Key Points
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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.
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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).
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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.
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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.
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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).
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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.
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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 molecules, and they are presented to TCRs and NK-cell receptors. Peptides derived from cytomegalovirus and other viruses mimic Qdm. Furthermore, peptides derived from stress-induced mitochondrial heat-shock protein 60 and bacterial GroEL are highly crossreactive, and their presentation in the context of Qa1 or HLA-E might lead to cross-protection and autoimmunity. Finally, at least some CD8+ T suppressor cells detect peptides derived from the variable region of the TCR β-chain (Vβ) of autoimmune CD4+ T cells, and these cells can suppress autoimmunity.
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Production of Qdm peptide involves signal-peptide peptidase (SPPase), which releases Qdm from the parent signal peptide into the cytoplasm, where it enters the canonical antigen-processing pathway. SPPase might also be important for processing other signal-peptide-derived epitopes.
Abstract
Our understanding of the classical MHC class I molecules (MHC class Ia molecules) has long focused on their extreme polymorphism. These molecules present peptides to T cells and are central to discrimination between self and non-self. By contrast, the functions of the non-polymorphic MHC class I molecules (MHC class Ib molecules) have been elusive, but emerging evidence reveals that, in addition to antigen presentation, MHC class Ib molecules are involved in immunoregulation. As we discuss here, the subset of MHC class Ib molecules that presents peptides to T cells bridges innate and acquired immunity, and this provides insights into the origins of acquired immunity.
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Acknowledgements
We thank former members of our laboratory for many years of discussions. We also thank colleagues who sent us preprints and clarifications, and D. Lewis for close and critical reading of the manuscript. We apologize to colleagues whose work we were unable to cite due to space restrictions.
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Glossary
- POLYMORPHIC
-
In population genetics, a gene is polymorphic when it has many alleles in a population.
- ANCHOR
-
Peptide ligands of most MHC molecules are anchored in the binding groove by specific binding to particular pockets within the groove. Each MHC molecule is specific for two or three anchor residues in the peptide.
- OLIGOMORPHIC
-
In population genetics, a locus is oligomorphic when it has only a few main alleles in a population. Most loci are oligomorphic.
- ORTHOLOGOUS
-
Genes in different species are orthologous when their phylogeny is identical to the phylogeny of the species. So, α-globins are orthologous, because a single copy present in ancestral species gives rise to α-globins in descendent species. By contrast, α-globin and β-globin are paralogous, because a gene duplication occurred in an ancestral species, leaving two copies in all descendants.
- N-FORMYL
-
Bacteria initiate protein synthesis with N-formylmethionine, a modified form of the amino acid methionine. Almost the only eukaryotic proteins that contain N-formylmethionine, and are therefore N-formylated, are those encoded by mitochondria.
- SIGNAL PEPTIDES
-
Co-translational translocation of most secreted and membrane-bound proteins is initiated by a hydrophobic signal peptide that is recognized by the translocation apparatus. After translocation, signal peptides are usually removed from the mature protein by signal peptidase.
- GroEL
-
(Bacteriophage growth mutant, restored by mutants in λ head protein gene E, long form). A bacterial chaperone that is closely related to mitochondrial heat-shock protein 60.
- POCKET TRANSPLANT
-
The amino acids that confer specificity to individual pockets of the peptide-binding groove can be genetically introduced into other MHC molecules, creating hybrid MHC molecules with new specificities.
- CROSS-PRESENTATION
-
The ability of certain antigen-presenting cells to load peptides that are derived from exogenous antigens onto MHC class I molecules and present these at the cell surface. This property is atypical, as most cells exclusively present peptides derived from endogenous proteins on MHC class I molecules. Cross-presentation is essential for the initiation of immune responses to viruses that do not infect antigen-presenting cells.
- CHAPERONE
-
Newly synthesized proteins must fold into a particular three-dimensional conformation, which is an extremely difficult process that most proteins fail to accomplish. Folding is assisted by chaperone proteins that bind and stabilize folding intermediates.
- FETAL THYMIC ORGAN CULTURES
-
Removal of day-16 fetal thymi allows the analysis of antigen-driven positive- and negative-selection events during in vitro culture.
- HOMOLOGUE
-
Sequences or structures that are related to each other by descent from a common ancestral sequence or structure are homologues. All members of a gene family are homologues, by definition.
- MIXED-LYMPHOCYTE REACTIONS
-
A tissue-culture technique for testing T-cell reactivity. The proliferation of one population of T cells, induced by exposure to inactivated MHC-mismatched stimulator cells, is determined by measuring the incorporation of 3H-thymidine into the DNA of dividing cells.
- PRESENILIN-TYPE ASPARTIC PEPTIDASES
-
A family of transmembrane proteases that have an active site in the plane of the membrane and can therefore cleave transmembrane peptides. Examples include presenilin-1, mutations of which are associated with early onset of Alzheimer's disease, and signal-peptide peptidase.
- QE-RESTRICTED CD8+ TSUP cells
-
(QE-RESTRICTED CD8+ T suppressor cells). A subset of CD8+ T cells that can suppress the responses of CD4+ T cells, usually T helper 1 cells. These cells are characterized by T-cell receptors that are restricted by Qa1 or HLA-E, but they often express additional markers that are characteristic of natural killer T cells, such as natural-killer-cell receptors. In humans, these T cells are often CD28−
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Rodgers, J., Cook, R. MHC class Ib molecules bridge innate and acquired immunity. Nat Rev Immunol 5, 459–471 (2005). https://doi.org/10.1038/nri1635
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DOI: https://doi.org/10.1038/nri1635
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