As cell signaling molecules, T-cell receptors are particularly intriguing because they initiate so many different cell-mediated processes that are dependent on a variety of factors, including the host cell expressing these molecules and co-signaling events triggered by various environmental stimuli or by other receptors expressed on the same cell. For example, antigen engagement of the T-cell receptors expressed on mature T cells typically results in activation of TH helper or TC cytotoxic effector functions along with clonal expansion of antigen-specific T-cell populations. In some situations, however, T-cell receptor engagement results in a state of clonal anergy or antigen non-responsiveness of the T-cell. In the thymus, T-cell receptors play a pivotal role in the T-lymphocyte maturation process. When the T-cell receptors on a pre-T-cell thymocyte are engaged, the thymocyte can be either positively or negatively selected depending on the balancing effects of several other factors regulating this process. As illustrated in Figure 12-5, thymocytes surviving these selection events emerge from the thymus as mature T cells.
Figure 12-5. Positive and negative selection of thymocytes in the thymus. Because of thymic selection, which involves thymic stromal cells (epithelial cells, dendritic cells, and macrophages), mature T cells are both self-MHC restricted and self-tolerant.
In addition to their normal physiological functions, T-cell receptors also play a key role in some immunopathological responses such as those driven by superantigens. Superantigens are the molecular products of microbial pathogens and these effectively over-stimulate the immune system, creating an immunological "smoke screen" that diverts the activities of immune cells away from the invading microorganism. As illustrated in Figure 12-16, superantigens have the unique capacity to crosslink MHC class II molecules on antigen presenting cells simultaneously with T-cell receptors on helper TH cells, bringing these cells together and falsely inducing their activation. By bypassing the normal steps in the antigen-specific activation of T cells, superantigens polyclonally activate sizeable populations of TH cells, exaggerating the immune response. Hyperactive immune responses induced by superantigens can result in a number of serious diseases that may even be life-threatening owing to excessive levels of tissue-damaging cytokines and immune effector cell activity. Food poisoning, as one example, is caused by bacterial superantigens, such as the Staphylococcal enterotoxin B (SEB) produced by bacteria in contaminated food. Toxic shock syndrome (TSS) is another superantigen-induced disease caused by yet another Staphylococcal toxin produced from bacteria on contaminated tampons.
Fresh insights regarding the special properties of these potent toxins have come from X-ray crystallographic analyses of superantigens complexed to MHC class II molecules, as illustrated by the image below which shows two SEB superantigen toxins of Staphylococcal aureas bound to a human MHC class II (ab)2 dimer at the center of the complex.
An
exposed surface located on top of each SEB molecule
in this image has been implicated (by mutational analysis) in T-cell
receptor binding. The T-cell receptor binding sites on the superantigen
molecules in the complex are also positioned near but not within the MHC
peptide binding pockets. Thus, a mechanism for antigen-nonspecific, T-cell
receptor crosslinking by superantigen is suggested by the fact that two SEB
molecules are vertically oriented in similar directions in thiscomplex.
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