The major histocompatibility complex (MHC) is a region of the genome containing linked genes involved in the immune system, particularly the processing and display of antigens. Its best-known products are cell-surface proteins that present short protein fragments to T cells, enabling recognition of infected or otherwise altered cells. The term also commonly refers to these antigen-presenting molecules. In humans, the region is called the human leukocyte antigen (HLA) complex and lies on the short arm of chromosome 6. Its name reflects its discovery through studies of tissue compatibility and transplantation. (ncbi.nlm.nih.gov)
Genetic organization and diversity
The human MHC contains class I, class II, and class III regions. Classical class I genes include HLA-A, HLA-B, and HLA-C; the principal classical class II molecules are HLA-DP, HLA-DQ, and HLA-DR, encoded by genes for their constituent chains. Other genes participate in peptide processing or regulate peptide loading. The class III region contains genes with other immune functions, including components of the complement system; “class III” does not describe another family of peptide-presenting molecules. (ncbi.nlm.nih.gov)
MHC diversity has two distinct aspects: polygeny, meaning that several related genes encode molecules with overlapping functions, and polymorphism, meaning that individual genes have many alleles within a population. Maternal and paternal alleles are generally expressed codominantly. Variation is particularly important around the peptide-binding groove, where it influences which fragments bind and how T cells recognize them. Thus, individuals differ in their repertoire of presentable peptides rather than possessing a unique receptor for every possible antigen. (ncbi.nlm.nih.gov)
Class I and class II molecules
MHC class I molecules occur on almost all nucleated cells. Each consists of a membrane-spanning heavy chain associated noncovalently with β2-microglobulin, whose gene lies outside the MHC. The heavy chain forms a peptide-binding groove with relatively closed ends, usually accommodating peptides about 8–10 amino acids long. Class I peptide complexes are recognized primarily by CD8-positive T cells, which can develop into cytotoxic cells capable of destroying infected or abnormal targets. (ncbi.nlm.nih.gov)
MHC class II molecules consist of two membrane-spanning chains, α and β. Their groove is open at both ends and accommodates longer peptides, commonly around 13–17 amino acids, although longer fragments also occur. Expression is concentrated in professional antigen-presenting cells, including dendritic cells, macrophages, and B cells, and can be induced in additional cell types. Class II complexes are recognized primarily by CD4-positive T cells, which coordinate immune responses through interactions with other cells. (ncbi.nlm.nih.gov)
Both classes display self-derived as well as foreign peptides. They are therefore not simply labels distinguishing “self” from “non-self”; the biological outcome depends on the responding lymphocyte and its activation context. (ncbi.nlm.nih.gov)
Antigen processing and presentation
In the conventional class I pathway, intracellular proteins are broken down by the proteasome. The transporter associated with antigen processing, TAP, carries many resulting peptides into the endoplasmic reticulum, where they are loaded onto class I molecules. Stable peptide–MHC complexes then travel to the cell membrane. This pathway samples normal cellular proteins as well as proteins produced during infection or cellular transformation. (immunology.org)
The conventional class II pathway samples proteins degraded within endocytic compartments. Newly assembled class II molecules associate with the invariant chain, which protects their binding groove and directs trafficking. Its degradation leaves a fragment called CLIP; HLA-DM facilitates replacement of CLIP with other peptides before surface display. (immunology.org)
These pathways are not absolute divisions between intracellular and extracellular material. In cross-presentation, certain dendritic cells display externally acquired antigens on class I molecules. Recognition of peptide–MHC provides an antigen-specific signal, but activation of naïve T cells also depends on costimulation and cytokine signals. (immunology.org)
T-cell recognition and tolerance
The T-cell receptor contacts both the bound peptide and the MHC molecule. Recognition is consequently MHC-restricted: a T cell responds to a particular peptide in the context of an appropriate MHC molecule, rather than to free peptide alone. This relationship is central to adaptive immunity. (ncbi.nlm.nih.gov)
During development in the thymus, positive selection preserves cells capable of interacting appropriately with self peptide–MHC complexes. Negative selection removes many cells that react too strongly to these complexes, contributing to central immune tolerance. These processes produce a repertoire capable of using the individual’s MHC molecules while limiting harmful self-reactivity. They do not eliminate every self-reactive cell; additional mechanisms of peripheral immune tolerance operate after thymic development. (ncbi.nlm.nih.gov)
Transplantation and research significance
Differences in HLA molecules can provoke immune responses against donor tissue and contribute to transplant rejection. HLA compatibility is therefore important in organ transplantation and hematopoietic cell transplantation, although its significance depends on the transplant type and other immunological factors. MHC variants are also associated with differences in susceptibility to some autoimmune diseases. Such associations describe altered risk, not an inevitable disease outcome. (ncbi.nlm.nih.gov)
Research connecting tissue compatibility, human leukocyte antigens, and genetic control of immune responses earned George D. Snell, Jean Dausset, and Baruj Benacerraf the 1980 Nobel Prize in Physiology or Medicine. Today, standardized HLA nomenclature and sequence resources, including the IPD-IMGT/HLA Database, support allele identification and comparison across laboratory and clinical studies. (nobelprize.org)