The major histocompatibility complex (MHC) of genes consists of a linked set of genetic loci encoding many of the proteins involved in antigen presentation to T cells, most notably the MHC class I and class II glycoproteins (the MHC molecules) that present peptides to the T-cell receptor. The outstanding feature of the MHC molecules is their extensive polymorphism. This polymorphism is of critical importance in antigen recognition by T cells. A T cell recognizes antigen as a peptide bound by a particular allelic variant of an MHC molecule, and will not recognize the same peptide bound to other MHC molecules. This behavior of T cells is called MHC restriction. Most MHC alleles differ from one another by multiple amino acid substitutions, and these differences are focused on the peptide-binding site and the surface-exposed regions that make direct contact with the T-cell receptor. At least three properties of MHC molecules are affected by MHC polymorphism: the range of peptides bound; the conformation of the bound peptide; and the direct interaction of the MHC molecule with the T-cell receptor. Thus, the highly polymorphic nature of the MHC has functional consequences, and the evolutionary selection for this polymorphism suggests that it is critical to the role of the MHC molecules in the immune response. Powerful genetic mechanisms generate the variation that is seen among MHC alleles, and a compelling argument can be made that selective pressure to maintain a wide variety of MHC molecules in the population comes from infectious agents. As a consequence, the immune system is highly individualized—each individual responds differently to a given antigen.
Generation of ligands for unconventional T-cell subsets.
So far we have focused on how peptide:MHC complexes—the ligands for α:β T cells—are generated. We now turn to the question of how other types of T cells recognize their ligands and how these ligands are generated. Our current knowledge in this area is still incomplete, and is perhaps most apparent in the area of γ:δ T cells, where a growing list of ligands for individual γ:δT cells suggests an innate-like pattern of recognition. The recent discovery that the mucosal associated invariant T (MAIT) cells (see Section 4-18) recognize a microbial metabolite when it is presented by a nonpolymorphic MHC class I-like molecule solved a long-standing mystery regarding the function of this particular T-cell subset. Another invariant subset, the invariant NKT cells, provides a system for detecting and responding to lipid rather than peptide antigens. These findings suggest that these invariant and unconventional T cells operate somewhere between innate and adaptive immunity. In this part of the chapter, we will discuss the ligands they recognize and what is known about how they are generated or expressed.
6-16 A variety of genes with specialized functions in immunity are also encoded in the MHC.
In addition to the highly polymorphic ‘classical’ MHC class I and class II genes, there are many ‘nonclassical’ MHC genes, many encoded in the MHC but others encoded outside this region. The MHC class I-type molecules show comparatively little polymorphism; many of these have yet to be assigned a function. They are linked to the class I region of the MHC, and their exact number varies greatly among species and even among members of the same species. These genes have been termed MHC class Ib genes; like MHC class I genes, many, but not all, associate with β2-microglobulin when expressed on the cell surface. Their expression on cells is variable, both in the amount present at the cell surface and in tissue distribution. The characteristics of several MHC class Ib gene products are shown in Fig. 6.26.
One mouse MHC class Ib molecule, H2-M3, can present peptides with N-formylated amino termini, which is of interest because all bacteria initiate protein synthesis with N-formylmethionine. Cells infected with cytosolic bacteria can be killed by CD8 T cells that recognize N-formylated bacterial peptides bound to H2-M3. Whether an equivalent MHC class Ib molecule exists in humans is not known.