The major histocompatibility complex (MHC) is a large genomic region encoding proteins essential for adaptive immune recognition. MHC molecules display peptide fragments derived from intracellular and extracellular proteins on the cell surface for surveillance by T lymphocytes, enabling the immune system to detect infected, malignant, or foreign cells. The extreme polymorphism of MHC genes within populations ensures broad antigen coverage but also presents challenges for transplantation.
Genomic Organization of the MHC
The MHC, termed the human leukocyte antigen (HLA) system in humans, spans approximately 4 megabases on the short arm of chromosome 6. The classical MHC is divided into three regions. MHC class I region contains the HLA-A, HLA-B, and HLA-C genes, which encode the highly polymorphic α chains of class I molecules. MHC class II region contains HLA-DR (with multiple DRA and DRB genes), HLA-DQ (DQA1 and DQB1), and HLA-DP (DPA1 and DPB1), encoding the α and β chains of class II molecules. MHC class III region lies between class I and II and encodes diverse proteins with immune functions, including complement components (C2, C4, factor B), cytokines (TNF-α, lymphotoxin), heat shock proteins, and proteins involved in antigen processing such as TAP1, TAP2, tapasin, and proteasome subunits (LMP2, LMP7). The MHC is the most gene-dense and polymorphic region of the human genome, with over 30,000 known HLA alleles, most of which are concentrated in the peptide-binding grooves of class I and class II molecules.
MHC Class I Antigen Presentation Pathway
MHC class I molecules are expressed on all nucleated cells and present endogenous antigens derived from proteins synthesized within the cell. Cytosolic proteins are degraded by the proteasome, with the immunoproteasome (containing LMP2, LMP7, and MECL-1 subunits) generating peptides of 8–10 amino acids optimized for MHC class I binding. Peptides are transported into the endoplasmic reticulum by TAP (transporter associated with antigen processing), a heterodimer of TAP1 and TAP2, in an ATP-dependent manner. Within the ER, the peptide-loading complex, composed of tapasin, calreticulin, ERp57, and calnexin, facilitates peptide loading onto newly synthesized MHC class I α chains that have assembled with β₂-microglobulin. Peptide binding stabilizes the class I molecule, which then traffics through the Golgi to the cell surface. Surface MHC class I-peptide complexes are surveyed by CD8+ T cells, which recognize foreign or altered peptides and initiate cytotoxic responses.
MHC Class II Antigen Presentation Pathway
MHC class II molecules are expressed primarily on professional antigen-presenting cells, including dendritic cells, macrophages, and B cells, and present exogenous antigens internalized from the extracellular environment. Antigens are taken up by phagocytosis, receptor-mediated endocytosis, or macropinocytosis and processed in endosomal and lysosomal compartments by acidic proteases including cathepsins. MHC class II α and β chains assemble in the ER with the invariant chain (Ii, CD74), which occupies the peptide-binding groove and directs class II molecules to endosomal compartments. In the endosome, the invariant chain is progressively degraded, leaving a small fragment called CLIP (class II-associated invariant chain peptide) in the binding groove. HLA-DM, a non-classical MHC molecule, catalyzes the exchange of CLIP for antigenic peptides, and HLA-DO modulates HLA-DM activity in B cells. Peptide-loaded class II molecules are transported to the cell surface for presentation to CD4+ T cells.
MHC Polymorphism and Peptide Binding
The extraordinary polymorphism of MHC genes, particularly in the peptide-binding groove, determines the repertoire of peptides each MHC molecule can present. MHC class I binding grooves are closed at both ends, accommodating peptides of 8–10 amino acids anchored at their termini by interactions with conserved pockets in the groove. MHC class II binding grooves are open at both ends, allowing longer peptides of 13–25 amino acids to bind with the peptide backbone extended and the central core of 9 amino acids anchored in the groove. Each MHC allele has a distinct peptide-binding motif characterized by preferred anchor residues at specific positions. HLA-B*27, for example, prefers peptides with arginine at position 2 and basic or aliphatic residues at the C-terminus. The high degree of polymorphism ensures that at the population level, the species can present a vast array of pathogen-derived peptides, but at the individual level, any person can present only a subset. This variation influences susceptibility to infectious diseases, autoimmune conditions, and adverse drug reactions.
MHC and Transplantation
MHC molecules are the major histocompatibility barriers recognized during transplantation. The degree of HLA matching between donor and recipient is a critical determinant of graft survival in solid organ and hematopoietic stem cell transplantation. HLA-A, HLA-B, and HLA-DR matching is most strongly associated with outcomes, and HLA matching at the allelic level using high-resolution typing improves graft survival compared to serologic matching. Hyperacute rejection, mediated by pre-existing antibodies against donor HLA, occurs within minutes and is prevented by crossmatching. Acute rejection, driven primarily by recipient T cells recognizing donor MHC molecules through direct and indirect allorecognition pathways, can occur days to months after transplantation. Chronic rejection involves both T cell and antibody-mediated mechanisms, with donor-specific antibodies (DSA) against donor HLA playing a major role in long-term graft loss.
MHC and Disease Association
Certain HLA alleles are strongly associated with susceptibility or resistance to a wide range of diseases, particularly autoimmune and inflammatory conditions. The most well-known association is HLA-B27 with ankylosing spondylitis, where over 90% of patients carry this allele compared to approximately 8% of healthy controls. HLA-DRB104:01 and related alleles are associated with rheumatoid arthritis, particularly in individuals carrying the shared epitope, a conserved amino acid sequence in the peptide-binding groove. HLA-DQ2 and HLA-DQ8 are associated with celiac disease, where these molecules preferentially present deamidated gluten peptides to T cells. HLA-DRB1*15:01 is the strongest genetic risk factor for multiple sclerosis. The mechanisms underlying these associations include presentation of self-peptides or modified self-peptides that trigger autoreactive T cell responses, molecular mimicry between microbial and self-antigens, and the influence of MHC molecules on T cell repertoire selection during thymic development.
Non-Classical MHC Molecules
In addition to classical MHC molecules, the genome encodes non-classical MHC class I molecules with more specialized and restricted functions. HLA-E presents leader peptides derived from classical MHC class I molecules and is recognized by NK cell receptors CD94/NKG2A and CD94/NKG2C, providing an inhibitory or activating signal that allows NK cells to monitor MHC class I expression levels. HLA-G is expressed primarily at the maternal-fetal interface and suppresses immune responses to protect the fetus from maternal immune attack. HLA-F and HLA-H have less defined functions, with HLA-F involved in immune regulation and HLA-H being a pseudogene. CD1 family molecules present lipid and glycolipid antigens to specialized T cell subsets including invariant natural killer T (iNKT) cells, bridging innate and adaptive immunity.
