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 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. This functional gene has been found almost in all the mammals, that prooves the importance of MR1 across the mammalian kingdom and the fact that the duplication has occurred early in the evolution of vertebrates. For example another non-classical MHC class I CD1 is missing in certain species. There is 90% protein homology of the MR1 binding site within mice and human. MR1 shares greater homology with classical MHC I class than with non-classical MHC class I. Human MR1 protein has 341 amino acid residues with a molecular weight of 39 366 Daltons.
Structure
MR1, similary as other MHC class I molecules, is composed of α1, α2 and α3 domains. α1 and α2 interact together and bind the antigen, the ligand bindingpocket contains aromatic and basic residues, also is very small. This indicates that only small molecules can fit in the groove. α3 interacts with β2 microglobulin. It has been identified many different isoforms of MR1, many of them have premature terminating codon generating non-functional proteins. MR1B isoform lacks α3 domain. α3 domain is interacting with β2 microglobulin, this interaction and bounded antigen stabilize the whole MHC Imolecule. In a case of MR1B is β2 microglobulin not needed for stabilized structure and MR1B is expressed on the cell surface. This isoform binds antigen via α1 and α2 interaction. Some bacteria are able to target specifically β2 microglobulin thus unabling the MHC I presentation. This might be a way how to avoid bacterial immune evasion during bacterial infections.
Antigens presentation
The MR1 protein is capable of binding to molecules derived from bacterial riboflavin biosynthesis, and then present them to MAIT for activation. 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. The first discovered MR1 ligand was 6-formyl pterin. Within cells, MR1 is mostly stored inside the endoplasmic reticulum, where the binding of bacterial riboflavin-related molecules to MR1 occurs. The MR1 pocket is composed primary of aromatic and basic amino acids and the pocket volume is small. After antigen binding MR1 undergoes conformational change, associate with β2 microglobulin and is directed to the cell membrane. MR1 stimulation is needed for MAIT development in thymus, the mechanism of antigen presentation in thymus is not clear.
MR1 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. They are chemically unstable, but have been synthesised as chemical tools for studying MR1 biology. Ac-6-FP and 6-FP also bind MR1, but they do not activate MAIT cells. 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.
Clinical signficance
Recently Crowther´s study revealed that MR1 T lymphocytes were able to effectively kill various cancer cells in vivo and in vitro and didn´t harm noncancerous cells. The MR1 recognition was independent of bacterial load. MR1 deficient mice had impaired early phase mucosal cytokine production and delayed recruitment of activated T lymphocytes into infection site. There has not been any evidence of self antigens stimulating MR1 autoreactive T cells in any autoimmune disease.
