracellularly by antigen-presenting cells (APC) and presented to the T cells as small peptides on a groove on the surface of MHC-II. In contrast, superantigens bind a different site on MHC-II, leaving the groove for peptide presentation free and functional. The normal antigen-MHC-II complex interacts with TCR using multiple contacts involving both variable (V) and constant segments of the TCR a and b chains, and this ensures stimulation of the few T cells bearing the appropriate receptor. The superantigen-MHCII complex interacts with the VB region of TCR, leading to an unspecific stimulation of a large proportion of the total T-cell population.
The MHC-II-complexed T-cell epitopes interact with the TCR via multiple contacts to both its a and B chains (Fig. 1). In contrast, the superantigen toxin interacts merely with the VB region of the TCR, whereas it interacts with the Vg region of gd-T-cell receptors. The VB region is well conserved, and it might be involved in the crucial elimination of antiself T-cells. This reduces the possibility that the host mutates its T-cell receptor to delete the superantigen-binding region.
Superantigen toxins induce an unspecific stimulation of a large proportion of the total T-cell population of the host (from 8 to 40%, depending on the type of toxin) with a massive release of cytokines, which cause a variety of pathological consequences, including fever, malaise, nausea, vomiting, and diarrhea (common symptoms of food poisoning) and systemic shock reaction. Superantigen toxins can also potentiate the effect of lipopolysaccharide endotoxins, and they may activate other cells, such as mast cells. T-cell clones amplified by superantigens often disappear, or become inactive after being stimulated, and this might lead to immune depression.
