MHC class Ib molecules bridge innate and acquired immunity

Key Points Classical MHC class I molecules (also known as MHC class Ia molecules) are extremely polymorphic. They are the main molecules that present pathogen-derived peptides to T cells, and they also interact with natural killer (NK)-cell receptors. By contrast, non-classical MHC class I molecules (also known as MHC class Ib molecules) are diverse in function and genetic relatedness, but each locus is oligomorphic. We distinguish between three loose groupings of MHC class Ib molecules. 'Young' molecules have only recently diverged from the MHC class Ia molecules of their taxonomic group, and they have many similar physical properties, including the ability to bind peptides. They differ mainly in terms of patterns of tissue expression and, sometimes, in their cellular trafficking. 'Middle-aged' molecules — such as H2–M3, Qa1 and HLA-E — seem to have arisen early in mammalian evolution. 'Old' molecules include molecules — such as CD1, and MICA (MHC-class-I-polypeptide-related sequence A) and MICB — that interact with NK-cell receptors and/or T-cell receptors (TCRs). The mouse molecule H2–M3 is specialized for binding N -formyl peptides, which are products of prokaryotic-type protein synthesis (by bacteria and mitochondria), but H2–M3 shows little specificity beyond this biochemical requirement. Such N -formyl peptides are rare in mammalian cells. H2–M3 must acquire its ligands intracellularly. Other MHC class I molecules can use weakly binding peptides to exit the endoplasmic reticulum (ER) and can exchange them for high-affinity peptides at the cell surface. There are few weak-binding peptides available to bind H2–M3, so it must wait in the ER. Positive selection of H2–M3-restricted T cells makes use of only a few mitochondrial peptides, but these can select a diverse group of T cells (which is known as the gemisch model). H2–M3-restricted CD8 + T cells are early responders in primary infection. For reasons that are not yet clear, these cytotoxic T lymphocytes (CTLs) appear 1 or 2 days earlier than MHC-class-Ia-restricted CTLs. There do not seem to be H2–M3-restricted memory CTLs, however, because MHC-class-Ia-restricted memory CTLs destroy the dendritic cells that would restimulate them. Qa1 and HLA-E (collectively denoted as QE in this article) are not closely related, but they have almost identical functions. QE molecules bind several unusual sets of peptides. Qa1 determinant modifier (Qdm) peptides derive from the signal peptides of other MHC class I