Major histocompatibility complex

The major histocompatibility complex (MHC) is a set of genes encoding cell-surface proteins that display fragments of proteins to T cells, letting the immune system inspect what is being made inside the body's cells. In humans the MHC is called the human leukocyte antigen (HLA) system. It sits on the short arm of chromosome 6 and contains the most variable genes in the human genome.

MHC molecules sit at the heart of adaptive immunology: they determine which pieces of a virus or tumor T cells can "see", why organ transplants are rejected, and why some people are prone to particular autoimmune diseases or drug reactions.

The MHC was discovered through tissue transplantation. In the 1930s and 1940s, George Snell's studies of tumor and skin grafts in mice identified a gene region that controlled whether grafts were accepted, which he named "histocompatibility" genes. In the 1950s Jean Dausset found the first human leukocyte antigens, and Baruj Benacerraf showed that MHC genes control immune responsiveness. The three shared the 1980 Nobel Prize in Physiology or Medicine.

In 1974, Rolf Zinkernagel and Peter Doherty discovered MHC restriction: killer T cells recognize virus-infected cells only when the viral fragment is presented by the "right" MHC molecule. This revealed the true job of the MHC and earned them the 1996 Nobel Prize.

MHC class I molecules (HLA-A, HLA-B, and HLA-C in humans) are found on nearly every nucleated cell. Each consists of a heavy chain paired with a small protein called β₂-microglobulin. They present short peptides, usually 8–10 amino acids long, drawn from proteins made inside the cell:

1. Cytosolic proteins, including viral proteins in an infected cell, are chopped up by the proteasome.
2. The transporter TAP pumps the peptides into the endoplasmic reticulum.
3. A peptide-loading complex fits suitable peptides into the class I groove, and the loaded molecule travels to the cell surface.

Here CD8⁺ cytotoxic T cells inspect it. If the peptide is foreign, for example from a virus or a mutated tumor protein, the T cell kills the cell. Many viruses try to evade this by blocking class I display. Natural killer cells counter this trick by attacking cells that have "missing self", meaning too little class I on their surface.

MHC class II molecules (HLA-DR, HLA-DQ, and HLA-DP) are normally made by professional antigen-presenting cells: dendritic cells, macrophages, and B cells. They present longer peptides, usually 13–25 amino acids, from proteins the cell has taken up from its surroundings:

1. While assembling in the endoplasmic reticulum, class II molecules are protected by the invariant chain, which blocks the groove.
2. In endosomal compartments, the invariant chain is broken down, leaving a placeholder fragment called CLIP.
3. The editing molecule HLA-DM swaps CLIP for peptides from engulfed proteins, such as bacterial proteins or vaccine antigens.

CD4⁺ helper T cells recognize class II–peptide complexes. They then coordinate the response, helping B cells make antibodies and activating macrophages and killer T cells.

The MHC region also contains class III genes that are not antigen-presenting, including several complement components and tumor necrosis factor.

HLA genes are extraordinarily polymorphic: tens of thousands of alleles have been catalogued across human populations, with HLA-B alone among the most variable genes known. Each person inherits one set of HLA genes from each parent as a block (a haplotype) and expresses both sets (codominance). Most people can therefore display a wide range of peptides.

This diversity is maintained by natural selection from pathogens. A population with varied MHC types is unlikely to be wiped out by a single pathogen that evades one MHC type. People who carry two different alleles at a locus can present more peptides than people with two identical copies, an advantage known as heterozygote advantage. Variation at the MHC is a classic example of balancing selection in population genetics.

• Transplantation: Donor and recipient are matched for HLA as closely as possible, because the recipient's T cells react strongly to foreign MHC molecules. Matching is especially critical for bone marrow and stem cell transplants.
• Autoimmune disease: Certain alleles strongly raise disease risk. HLA-B27 is linked to ankylosing spondylitis, and HLA-DQ2 and HLA-DQ8 to celiac disease and type 1 diabetes.
• Drug hypersensitivity: HLA-B\*57:01 predicts severe reactions to the HIV drug abacavir. HLA-B\*15:02, common in parts of Asia, predicts serious skin reactions to carbamazepine. Screening for these alleles before prescribing is an established example of pharmacogenomics and personalized medicine.
• Infection and vaccines: HLA type influences how people control infections such as HIV and how they respond to vaccines.
• Cancer immunotherapy: Engineered T-cell therapies (see advanced immunotherapy) and cancer vaccines must account for the patient's HLA type, because T cells recognize tumor peptides only on specific MHC molecules.