Major Histocompatibility Complex (MHC)

Overview

Major Histocompatibility Complex (MHC) Molecules are large, multi-subunit membrane proteins which are specialized for displaying short peptide fragments on the surface of cells. MHC molecules along with their bound peptides are detected by T-cell Receptor and this interaction plays a major role in Cell-mediated Immunity which is discussed further in that section. Here we largely discuss the molecular and genetic structure of MHC molecules and how their structure relates to their capacity to bind short peptides.

Subtypes

There are two basic subtypes of MHC Molecules, MHC I and MHC II, which are expressed on different cell types and serve difference purposes in immunity. Although they possess different amino acid sequences, their overall structure is roughly equivalent. Although MHC molecules are recognized by T-cell Receptor, this interaction is relatively weak and requires physical stabilization by T-cell Coreceptors. CD8 is required to stabilize the MHC I-TCR interaction whereas CD4 is required to stabilize the MHC II-TCR interaction. Consequently, MHC I can only be recognized by CD8-expressing T-cells (CD8+ T-cells) whereas MHC II can only be recognized by CD4-expressing T-cells (CD4+ T-cells).

MHC I is expressed on all nucleated cells and is recognized by T-cells which possess the CD8 T-cell Coreceptor found on CD8+ T-cells. The peptides which are loaded onto MHC I are derived from the degradation of cytosolic proteins. Consequently, MHC I is largely used to expose a cell's cytosolic milieu of proteins to CD8+ T-cells. If the peptides presented on MHC I are microbial in origin, the CD8+ T-cells kills the presumably infected cell. Consequently, MHC I is critical for elimination of cytosolic microbes.

MHC II is expressed only on Antigen Presenting Cells (APCs) which include Dendritic Cells, Macrophages, and B-cell. MHC II is recognized by T-cell which express the CD4 co-receptor (CD4+ T-cells). The peptides which are loaded onto MHC II are derived from the degradation of extracellular proteins that Antigen Presenting Cells have internalized. If the peptides presented on MHC II are microbial in origin, the CD4+ T-cell then coordinates Humoral Immunity to synthesize antigen-specific antibody to the microbe or induces macrophages which have phagocytosed the microbe to kill the organisms. Consequently, MHC II is critical for elimination of extracellular microbes or those which can survive in macrophage phagosomes.

MHC Structure

Although the two classes of MHC molecules possess different sequences and domains, their overall structure is largely similar. MHCs possess a peptide binding clefts which can bind a large diversity of peptides of a fairly short length. Because of the non-specific nature of peptide binding, MHCs are ideal for presenting the large diversity of peptides that might be produced following protein degradation.

MHC I is composed of a single polypeptide chain which requires support by the Beta-2-microglobulin protein. The long alpha chain possesses the entire peptide binding groove.

MHC II is composed of two separate polypeptide chains of equivalent length. The alpha and beta chains dimerize and the peptide binding groove is formed at their intersection.

MHC Genetics

The genes which encode both MHC I and MHC II molecules are found within a specific region of Chromosome 6. Several distinct genes exist that can encode the MHC molecules and in any given cell MHC proteins are synthesized from all of these genes.

The long, alpha chain of MHC I is encoded by three distinct but adjacent genes termed A, B, and C. Beta-2 Microglobulin is synthesized from a single gene located on a different chromosome.

MHC II is encoded by three distinct but adjacent genetic clusters termed DP, DQ, and DR which possess the genes for alpha and beta chains.

MHC Diversity

The peptide binding groove of MHC molecules is not completely non-specific and does possess some structural bias in binding of peptides. For example, any given MHC molecule may preferentially bind peptides with certain sequences over others and will thus be better capable of presenting these peptides. This provides a potential opportunity for exploitation by microbes as they might evolve protein sequences which display reduced binding to MHC. This potential problem in host-defense is addressed through MHC diversity on both a population and individual level.

MHC genes are some of the most polymorphic genes in the human genome, meaning that there are literally hundreds of different alleles for some of these genes. Consequently, for any two individuals, the probability that they will possess precisely the same alleles for MHC I A/B/C and MHC II DP/DQ/DR is extremely low. This population-level diversity of MHC means that no microbe can evolve which possesses MHC-unbindable peptides for our entire species.

Because of the polymorphic nature of MHC genes, the MHC I A/B/C and MHC II DP/DQ/DR genes of any single individual will likely be composed of different alleles. Since the MHC molecules in cells are synthesized from all of the genes within the MHC locus, each cell will possess a large diversity of MHC molecules which can thus bind a structurally diverse pool of microbial peptides. This diversity is further enhanced because the alpha and beta chains of MHC II can mix and match from the different DP/DQ/DR gene clusters.

Immunological Sequelae of Diversity

The unique MHC milieu of any individual may explain certain important immunological differences between individuals.

The presence of foreign MHC molecules in a host is extremely inflammatory and the host immune system will potently attack cells which display foreign MHC alleles. Consequently, transplantation of organs or tissues which possess different MHC alleles into a host can result in Hyperacute Rejection and Acute Rejection of the organ or tissue. The importance of MHC molecules in transplant rejection was recognized prior to their physiological role in immunity. Indeed, the "Major Histocompatibility Complex" namesake of these molecules is due to the recognition of their importance in immuno-compatibility between organ donors and recipients.

The possession of certain MHC alleles is correlated with an increased risk of certain Autoimmune Diseases. It is thought that these specific alleles may bind particular self-peptides with increased affinity, thus increasing the risk that the immune response will be inappropriately directed against host tissues. MHC alleles associated with increased risk of autoimmune disease are: HLA-B27, HLA-B8, HLA-DR2, HLA-DR3, HLA-DR4, HLA-DR5, and HLA-DR7.

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