Superantigens Are Extremely Powerful Activators of T‐cells
Bacterial pyogenic toxins can activate whole families of T‐cells
The variable (V) gene sequences of the T‐cell receptors can be grouped together into a number of families as previously described for the immunoglobulin V genes. Thus there are approximately 50 functional human TCR Vβ genes which are grouped into 23 families (several of which only have one member), with some families much more highly represented in the repertoire than others. Whereas an individual peptide complexed to MHC will react with antigen‐specific T‐cells that represent a relatively small percentage of the T‐cell pool because of the requirement for specific binding of peptide to particular αβ TCR CDR3 regions, a special class of molecule has been identified that stimulates the approximately 5–20% of the total T‐cell population expressing the same TCR Vβ family structure. These molecules do this regardless of the antigen specificity of the receptor. They are referred to as superantigens and do not need to be processed by the APC, instead cross‐linking the class II and Vβ independently of direct interaction between MHC and TCR molecules (Figure 5.29).
Figure 5.29 Interaction of superantigen with MHC and TCR. (a) In this composite model, the interaction with the superantigen staphylococcal enterotoxin B (SEB) involves SEB wedging itself between the T‐cell receptor (TCR) Vβ chain and the MHC, effectively preventing interaction between the TCR and the peptide in the groove, and between the TCR β chain and the MHC. Thus direct contact between the TCR and the MHC is limited to Vα amino acid residues. Other superantigens disrupt direct TCR interactions with peptide–MHC to varying extents, and in some cases (e.g., Mycoplasma arthritidis mitogen) there is no direct contact at all between the TCR and peptide/MHC.
The pyogenic toxin superantigen family can cause food poisoning, fever, vomiting, and diarrhea and includes Staphylococcus aureus enterotoxins (SEA, SEB, and several others), staphylococcal toxic shock syndrome toxin‐1 (TSST‐1), streptococcal superantigen (SSA), and several streptococcal pyogenic exotoxins (SPEs). Although these molecules all have a similar structure, they stimulate T‐cells bearing different Vβ sequences. They are strongly mitogenic (i.e., stimulate mitosis) for these T‐cells in the presence of MHC class II‐expressing cells. SEA is one of the most potent T‐cell mitogens known, causing dramatic proliferation in the concentration range 10−13 to 10−16 M. Like the other superantigens it can cause a “cytokine storm” involving the release of excessive amounts of IL‐2, IFNγ, TNFα, TNFβ (lymphotoxin), and other cytokines, and of mast cell leukotrienes, which form the basis for its ability to produce toxic shock syndrome.
Other T‐cell superantigens
Other T‐cell superantigens, not belonging to the pyogenic toxin superantigen family, include staphylococcal exfoliative toxins (ETs), Mycoplasma arthritidis mitogen (MAM), and Yersinia pseudotuberculosis mitogen (YPM). Polyclonal activation of T‐cells can also occur in response to viral superantigens such as rabies virus nucleocapsid protein.
Microbes can also provide B‐cell superantigens
There are a number of superantigens that are capable of stimulating a substantial proportion of B-lymphocytes, For example, staphylococcal protein A reacts not only with the Fcγ region of IgG but also with the 15–50% of antibodies that utilize the VH3 family. The human immunodeficiency virus (HIV) glyco- protein gp120 also reacts with immunoglobulins that utilize VH3 family members.