Major Histocompatibility Complex (MHC)

The MHC comprises tightly linked genes that encode proteins associated with intercellular recognition and antigen presentation to T lymphocytes. The MHC plays a crucial role in the development of both humoral and cell mediated immune responses because MHC molecules function as antigen presenting structures. The set of MHC molecules expressed by an individual influences the antigens to which that individual's T_H and T_c cells can respond since T cells can only recognize antigen when it is associated with a self MHC molecule.

Genes of the MHC:  There is a tremendous amount of diversity exhibited by MHC molecules within a species and within individuals. The diversity is due to polymorphism or the presence of multiple alleles at a given genetic locus with a species. These alleles differ in their DNA sequences from one individual to another by as much as 10%. Each different set of alleles that have been found are referred to as a haplotype, and an individual inherits one haplotype from the mother and one from the father. The strains of various types of mice are designated by an italic superscript to note such different haplotypes (i.e., H-2^a, H-2^b). Inbred mouse strains are syngeneic or identical at all genetic loci and allogeneic if they are genetically different. Congenic or strains which are genetically identical except at a single region can be bred by a series of crosses.

Unlike with the source of diversity of antibodies and T cells which is generated by a continual process of random gene rearrangements which changes over time within an individual, the MHC molecules expressed by an individual do not change over time. But they may differ significantly from those expressed by another individual of the same species due to recombination events during crossover. This diversity creates problems with respect to matching MHC molecules for successful organ transplants. Peptide binding by class I and II molecules does not exhibit the fine specificity of antigen binding by antibodies and T-cell receptors. Instead, a given MHC molecule can bind numerous different peptides and is often referred to as "promiscuous."

The MHC genes are contained are contained on chromosome 6 and referred to as the HLA complex in humans and on chromosome 6 and referred to as the H-2 complex in mice. The genes are organized into regions encoding the following 3 classes of molecules:

• Class I MHC genes encode glycoproteins expressed on the surface of nearly all nucleated cells and are recognized on receptors on CD8+ killer T cells and natural killer cells. In humans, the MHC class I cell surfaced expressed molecules are referred to as HLA-A, -B or -C.

• Class II MHC In humans, MHC class II cell surface molecules are referred to as HLA-DR, -DP and DQ.

• Class III MHC genes encode components of the complement system and molecules involved in inflammation such as tumor necrosis factor (TNF) and heat-shock proteins.

Regulation

The expression of MHC molecules is also regulated by various cytokines. The interferons (alpha, beta, and gamma), for example, and tumor necrosis factor have each been shown to increase expression of class I MHC molecules on cells. IFN-γ, for example, may do this by inducing the formation of a specific transcription factor that binds to the promoter sequence flanking the class I MHC genes.

MHC expression is also influenced by various viruses. For example, HIV decreases Class I MHC expression whereas it increases Class II MHC expression. As another example, cytomegalovirus binds to the Β₂-microglobulin, preventing assembly of class I MHC molecules and their transport to the plasma membrane. Decreased expression of class I MHC molecules helps viruses evade the immune response by reducing the likelihood that virus infected cells will become targets for CTL mediated destruction.