In the cell-mediated arm of the adaptive immune response, short peptides are bound by major histocompatibility complex (MHC) class I and class II molecules and presented at the cell surface where they are recognized by the antigen receptors of T lymphocytes. Binding of a T-cell receptor (TCR) that recognizes a particular MHC–peptide complex induces naïve lymphocytes to differentiate into effector cells (cytotoxic and helper T cells) that destroy infected host cells or stimulate antibody production, and memory cells that provide protective immunity against reinfection.
Structure and function of MHC molecules
Two multigene families located within the MHC genomic region encode antigen-binding molecules that present foreign peptides at the cell surface. In actuality, MHC molecules also present self-derived peptides. However, negative thymic selection against autoreactive T cells prevents MHC–self-peptide complexes from eliciting an immune response. MHC class I molecules are expressed on most nucleated cells and typically present endogenous peptides derived from intracellular pathogens replicating within the cytosol (e.g. viruses). Cytosolic proteins are degraded into short peptide fragments by the proteasome, and are first transported into the endoplasmic reticulum (ER) by the ATP-dependent transporters TAP1 & 2 for MHCI loading, and then to the cell surface for presentation to circulating cytotoxic CD8+ T cells whose function is to induce apoptosis and lysis of the infected target cell. (Figures are adapted from Murphy et al. (2008) Figs. 3.12, 3.25, 5.5, & 5.11.)
Structural similarities of MHCI and MHCII molecules likely reflect their descent from a common ancestor. Mature MHC molecules are type I integral membrane glycoproteins composed of a peptide-binding groove and immunoglobulin-like, transmembrane, and cytoplasmic domains. The extracellular portions of MHC molecules consist of two membrane-distal domains that together form a peptide-binding cavity that is bounded by two interrupted α helices resting atop an antiparallel β sheet, and two membrane-proximal immunoglobulin-like (Ig-like) domains that participate in CD4 and CD8 coreceptor binding.
Despite these structural similarities, the protein subunits are encoded differently for class I and II molecules. MHCI molecules are heterodimers formed by noncovalent association between a MHCIα heavy chain and β2-microglobulin (β2m), which is encoded by a largely invariant locus situated outside the MHC genomic region. The heavy chain contributes both of the peptide-binding cleft and one of the Ig-like domains, while β2m supplies only a second Ig-like region that lacks a transmembrane anchor. MHC class II molecules are heterodimers that are formed by the noncovalent association of an α and β chain, both of which contribute single peptide-binding and membrane-anchored Ig-like domains, and each of which is transcribed from a distinct locus typically found within the MHC region.
MHC gene family members can be further subdivided into classical or nonclassical loci, in addition to nonfunctional pseudogenes. Classical MHC Ia loci are widely expressed and are typically associated with high sequence variability and positive selection acting on substitutions at peptide-binding region (PBR) residues. Nonclassical MHC Ib loci instead have reduced ex
Extreme polymorphism at the population level and evidence of balancing selection indicate that substantial allelic variation of MHC genes is likely needed to recognize and respond to a diverse assemblage of pathogens. However, despite extensive gene duplication in some species, individuals typically express only a moderate number of classical MHC loci and reversion to disomic inheritance is also observed in some polyploid Xenopus species. Constraints to intra-individual MHC variation (at least for highly expressed classical loci) are thought to reflect a functional tradeoff between increasing the allelic repertoire to present a greater variety of pathogenic peptides against the accompanying reduction in T-cell repertoire that would be needed to maintain self-tolerance. Individual MHC molecules must therefore be capable of permissive peptide binding to adequately recognize a broad range of foreign antigens. However, there is also a need to generate stable MHC–peptide complexes that will persist for sufficient duration to allow T cell recognition and that will not exchange peptides at the cell surface, which could result in the destruction of uninfected cells. Such stability is generally associated with high affinity, and therefore restrictive, intermolecular interactions.
MHC molecules reconcile these competing binding requirements through an elegant structural solution: contacts between highly conserved peptide-binding region (PBR) residues of the MHC molecule and peptide mainchain atoms stabilize the promiscuous binding of most peptidic ligands, whereas polymorphic residues lining the peptide-binding groove create irregular pockets with differing stereochemistry that accommodate peptide residues in a sequence-dependent manner. Restrictions imposed by sidechain-binding pockets vary both between alleles and between pockets within a single MHC molecule. Pockets imposing more stringent binding requirements are said to accommodate “primary anchor” peptide residues, while “secondary anchors” are more flexible in their binding preferences. Together, these specificities determine the peptide-binding motif of a particular MHC allele to confer selectivity upon antigen presentation.