Overview

The major histocompatibility complex (MHC) is a contiguous genomic region that encodes membrane glycoproteins which present peptide antigens to T lymphocytes, coordinating the Adaptive Immune System via Antigen Presentation and driving self–nonself discrimination. In humans this region is called the Human Leukocyte Antigen (HLA) system and maps to chromosome 6p21, with classical class I genes (HLA-A, -B, -C), class II genes (HLA-DR, -DQ, -DP), and an intervening class III region containing immune effectors such as complement and TNF. Authoritative immunology texts and reviews describe these organization and functions. See, for example, Janeway’s Immunobiology and clinical overviews of the HLA system. Janeway’s Immunobiology (NCBI Bookshelf); The HLA System review (PMC). (ncbi.nlm.nih.gov)

Genomic organization and nomenclature

• –Location and span: The human MHC resides on chromosome 6p21 and spans roughly 3.6 Mb. It is divided into class I, class II, and class III regions. The class I region contains HLA-A, -B, and -C; the class II region contains the DRA/DRB, DQA1/DQB1, and DPA1/DPB1 genes; the class III region encodes complement components (C2, C4, factor B), 21-hydroxylase, and TNF genes. The HLA System (PMC). (pmc.ncbi.nlm.nih.gov)
• –Allelic diversity: The IPD-IMGT/HLA Database catalogs named HLA alleles and is updated continuously; as of October 2025 it reported approximately 42,996 total HLA alleles (>29,000 class I and >13,000 class II), reflecting extraordinary polymorphism at classical loci. IPD-IMGT/HLA Statistics; EBI IPD-IMGT/HLA; Nucleic Acids Research – IPD-IMGT/HLA 2025 update. (hla.alleles.org)

Classes and molecular structure

• –Class I: Classical class I molecules (HLA-A, -B, -C) are heterodimers of a polymorphic heavy chain and β2-microglobulin that present peptides (typically 8–11 residues) to CD8 T cells, enabling recognition of intracellularly derived antigens. Nonclassical class I (e.g., HLA-E, -F, -G) have specialized immunoregulatory roles. Janeway’s Immunobiology; Annual Reviews – MHC I processing. (ncbi.nlm.nih.gov)
• –Class II: Class II molecules (HLA-DR, -DQ, -DP) are α/β heterodimers that present peptides (typically 13–25 residues) to CD4 T cells, sampling antigens from the endosomal/lysosomal pathway in professional antigen-presenting cells. Janeway’s Immunobiology; The ins and outs of MHC class II-mediated antigen processing. (ncbi.nlm.nih.gov)
• –Class III: While not encoding peptide-presenting molecules, the class III region includes complement proteins (C2, C4, factor B) and cytokines such as TNF that influence inflammation and host defense. The HLA System (PMC). (pmc.ncbi.nlm.nih.gov)

Antigen processing and presentation pathways

• –Class I (cytosolic pathway): Endogenous proteins are degraded by the proteasome; peptides are translocated into the ER by TAP1/TAP2 and trimmed by ERAP1/ERAAP, then loaded onto nascent class I in a peptide-loading complex containing tapasin, calreticulin, and ERp57 before export to the cell surface for CD8 T-cell surveillance. Alternative Antigen Processing for MHC Class I (PMC); MHC class I assembly review; ERp57 association study. (pmc.ncbi.nlm.nih.gov)
• –Cross-presentation: Dendritic cells can present exogenous antigens via class I to prime naïve CD8 T cells, through TAP-dependent and vacuolar mechanisms. Nature Reviews Immunology – Cross‑presentation by dendritic cells (bibliographic portals); Review summary (OUCI). (ouci.dntb.gov.ua)
• –Class II (endocytic pathway): Newly synthesized class II associates with invariant chain (Ii); after endosomal proteolysis leaves CLIP in the groove, HLA-DM catalyzes CLIP release and edits the peptide repertoire; HLA-DO modulates DM activity in a context-dependent fashion. HLA-DM induces CLIP dissociation; DM enhances peptide exchange; DM/DO regulation (PMC). (pubmed.ncbi.nlm.nih.gov)

MHC restriction and T‑cell recognition

Cytotoxic T lymphocytes recognize antigenic peptides only when bound to self MHC molecules, a phenomenon termed MHC restriction. This principle was discovered in mice infected with LCMV and reported in 1974; its significance for immune surveillance was recognized with the 1996 Nobel Prize to R. Zinkernagel and P. Doherty. Nobel Prize press release; J Exp Med historical perspective. (nobelprize.org)

Expression patterns and immunoregulatory roles

• –Class I molecules are expressed on nearly all nucleated cells and present to CD8 T cells; class II is constitutively expressed on professional APCs (dendritic cells, B cells, macrophages) and specialized thymic epithelium, with inducible expression in other cells under inflammatory cytokines. The ins and outs of MHC class II-mediated antigen processing; Janeway’s Immunobiology. (pubmed.ncbi.nlm.nih.gov)
• –Nonclassical class I ligands for innate receptors: HLA‑E presents leader-sequence peptides from class I to CD94/NKG2 receptors on Natural killer cell subsets; HLA‑E engagement by CD94/NKG2A is inhibitory and depends on peptide loading. HLA‑E and CD94/NKG2A binding; Specific recognition of HLA‑E by CD94/NKG2A. (pubmed.ncbi.nlm.nih.gov)
• –HLA‑G in pregnancy: HLA‑G expression on extravillous trophoblasts contributes to maternal–fetal tolerance through interactions with inhibitory receptors (e.g., LILRB1/ILT2, LILRB2/ILT4, KIR2DL4) and indirect stabilization of HLA‑E. HLA‑G in pregnancy (PMC review); siRNA knockdown study. (pmc.ncbi.nlm.nih.gov)

Polymorphism and evolution

Classical HLA loci are among the most polymorphic in the human genome. Balancing selection within the extended MHC contributes to maintaining allelic diversity, particularly at loci involved in antigen processing and presentation (e.g., TAP2, BTNL2). BMC Evolutionary Biology – balancing selection in MHC region; IPD‑IMGT/HLA Database – growth and counts. (bmcecolevol.biomedcentral.com)

Clinical significance

Transplantation

Compatibility at HLA loci is a major determinant of graft outcomes. In unrelated hematopoietic stem cell transplantation, allele-level matching at HLA‑A, ‑B, ‑C, and ‑DRB1 (an “8/8” match) is associated with superior survival, whereas single-allele mismatches (7/8) reduce survival probability and increase severe acute GVHD. NCI PDQ – HLA matching in HSCT; supportive cohort analyses link increasing mismatches with higher mortality and graft failure. Evaluation of HLA matching in unrelated HSCT (PMC). (cancer.gov) In renal transplantation, fewer HLA mismatches correlate with improved long‑term graft survival; effects are particularly notable for DR and B locus mismatches. Effect of HLA matching on renal transplant survival; HLA mismatch and 20‑year graft survival. (pubmed.ncbi.nlm.nih.gov)

Disease associations

Specific HLA alleles confer risk or protection for immune-mediated diseases. The association of HLA‑B27 with ankylosing spondylitis is among the strongest known HLA–disease links, with meta-analyses confirming elevated risk and allele-subtype effects. Modern Rheumatology meta‑analysis; Comprehensive meta‑analysis (PubMed). (academic.oup.com)

Pathogen immune evasion

Viruses have evolved strategies to subvert MHC pathways; for example, HSV ICP47 blocks TAP-dependent peptide transport, impairing class I assembly and antigen display. Annual Reviews – Viral interference with MHC I (NCBI Bookshelf). (ncbi.nlm.nih.gov)

Species and comparative notes

The MHC is conserved across jawed vertebrates with species-specific nomenclature (e.g., H‑2 in mouse). Functional principles—peptide binding grooves, polymorphic residues shaping peptide repertoire, and TCR recognition—are broadly conserved. Standard immunology texts provide comparative context. Janeway’s Immunobiology (NCBI Bookshelf). (ncbi.nlm.nih.gov)