Two other closely related mouse MHC class Ib genes, T22 and T10, are expressed by activated lymphocytes and are recognized by a subset of γ:δT cells. Although the precise purpose remains unclear, it has been proposed that this interaction allows γ:δ T cells to regulate these activated lymphocytes expressing T22 and T10 proteins.
The other genes that map within the MHC include some that encode complement components (for example, C2, C4, and factor B) and some that encode cytokines—for example, tumor necrosis factor-α (TNF-α) and lymphotoxin— all of which have important functions in immunity. These genes lie in the so-called ‘MHC class III’ region (see Fig. 6.17), a somewhat misleading name, since genes in this region are not MHC molecules at all.
Many studies have established associations between susceptibility to certain diseases and particular alleles of MHC genes (see Chapter 15), and we now have considerable insight into how polymorphism in the classical MHC class I and class II genes can affect disease resistance or susceptibility. Most MHC-influenced traits or diseases are known or suspected to have an immunological cause, but this is not so for all of them: some genes residing within the MHC have no known or suspected immunological function. For example, the class Ib gene M10 encodes a protein that functions in the vomeronasal organ as a chaperone to escort certain types of pheromone receptors to the cell surface. M10 could potentially influence mating preference, a trait that has been linked to the MHC region in rodents.
The HFE gene, encoding the hemochromatosis protein, lies some 4 million base pairs from HLA-A. Its protein product is expressed in cells of the intestinal cells (see the text and Section 3-24). HLA-C, which is a classical MHC molecule (class Ia), is included here because, in addition to presenting peptides to T-cell receptors, all HLA-C isoforms interact with the KIR class of NK-cell receptors to regulate NK-cell function in the innate immune response. CTL, cytotoxic T lymphocyte.
tract and acts in iron metabolism by regulating the uptake of dietary iron into the body. It seems to interact with the transferrin receptor and decrease the receptor’s affinity for iron-loaded transferrin. Individuals defective for this gene have an iron-storage disease, hereditary hemochromatosis, in which an abnormally high level of iron is retained in the liver and other organs. Mice lacking β2-microglobulin have defective expression of all class I molecules and thus also show a similar iron overload. Another MHC gene with a nonimmune function encodes the enzyme 21-hydroxylase, which, when deficient, causes congenital adrenal hyperplasia and, in severe cases, salt-wasting syndrome. Even where a disease-related gene is clearly homologous to immune-system genes, as is the case with HFE, the disease mechanism may not be immune-related. Disease associations mapping to the MHC must therefore be interpreted with caution, in the light of a detailed understanding of its genetic structure and the functions of its individual genes. Much remains to be learned about the significance of all the genetic variation localized within the MHC. For instance, the human complement component C4 comes in two versions, C4A and C4B, not to be confused with the C4 convertase cleavage products C4a and C4b, and different individuals have variable numbers of the gene for each type in their genomes, but the adaptive significance of this genetic variability is not well understood.
6-17 Specialized MHC class I molecules act as ligands for the activation and inhibition of NK cells and unconventional
T-cell subsets.