T-cell receptor and MHC molecule.
The next few sections describe how MHC polymorphisms benefit the immune response and how pathogen-driven selection can account for the large number of MHC alleles. The products of individual MHC alleles, often known as protein isoforms, can differ from one another by up to 20 amino acids, making each variant protein quite distinct. Most of the differences are localized to exposed surfaces of the extracellular domain furthest from the membrane, and to the peptide-binding groove in particular (Fig. 6.21). We have seen that peptides bind to MHC class I and class II molecules through the interaction of specific anchor residues with peptide-binding pockets in the peptide-binding groove (see Sections 4-15 and 4-16). Many of the polymorphisms in MHC molecules alter the amino acids that line these pockets and thus change
Fig. 6.20 Gene conversion can create new alleles by copying sequences from one MHC gene to another. Multiple MHC genes of generally similar structure were derived over evolutionary time by duplication of an unknown ancestral MHC gene (gray) followed by genetic divergence. Further interchange between these genes can occur by a process known as gene conversion, in which sequences can be transferred from part of one gene to a similar gene. For this to happen, the two genes must become apposed during meiosis. This can occur as a consequence of the misalignment of the two paired homologous chromosomes when there are many copies of similar genes arrayed in tandem—somewhat like buttoning in the wrong buttonhole. During the process of crossing-over and DNA recombination, a DNA sequence from one chromosome is sometimes copied to the other, replacing the original sequence. In this way, several nucleotide changes can be inserted all at once into a gene and can cause several simultaneous amino acid changes in the gene product. Because of the similarity of the MHC genes to each other and their close linkage, gene conversion has occurred many times in the evolution of MHC alleles.
The high polymorphism of the classical MHC genes ensures diversity in MHC gene expression in the population as a whole. However, no matter how polymorphic a gene is, no individual can express more than two alleles at a single gene locus. Polygeny, the presence of several different related genes with similar functions, ensures that each individual produces a number of different MHC molecules. The combination of polymorphism and polygeny produces the diversity of MHC molecules seen both within an individual and in the population at large.
Fig. 6.21 Allelic variation in MHC molecules occurs Moreover, allelic variability is clustered in specific sites within the predominantly within the peptide-binding region. Variability amino-terminal domains, lying in positions that line the peptide-plots of the amino acid sequences of MHC molecules show that binding groove, either on the floor of the groove or inward from the the variation arising from genetic polymorphism is restricted to walls. For the MHC class II molecule, the variability of the HLA-DR the amino-terminal domains (α1 and α2 domains of MHC class I alleles is shown. For HLA-DR, and its homologs in other species, the molecules, and α1 and β1 domains of MHC class II molecules). α chain is essentially invariant and only the β chain shows significant These are the domains that form the peptide-binding groove. polymorphism.
the pockets’ binding specificities. This in turn changes the anchor residues of peptides that can bind to each MHC isoform. The set of anchor residues that allows binding to a given isoform of an MHC class I or class II molecule is called a sequence motif, and this can be used to predict peptides within a protein that might bind that variant (Fig. 6.22). Such predictions may be very important in designing peptide vaccines, as we will see in Chapter 16, where we discuss recent progress in cancer immunotherapy.