Alternative titles; symbols
HGNC Approved Gene Symbol: MR1
Cytogenetic location: 1q25.3 Genomic coordinates (GRCh38): 1:181,033,387-181,061,938 (from NCBI)
Hashimoto et al. (1995) identified an expressed class I gene, which they called MR1 (or MHC-related 1), by means of a PCR-based strategy using 2 primers that correspond to the 2 conserved regions in the alpha-3 domain of class I molecules. Similar to a typical class I molecule, the MR1 protein comprises a signal sequence, 3 extracellular domains (alpha-1, alpha-2, and alpha-3), a transmembrane domain, and a cytoplasmic domain.
Treiner et al. (2003) showed that T cells that express the canonical hV-alpha-7.2-J-alpha-33 T-cell receptor (TCR) rearrangement are preferentially located in the gut lamina propria of humans and are therefore genuine mucosal-associated invariant T (MAIT) cells. Selection and/or expansion of this population requires B lymphocytes, as MAIT cells are absent in B-cell-deficient patients. In addition, Treiner et al. (2003) demonstrated that MAIT cells are selected and/or restricted by MR1, a monomorphic major histocompatibility complex class I-related molecule that is markedly conserved in diverse mammalian species. MAIT cells are not present in germ-free mice, indicating that commensal flora are required for their expansion in the gut lamina propria. Treiner et al. (2003) concluded that this indicates that MAIT cells are probably involved in the host response at the site of pathogen entry, and may regulate intestinal B-cell activity.
Kjer-Nielsen et al. (2012) demonstrated that the structure and chemistry within the antigen-binding cleft of MR1 is distinct from the MHC and CD1 families. MR1 is ideally suited to bind ligands originating from vitamin metabolites. The structure of MR1 in complex with 6-formyl pterin, a folic acid (vitamin B9) metabolite, shows the pterin ring sequestered within MR1. Furthermore, Kjer-Nielsen et al. (2012) characterized related MR1-restricted vitamin derivatives, originating from the bacterial riboflavin (vitamin B2) biosynthetic pathway, which specifically and potently activate MAIT cells. Accordingly, the authors showed that metabolites of vitamin B represent a class of antigen that are presented by MR1 for MAIT cell immunosurveillance. Kjer-Nielsen et al. (2012) concluded that since many vitamin biosynthetic pathways are unique to bacteria and yeast, MAIT cells use these metabolites to detect microbial infection.
Mucosal-associated invariant T (MAIT) cells express a semi-invariant TCR that engages antigenic ligands presented by the nonpolymorphic MHC-like molecule MR1. MAIT TCRs typically comprise an alpha chain of TRAV1-2 (see 615442)/TRAJ33 (see 615443) paired with a beta chain of TRBV20-1 or TRBV6 (see 615446). MAIT cells are an innate T-cell subset with conserved recognition properties, but they also have an adaptive and specific TCR repertoire through V(D)J recombination. By stimulating human MAIT cells using a lung cell line infected with either Mycobacterium smegmatis, Candida albicans, or Salmonella typhimurium, followed by flow cytometric and molecular analyses, Gold et al. (2014) demonstrated differential TRAJ and TRBV gene usage across pathogen species. Gold et al. (2014) concluded that MAIT cells can detect a diverse array of MR1-restricted ligands and differentiate selectively in response to specific pathogens akin to classically restricted T cells.
Le Nours et al. (2019) described a diverse population of human gamma-delta T cells isolated from peripheral blood and tissues that exhibited autoreactivity to the monomorphic MR1 protein. The crystal structure of a gamma-delta TCR-MR1-antigen complex starkly contrasted with all other TCR-MHC and TCR-MHC-I-like complex structures. Namely, the gamma-delta TCR binds underneath the MR1 antigen-binding cleft, where contacts are dominated by the MR1 alpha-3 domain. A similar pattern of reactivity was observed for diverse MR1-restricted gamma-delta TCRs from multiple individuals. Accordingly, Le Nours et al. (2019) simultaneously reported MR1 as a ligand for human gamma-delta T cells and redefined the parameters for TCR recognition.
Hashimoto et al. (1995) mapped the MR1 gene by fluorescence in situ hybridization to 1q25.3. The localization of MR1 on chromosome 1 was also supported by the results of PCR amplification of the MR1 fragment from somatic cell hybrid DNAs.
Major histocompatibility complex (MHC) class I molecules present antigenic peptides to CD8-positive T cells. The HLA class I gene family in humans consists of 6 members: polymorphic HLA-A (142800), HLA-B (142830), and HLA-C (142840), and oligomorphic HLA-E (143010), HLA-F (143110), and HLA-G (142871). The functions of HLA-E, -F, and -G molecules are unknown, although HLA-G may play a role in the maternal-fetal interaction. Several groups of human class I-related molecules have been identified, including the CD1 family (e.g., CD1A; 188370), zinc-alpha-2-glycoprotein (AZGP1; 194460), MHC class I chain-related molecule A (MICA; 600169), and a human homolog of the rat neonatal Fc receptor (Simister and Mostov, 1989) (summary by Hashimoto et al., 1995).
In contrast to other known human divergent class I genes, MR1 encodes peptide-binding domains similar to those encoded by HLA class I genes on chromosome 6 and by nonmammalian classical MHC class I genes. Identification of a homolog of MR1 in the mouse genome implied that the ancestor of MR1 was present in the primordial mammalian species. Hashimoto et al. (1995) suggested that species at distinct evolutionary stages may adapt distinct gene lineages for their MHC. For example, in a New World primate (the cotton-top tamarin), the most broadly expressed class I gene lineage is HLA-G, which in the human is expressed only in a highly restricted manner and is oligomorphic. They suggested further that the location of the CD1 gene family, also on 1q, as well as many other members of the immunoglobulin gene superfamily, may be significant.
Gold, M. C., McLaren, J. E., Reistetter, J. A., Smyk-Pearson, S., Ladell, K., Swarbrick, G. M., Yu, Y. Y. L., Hansen, T. H., Lund, O., Nielsen, M., Gerritsen, B., Kesmir, C., Miles, J. J., Lewinsohn, D. A., Price, D. A., Lewinsohn, D. M. MR1-restricted MAIT cells display ligand discrimination and pathogen selectivity through distinct T cell receptor usage. J. Exp. Med. 211: 1601-1610, 2014. [PubMed: 25049333] [Full Text: https://doi.org/10.1084/jem.20140507]
Hashimoto, K., Hirai, M., Kurosawa, Y. A gene outside the human MHC related to classical HLA class I genes. Science 269: 693-695, 1995. [PubMed: 7624800] [Full Text: https://doi.org/10.1126/science.7624800]
Kjer-Nielsen, L., Patel, O., Corbett, A. J., Le Nours, J., Meehan, B., Liu, L., Bhati, M., Chen, Z., Kostenko, L., Reantragoon, R., Williamson, N. A., Purcell, A. W., Dudek, N. L., McConville, M. J., O'Hair, R. A. J., Khairallah, G. N., Godfrey, D. I., Fairlie, D. P., Rossjohn, J., McCluskey, J. MR1 presents microbial vitamin B metabolites to MAIT cells. Nature 491: 717-723, 2012. [PubMed: 23051753] [Full Text: https://doi.org/10.1038/nature11605]
Le Nours, J., Gherardin, N. A., Ramarathinam, S. H., Awad, W., Wiede, F., Gully, B. S., Khandokar, Y., Praveena, T., Wubben, JM., Sandow, J. J., Webb, A. I., von Borstel, A., and 23 others. A class of gamma-delta T cell receptors recognize the underside of the antigen-presenting molecule MR1. Science 366: 1522-1527, 2019. [PubMed: 31857486] [Full Text: https://doi.org/10.1126/science.aav3900]
Simister, N. E., Mostov, K. E. An Fc receptor structurally related to MHC class I antigens. Nature 337: 184-187, 1989. [PubMed: 2911353] [Full Text: https://doi.org/10.1038/337184a0]
Treiner, E., Duban, L., Bahram, S., Radosavljevic, M., Wanner, V., Tilloy, F., Affaticati, P., Gilfillan, S., Lantz, O. Selection of evolutionarily conserved mucosal-associated invariant T cells by MRI. Nature 422: 164-169, 2003. Note: Erratum: Nature 423: 1018 only, 2003. [PubMed: 12634786] [Full Text: https://doi.org/10.1038/nature01433]