Major histocompatibility complex, class I-related

MR1 is a protein that in humans is encoded by the MR1 gene and located on chromosome 1. Non-classical MHC class I genes are very often located on the same chromosome (mice chromosome 6, human chromosome 17) and interspaced within the same loci as the classical MHC genes. MR1 is located on another chromosome, the detailed gene analysis revealed that MR1 is a paralog originated by duplication of MHC locus on chromosome 6 (mice). This functional gene has been found in almost all mammals, proving the importance of MR1 across the mammalian kingdom and the fact that the duplication occurred early in the evolution of vertebrates.[5][7][8]

Another non-classical MHC class I CD1 is missing in certain species. There is 90% protein homology of the MR1 binding site between mice and humans. MR1 shares greater homology with classical MHC I class than with non-classical MHC class I. The human MR1 protein has 341 amino acid residues with a molecular weight of 39 366 Daltons.[9][5]

MR1, like other MHC class I molecules, is composed of α1, α2 and α3 domains. α1 and α2 interact and together bind the antigen. The ligand binding pocket is small and contains aromatic and basic residues. Its small size limits it to only binding molecules of a similarly small size. α3 interacts with β2 microglobulin.[5]

Many different isoforms of MR1 have been identified. Many of the identified proteins have a premature terminating codon which generates non-functional proteins. MR1B isoform lacks the α3 domain. The α3 domain interacts with β2 microglobulin. This interaction and binding of the antigen stabilize the MHC I molecule. In the case of MR1B β2 microglobulin is not needed for stabilization of the structure. MR1B is expressed on the cell surface. This isoform binds antigen via α1 and α2 interaction. Some bacteria are able to target specific β2 microglobulin that enable MHC I presentation. This might be a mechanism used to avoid bacterial immune evasion during bacterial infections.[5]

The MR1 protein is capable of binding to molecules derived from bacterial riboflavin biosynthesis, and then present them to MAIT for activation.[7][8]

MR1 is almost undetectable under physiological conditions, surface expression increase in cells infected by microbes. Due to the antigen necessity for MR1 stabilization. MR1 binds the intermediates of riboflavine synthesis. Human body can´t synthesize most of the vitamins, thus the presence of intermediates of riboflavin synthesis is a marker of non-self. Many bacteria are capable of vitamine synthesis.[10] The first discovered MR1 ligand was 6-formyl pterin (6-FP).[5]

Within cells, MR1 is mostly stored inside the endoplasmic reticulum (ER), where ligand binding occurs.[11] Inside the ER, MR1 is stabilised in a ligand-receptive conformation by chaperone proteins tapasin and TAP-binding protein related (TAPBPR) to facilitate ligand binding.[11] After antigen binding MR1 undergoes conformational change, associate with β2 microglobulin and is directed to the cell membrane.[12][5][10]

MR1 stimulation is needed for MAIT development in thymus, the mechanism of antigen presentation in thymus is not clear.[5]

The MR1 pocket is composed primary of aromatic and basic amino acids and the volume is small, thus suitable for binding small molecule ligands.

The ligands 5-OP-RU and 5-OE-RU are compounds derived from riboflavin biosynthesis that bind MR1 for presentation to MAIT cells for activation.[13] They are chemically unstable, but have been synthesised as chemical tools for studying MR1 biology.[14] Ac-6-FP (acetyl-6-formylpterin) and 6-FP (6-formylpterin) also bind MR1, but they do not activate MAIT cells.[8] There is an evidence, that MR1 can bind other antigens. MR1 was able to stimulate T lymphocytes in the presence of Streptoccocus pyogenes, that is unable to synthesise riboflavin. MR1 is important in the immune fight against cancer, because MR1 T lymphocytes were able to selectively kill various cancer cells.[15]

A study showed that MR1 T lymphocytes were able to kill various cancer cells in vivo and in vitro and ignored noncancerous cells. The MR1 recognition was independent of bacterial load.[16]

MR1 deficient mice had impaired early phase mucosal cytokine production and delayed recruitment of activated T lymphocytes into infection site.[10]

There has not been any evidence of self antigens stimulating MR1 autoreactive T cells in any autoimmune disease.[10]