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).
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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.
