The Major Histocompatibility Complex

• Antigen-presenting cells use receptors called MHC molecules to bind and present antigens.

• MHC molecules are encoded by genes located within the major histocompatibility complex.

• The classical MHC molecules are highly polymorphic. That is, they show an enormous variety of inherited structural variations that permit each individual animal to respond to a different set of antigens.

• Class I MHC molecules are found on all nucleated cells. Their function is to present endogenous antigens to CD8+ T cells.

• Class II MHC molecules are largely restricted to professional antigen-presenting cells such as dendritic cells, macrophages, and B cells. Their function is to present exogenous antigens to CD4+ T cells.

• The class III region of the MHC contains a mixture of genes, some of which encode complement components.

In order to trigger an adaptive immune response, antigen molecules must be broken up inside cells, and the fragments generated must then be bound to appropriate antigen-presenting receptors (Figure 11-1). These antigen-presenting receptors are glycoproteins encoded by genes located in a large gene cluster called the major histocompatibility complex (MHC). The receptors are therefore called MHC molecules. Antigen fragments can trigger an immune response only after they have bound to MHC molecules, and these antigen-MHC complexes have bound to T cell antigen receptors. Since the MHC molecules serve as specific antigen receptors, MHC genes determine which antigens can trigger adaptive immunity. Thus the MHC can be considered an organized cluster of genes that control antigen presentation and so determine an animal’s susceptibility to infectious or autoimmune diseases.

FIGURE 11-1 The key initial step in any immune response is the presentation of antigens by antigen-processing cells to antigen-sensitive cells. This step is mediated by MHC molecules located on the surface of antigen-processing cells.

Major Histocompatibility Complex

All vertebrates, from cartilaginous fish to mammals, possess cell-surface proteins coded for by genes clustered within an MHC. Each MHC has a fairly consistent structure consisting of about 200 expressed genes distributed over about 3 mb of DNA and divided into three regions containing different classes of MHC gene loci (I, II, and III) (Figure 11-2). Classical class I loci code for the MHC molecules expressed on most nucleated cells. Class I genes can be subdivided into those that are highly polymorphic (class Ia genes) and those that show very little polymorphism (class Ib, Ic, or Id genes). (Polymorphism refers to structural variations between proteins.) Class Id genes are located outside the MHC on a different chromosome. Genes in class II loci, on the other hand, encode polymorphic MHC molecules mainly restricted to professional antigen-presenting cells (dendritic cells, macrophages, and B cells) (Table 11-1). Genes in the class III region code for a diverse mixture of proteins, many of which are linked to innate immunity, such as complement proteins. Although each MHC contains all three gene regions, their gene content, and arrangement vary between species.

Table 11-1

Comparison of MHC Class I and Class I Structure

	CLASS I	CLASS II
Loci include	Typically A, B, and C	DP, DQ, and DR,
Distribution	Most nucleated cells	B cells, macrophages, and dendritic cells
Function	Present antigen to cytotoxic T cells	Present antigen to T helper cells
Result	T-cell–mediated toxicity	T-cell–mediated help

The collective name given to the proteins encoded by MHC genes depends on the species. In humans these molecules are called human leukocyte antigen (HLA); in dogs they are called DLA; in rabbits, RLA; in cattle (bovines), BoLA; in horses, ELA; in swine, SLA; and so forth. In some species, MHC molecules were identified as transplantation antigens before their true function was recognized. In these cases, the nomenclature is anomalous. Thus, in the mouse the MHC is called H-2, and in chickens it is called B. The complete set of alleles found within an individual animal’s MHC is called its MHC haplotype.

MHC Class Ia Molecules

Class Ia molecules are expressed on most nucleated cells. In pigs, for example, class I molecules have been detected on lymphocytes, platelets, granulocytes, hepatocytes, kidney cells, and sperm. They are not usually found on mammalian red cells, gametes, neurons, or trophoblast cells. Some cells, such as myocardium and skeletal muscle, may express very few class Ia molecules.

Structure

Class Ia molecules consist of two linked glycoprotein chains. An α chain (45 kDa) is associated with a much smaller chain called β₂-microglobulin (β₂M) (12 kDa). The α chain is inserted in the cell membrane (Figure 11-3). It consists of five domains: three extracellular domains called α₁, α₂, and α₃, each about 100 amino acids long; a transmembrane domain; and a cytoplasmic domain. The antigen-binding site on these molecules is formed by the α₁ and α₂ domains. β₂M consists of a single domain and serves to stabilize the structure.

Gene Arrangement

The size of the MHC class I region varies among mammals. Humans and rodents have the largest, and pigs have the smallest. The chicken class I region is very much smaller than in mammals (Chapter 40). The MHC class I region has a common framework of non-MHC genes, and size differences are mainly due to variations in the size and number of these framework genes.

The number of class Ia gene loci varies between mammals. For example, rats have more than 60, mice have about 30, humans have 20, cattle have 13 to 15, and pigs have 11. Not all these genes are functional. For example, in mice, only two or three class I genes are expressed. The remainder are pseudogenes (defective genes that cannot be expressed). In humans the functional polymorphic genes are called A, B, and C. In mice they are called K and D (and in some strains, L) (Figure 11-4). In other species they are usually numbered.

FIGURE 11-4 Arrangement of major loci within the MHC of the mouse—a typical mammalian MHC.

Polymorphism

Some class Ia loci encode proteins with very large numbers of alleles. These allelic differences cause variations in the amino acid sequences of the α₁ and α₂ domains. This variation is called polymorphism. The most extreme polymorphism is restricted to three to four small regions located within the α₁ and α₂ domains. In these variable regions, two or three different amino acids may occur at each position. The other domains of MHC class Ia molecules show little variation.

The α₁ and α₂ domains of MHC class I molecules fold together to form an open-ended groove (Figure 11-5). A flat β sheet forms the floor of this groove, and its walls are formed by two α helices (Figure 11-6). This groove binds antigenic peptides, 8 to 10 amino acids in size. The variable regions located along the walls of this groove determine its shape. The shape of the groove in turn determines which peptides can be bound and thus trigger immune responses.