Major Histocompatibility Complex Structure and Function

Core Idea

The major histocompatibility complex (MHC) molecules present peptide antigens to T cells, controlling adaptive immune responses. MHC Class I (α-chain + β2-microglobulin) displays intracellular peptides to CD8+ T cells and is expressed on all nucleated cells. MHC Class II (α + β heterodimer) displays endosomal peptides to CD4+ T cells and is expressed on antigen-presenting cells. MHC polymorphism among individuals ensures population-level pathogen recognition diversity.

How It's Best Learned

Sketch the three-dimensional MHC-peptide complex showing the peptide-binding groove, anchor residues, and TCR contact surfaces. Compare MHC-I and MHC-II peptide binding pockets and binding preferences.

Common Misconceptions

• All MHC molecules bind the same peptides (peptide-binding specificity varies with MHC allotype). - MHC-I is only on immune cells (all nucleated cells express MHC-I).

Explainer

From your study of protein structure, you know that the three-dimensional shape of a protein determines its function and binding specificity. From cell signaling, you know that surface receptors allow cells to communicate information about their internal state. The major histocompatibility complex (MHC) molecules combine both principles: they are cell-surface proteins whose sole job is to display short peptide fragments — molecular snapshots of what is happening inside the cell — for inspection by T cells. Without MHC, T cells would be blind to intracellular infections, cancers, and foreign proteins, because T cell receptors cannot recognize free-floating antigens the way antibodies can.

MHC class I molecules are expressed on virtually all nucleated cells in the body. They consist of a transmembrane α chain with three extracellular domains (α1, α2, α3) non-covalently associated with β2-microglobulin, a small soluble protein. The α1 and α2 domains form a peptide-binding groove — a cleft with a floor of β-pleated sheet and walls of α-helices — that holds peptides of 8–10 amino acids. These peptides are derived from proteins degraded by the proteasome in the cytoplasm: normal self-proteins, viral proteins if the cell is infected, or mutant proteins in cancer cells. The loaded MHC-I complex is then transported to the cell surface, where CD8+ cytotoxic T cells survey it. If the displayed peptide is foreign (viral, for example), the CD8+ T cell kills the presenting cell. This system means that every nucleated cell in your body is continuously displaying a sample of its internal protein content for immune surveillance — a cellular "inspection window" that reveals infection or transformation.

MHC class II molecules have a different structure and a different job. They are heterodimers of an α chain and a β chain, each contributing one domain to form the peptide-binding groove. Unlike MHC-I, the groove is open at both ends, accommodating longer peptides of 13–25 amino acids. MHC-II expression is restricted to professional antigen-presenting cells — dendritic cells, macrophages, and B cells — rather than all nucleated cells. These cells capture extracellular pathogens and proteins through phagocytosis or receptor-mediated endocytosis, degrade them in acidic endosomal compartments, and load the resulting peptides onto MHC-II molecules. The MHC-II–peptide complexes are presented to CD4+ helper T cells, which then orchestrate the broader immune response by activating B cells, macrophages, and other effectors.

The most remarkable feature of MHC is its polymorphism — the MHC genes (called HLA in humans) are the most genetically variable loci in the human genome, with thousands of alleles in the population. Each allelic variant encodes a slightly different peptide-binding groove with different anchor residue preferences, meaning different MHC alleles present different subsets of peptides from the same pathogen. This diversity operates at the population level: a pathogen that evolves to avoid presentation by one person's MHC alleles will still be presented by someone else's. This is why MHC matching is critical for organ transplantation — the recipient's T cells recognize donor MHC molecules as foreign and attack the graft — and why populations with greater MHC diversity tend to be more resilient against epidemic pathogens.