Fig. 6.16 The genetic organization of the major histocompatibility complex (MHC) in humans and mice. The organization of the MHC genes is shown. In humans, the cluster is called HLA (short for human leukocyte antigen) and is on chromosome 6, and in mice, it is called H-2 (for histocompatibility) and is on chromosome 17. The organization is similar in both species, with separate clusters of MHC class I genes (red) and MHC class II genes (yellow). In mice, the MHC class I gene H-2K has been translocated relative to the human MHC, splitting the class I region in two. Both species have three main class I genes, which are called HLA-A, HLA-B, and HLA-C in humans, and H2-K, H2-D, and H2-L in the mouse. These encode the α chain of the respective MHC class I proteins, HLA-A, HLA-B, and so on. The other subunit of an MHC class I molecule, β2-microglobulin, is encoded by a gene located on a different chromosome—chromosome 15 in humans and chromosome 2 in the mouse. The class II region includes the genes for the α and β chains (designated A and B) of the MHC class II molecules HLA-DR, -DP, and -DQ (H-2A and -E in the mouse). Also in the MHC class II region are the genes for the TAP1:TAP2 peptide transporter, the PSMB (or LMP) genes that encode proteasome subunits, the genes encoding the DMα and DMβ chains (DMA and DMB), the genes encoding the α and β chains of the DO molecule (DOA and DOB, respectively), and the gene encoding tapasin (TAPBP). The so-called class III genes encode various other proteins with functions in immunity (see Fig. 6.17).
There are three class I α-chain genes in humans, called HLA-A, -B, and -C. There are also three pairs of MHC class II α-and β-chain genes, called HLA-DR, -DP, and -DQ. In many people, however, the HLA-DR cluster contains an extra β-chain gene whose product can pair with the DRα chain. This means that the three sets of genes can give rise to four types of MHC class II molecules. All the MHC class I and class II molecules can present peptides to T cells, but each protein binds a different range of peptides (see Sections 4-14 and 4-15). Thus, the presence of several different genes for each MHC class means that any one individual is equipped to present a much broader range of peptides than if only one MHC molecule of each class were expressed at the cell surface.
Figure 6.17 shows a more detailed map of the human MHC region. Many genes within this locus participate in antigen processing or antigen presentation, or have other functions related to the innate or adaptive immune response. The two TAP genes lie in the MHC class II region near the PSMB8 and PSMB9 genes, whereas the gene encoding tapasin (TAPBP) lies at the edge of the MHC nearest the centromere. The genetic linkage of the MHC class I genes (whose products deliver cytosolic peptides to the cell surface) with the TAP, tapasin, and proteasome (PSMB or LMP) genes (whose products deliver cytosolic peptides into the endoplasmic reticulum) suggests that the entire MHC has been selected during evolution for antigen processing and presentation.