We now know that MHC restriction is due to the fact that the binding specificity of an individual T-cell receptor is not for its peptide antigen alone but for the complex of peptide and MHC molecule, as discussed in Section 4-17. MHC restriction is explained in part by the fact that different MHC molecules bind different peptides. In addition, some of the polymorphic amino acids in MHC molecules are located in the α helices that flank the peptide-binding groove but have side chains oriented toward the exposed surface of the peptide:MHC complex that can directly contact the T-cell receptor (see Figs. 6.21 and 4.24). In retrospect, it is therefore not surprising that T cells can distinguish between a peptide bound to MHCa and the same peptide bound to MHCb. This restricted recognition may sometimes be caused both by differences in the conformation of the bound peptide imposed by the different MHC molecules and by direct recognition of polymorphic amino acids in the MHC molecule itself. Thus, the specificity of a T-cell receptor is defined both by the peptide it recognizes and by the MHC molecule bound to it (Fig. 6.23).
6-13 Alloreactive T cells recognizing nonself MHC molecules are very abundant.
The discovery of MHC restriction also helped to explain the otherwise puzzling phenomenon of recognition of nonself MHC in the rejection of organs and tissues transplanted between members of the same species. Transplanted organs from donors bearing MHC molecules that differ from those of the recipient—even by as little as one amino acid—are rapidly rejected owing to the presence in any individual of large numbers of T cells that react to nonself, or allogeneic, MHC molecules. Early studies on T-cell responses to allogeneic MHC molecules used the mixed lymphocyte reaction, in which T cells from one individual are mixed with lymphocytes from a second individual. If the T cells of this individual recognize the other individual’s MHC molecules as ‘foreign,’ the T cells will divide and proliferate. The lymphocytes from the second individual are usually prevented from dividing by irradiation or treatment with the cytostatic drug mitomycin C. Such studies have shown that roughly 1–10% of all T cells in an individual will respond to stimulation by cells from another, unrelated, member of the same species. This type of T-cell response is called an alloreaction or alloreactivity, because it represents the recognition of allelic polymorphisms in MHC molecules.
Before the role of the MHC molecules in antigen presentation was understood, it was a mystery why so many T cells should recognize nonself MHC molecules, as there is no reason that the immune system should have evolved a defense against tissue transplants. Once it was realized that T-cell receptors have evolved to recognize foreign peptides in combination with polymorphic MHC molecules, alloreactivity became easier to explain. We now know of at least two processes that can contribute to the high frequency of alloreactive T cells. The first is the process of positive selection. When developing in the thymus, T cells whose T-cell receptors interact weakly with the self MHC molecules receive survival signals, and so are favored for representation in the peripheral repertoire. It is thought that T-cell receptors that interact with one type of MHC molecule are more likely to cross-react with other (nonself ) MHC variants. We discuss positive selection in greater detail in Chapter 8.