What are Superantigens?

Certain species of infectious microorganisms produce powerful, immunostimulatory and disease-causing toxins called superantigens, so called because of their ability to polyclonally activate large fractions (2-20%) of the T-cell population cells at picomolar concentrations. They cause a number of diseases characterized by fever and shock and are virulence factors for two human commensal organisms, Staphylococcus aureus and Streptococcus pyogenes, as well as for some viruses. Their mode of action and variation around the common theme of over-stimulating T-cells provides a rich insight into the constant battle between microbes and the immune system.

In general, the potent immunostimulatory properties of superantigens are a direct result of their simultaneous interaction with the Vb domain of the T-cell receptor (TCR) and the major histocompatibility complex (MHC)class II molecules on the surface of an antigen-presenting cell.
A schematic of how antigen presentation can take place is shown below.(from http://medtech.cls.msu.edu/)

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Recent advances in knowledge of the three-dimensional structure of bacterial superantigens, and of their complexes with MHC class II molecules and the TCR beta chain, provide a framework for understanding how these potent mitogens circumvent the normal mechanism for T-cell activation by peptide/MHC and how they stimulate T-cells expressing TCR beta chains from a number of different families, resulting in polyclonal T-cell activation.

Superantigens achieve polyclonal T-cell activation by subverting the normal process of antigen presentation and T-cell activation. In healthy immune systems the two types of MHC molecule, Class I and Class II, perform a crucial role in ensuring specific T-cell activation (see Figure1). The MHC Class I and Class II molecules share several major structural features, including the two outer extracellular domains that form a long cleft. It is in this cleft that in a single peptide fragment is trapped during the synthesis and assembly of the MHC molecule, before being transported to the cell surface to be displayed to T-cells. As a consequence of the T-cell receptor binding a combined peptide:MHC ligand, T-cells manifest MHC-restricted antigen recognition, such that a given T-cell is specific for a specific peptide bound to a specific MHC molecule. MHC Class I molecules collect their (mainly viral) peptides from the cytosol and present them to cytotoxic T-cells. MHC Class II molecules bind peptides from intracellular membrane–bound vesicles – commonly derived from pathogens living in macrophage vesicles or internalised by phagocytic cells or B-cells, and present them for recognition by TH1 or TH2 cells. Upon recognition the three types of T-cells are stimulated to release a wide range of effector molecules, including the cytokines that are responsible for clonal expansion of lymphocytes. Only 0.001%-0.0001% of T-cells are activated upon normal antigen presentation.

Instead of binding in the groove of the MHC molecule, superantigens bind to the outer surface of both the MHC Class II molecule and the Vb region of the T-cell receptor, and therefore independently of the MHC-bound peptide (see Figures 2,3 and 4). Bacterial superantigens bind mainly to the Vb CDR2 loop, and to a smaller extent the Vb CDR1 loop and an additional loop called the hypervariable 4, or HV4 loop. Thus the a-chain V region and the CDR3 of the b chain of the T-cell receptor have little effect on superantigen recognition.

Superantigen recognition is determined largely by the V region of the expressed Vb gene segments, of which there are 20-50 in mice and humans; a superantigen can thus stimulate 2-20% of peripheral T-cells. This leads to a drastic skewing of the T-cell Vß repertoire. T-cells that undergo this expansion can subsequently exist in a state of anergy or undergo apoptosis. Concomitant to T-cell proliferation is a massive release of both lymphocyte-derived cytokines (interleukin [IL]-2, tumour necrosis factor ß, g-interferon) and monocyte-derived cytokines (IL-1, IL-6, tumour necrosis factor a). These proinflammatory cytokines serve as mediators of the hypotension, high fever, shock, and diffuse erythematous rash that are characteristic of toxic-shock syndrome.

Microbial superantigens are medium size proteins (Molecular weight 22-29 kDa) characterized by high resistance to proteases and to denaturation by heat. Comparison of those structures already solved indicates a conserved two-domain architecture (N- and C-terminal domains) and a long, solvent-accessible a helix spanning the centre of the molecule (Yellow in Figure 5). The N-terminal domain is characterized by the presence of hydrophobic residues in solvent-exposed regions and has considerable similarity to the oligosaccharide/oligonucleotide-binding fold (OB fold) (blue), present in other proteins of unrelated sequence where it is involved in DNA binding or carbohydrate recognition. Neither of these functions has, as yet, been attributed to superantigens. The C-terminal domain (red) comprises a four-stranded b sheet capped by the long a helix and has some structural features of the b-grasp motif found in several other proteins (e.g. the Ras-binding domain of the kinase Raf-1). A common feature of several superantigens is the presence of a highly flexible disulphide loop within the N-terminal (orange). Interestingly, this loop has been implicated in the emetic properties of these bacterial toxins.

Further research into the structure-function relationships of bacterial superantigens is vital for two reasons. Firstly to identify potential new treatments for the still-growing list of diseases in which these toxins are implicated. These already include food poisoning, toxic shock syndrome (TSS), diabetes mellitus, Kawasaki’s disease (now one of the leading causes of acquired heart disease in children), and some autoimmune conditions. A second potential benefit from studying these proteins would be to harness their T-cell proliferating abilities by using them as fusion proteins with Fab molecules, to direct T-cells against tumours expressing specific MHC class II antigens. Furthermore their ability to down-regulate the immune response following acute exposure (resulting in anergy and/or deletion of T-cells) could be exploited to eliminate populations of T-cells involved in autoimmune diseases.

A selection of superantigen images