When cells are treated with the interferons IFN-α, -β, or -γ, there is a marked increase in the transcription of MHC class I α-chain and β2-microglobulin genes and of the proteasome, tapasin, and TAP genes. Interferons are produced early in viral infections as part of the innate immune response, as described in Chapter 3. The increase in MHC expression they produce helps all cells to process viral proteins and present the resulting virus-derived peptides on their surface (except for red blood cells). On dendritic cells, this helps to activate the appropriate T cells and initiate the adaptive immune response to the virus. The coordinated regulation of the genes encoding these components may be facilitated by the linkage of many of them in the MHC.
The DMA and DMB genes encoding the subunits of the HLA-DM molecule that catalyzes peptide binding to MHC class II molecules are clearly related to the MHC class II genes, as are the DOA and DOB genes that encode the subunits of the regulatory HLA-DO molecule. Gene expression of the classical MHC class II proteins, along with the invariant-chain, DMα, DMβ, and DOα, but not DOβ, is coordinately increased by IFN-γ, which is produced by activated TH1 cells, CD8 T cells, and NK cells. This form of regulation allows dendritic cells and macrophages to upregulate molecules involved in processing of intravesicular antigens when presenting antigens to T cells and NK cells. Expression of all these molecules is induced by IFN-γ (but not by IFN-αor -β), via the production of a protein known as MHC class II transactivator (CIITA), which acts as a positive transcriptional co-activator of MHC class II genes. An absence of CIITA causes severe immunodeficiency due to the nonproduction of MHC class II molecules—MHC class II deficiency. Finally, the MHC contains many ‘non-classical’ MHC genes, so-called because while they resemble MHC genes in structure, their products do not function in presenting peptides to conventional α:β T cells. Many of these genes are now referred to as MHC class Ib genes, and their protein products have a variety of different functions, which we will describe in Section 6-16 , following our discussion of the conventional MHC genes.
Fig. 6.17 Detailed map of the human MHC. The organization of the class I, class II, and class III regions of the human MHC is shown, with approximate genetic distances given in thousands of base pairs. Most of the genes in the class I and class II regions are mentioned in the text. The additional genes indicated in the class I region (for example, E, F, and G) are class I-like genes encoding class Ib molecules; the additional class II genes are pseudogenes. The genes shown in the class III region encode the complement proteins C4 (two genes, shown as C4A and C4B), C2, and factor B (shown as Bf), as well as genes that encode the cytokines tumor necrosis factor-α (TNF) and lymphotoxin (LTA, LTB). Closely linked to the C4 genes is the gene encoding 21-hydroxylase (shown as CYP 21B), an enzyme involved in steroid biosynthesis. Immunologically important functional protein-coding genes mentioned in the text are color coded, with the MHC class I genes being shown in red, except for the MIC genes, which are shown in blue; these are distinct from the other class I-like genes and are under different transcriptional control. The immunologically important MHC class II genes are shown in yellow. Genes in the MHC region that have immune functions but are not related to the MHC class I and class II genes are shown in purple. Genes in dark gray are pseudogenes related to immune-function genes. Unnamed genes unrelated to immune function are shown in light gray.