MHC class I molecules are expressed on all body cells, where they “present” bound peptides to CD8+ T cells to facilitate peptide-specific cytotoxic T cell responses. MHC class I molecules also interact with a variety of natural killer (NK) cell receptors. This interaction is not peptide specific, although it has been demonstrated that peptide sequences may affect binding strength of some NK cell receptors. MHC class I molecules play critical roles in immune responses against tumors and viruses.
The pathway leading to formation of the HC/b2m/peptide complex (see Figure 1, above) was mapped out in the 1990s:10 Cytosolic proteins (including viral proteins in infected cells or tumor-associated proteins in cancer cells) are degraded by the proteasome. Peptides are then transported from the cytosol into the endoplasmic reticulum (ER) by a peptide pump called TAP (transporter associated with antigen processing). In the ER, these peptides are loaded into the peptide binding groove of nascent MHC class I molecules. This involves the interaction with chaperone proteins that facilitate the correct folding of the HC/b2m/peptide complex. Further, peptidases like ERAP1 (ER aminopeptidase 1) trim the peptides to a length of 8–9 amino acids, which is the optimal size to fit into MHC class I molecules. Once correctly assembled, the HC/b2m/peptide complex moves through the Golgi apparatus to the cell surface.
The amino acid sequence of the MHC class I HC determines which peptides can be loaded and presented on the cell surface (i.e., different MHC alleles present different peptides). The high degree of heterogeneity of HC sequences is thought to represent a safety mechanism that prevents pathogens from escaping an adaptive immune response by mutating their protein sequences so that no pathogen-derived peptide can be presented by any MHC molecule.
MHC Nomenclature & HLA-B27 Variants
The sequences of the polymorphic HLA genes are curated by the WHO Nomenclature Committee for Factors of the HLA System. The current system uses an eight-letter code to categorize each newly discovered MHC class I allele.11 In HLA-B*27:05:02:01, the B refers to the gene locus; the first two digits after the * identify an allele family, which in general corresponds to serological reactivity (e.g., HLA-B27 vs. HLA-B08); subsequent numbers separated by colons group alleles in a hierarchical manner according to differences in amino acid sequence, nucleotide sequence of the coding region and nucleotide sequence of introns/untranslated regions. For example, the protein sequence of HLA-B*27:04 differs from HLA-B*27:05 by three amino acid residues, whereas in HLA-B*27:05:02 and HLA-B*27:05:03 the same amino acid sequence is encoded by a slightly different nucleotide sequence owing to the redundancy of the genetic code.
