MR1 is aprotein that in humans is encoded by theMR1 gene and located onchromosome 1. Non-classical MHC class I genes are very often located on the same chromosome (micechromosome 17,humanchromosome 6) and interspaced within the same loci as theclassical MHC genes. MR1 is located on another chromosome, the detailedgene analysis revealed that MR1 is aparalog originated byduplication of MHClocus on chromosome 17 (mice). This functional gene has been found in almost allmammals, proving the importance of MR1 across themammalian kingdom and the fact that theduplication occurred early in theevolution of vertebrates.[5][7][8]
Another non-classical MHC class ICD1 is missing in certainspecies. There is 90% proteinhomology of the MR1 binding site between mice and humans. MR1 shares greaterhomology withclassical MHC I class than with non-classical MHC class I. The human MR1 protein has 341amino acid residues with a molecular weight of 39 366 daltons.[9][5]
MR1, like otherMHC class I molecules, is composed of α1, α2 and α3 domains. α1 and α2 interact and together bind theantigen. The ligand binding pocket is small and containsaromatic andbasic residues. Its small size limits it to only binding molecules of a similarly small size. α3 interacts withβ2 microglobulin.[5]
Many differentisoforms of MR1 have been identified. Many of the identified proteins have a premature terminating codon which generates non-functionalproteins. MR1B isoform lacks the α3 domain. The α3 domain interacts withβ2 microglobulin. This interaction and binding of theantigen stabilize the MHC I molecule. In the case of MR1Bβ2 microglobulin is not needed for stabilization of the structure. MR1B is expressed on thecell surface. This isoform bindsantigen via α1 and α2 interaction. Some bacteria are able to target specificβ2 microglobulin that enableMHC I presentation. This might be a mechanism used to avoid bacterialimmune evasion duringbacterial infections.[5]
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 ofriboflavine synthesis.
Many human cells can present antigensvia MR1 with varying efficiency.[10][11][12] Human body can't synthesize most of thevitamins, thus the presence of intermediates ofriboflavin synthesis is a marker of non-self. Manybacteria are capable ofvitamin synthesis.[13] The first discovered MR1 ligand was6-formyl pterin (6-FP).[5]
Within cells, MR1 is mostly stored inside theendoplasmic reticulum (ER), where ligand binding occurs.[14] Inside the ER, MR1 is stabilised in a ligand-receptive conformation by chaperone proteinstapasin and TAP-binding protein related (TAPBPR) to facilitate ligand binding.[14] After antigen binding MR1 undergoesconformational change, associate withβ2 microglobulin and is directed to thecell membrane.[15][5][13]
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 majority of MR1 ligands are uracil analogues, but some non-uracil drug-like molecules[16] also weakly bind to MR1.[17][18] Theligands 5-OP-RU and 5-OE-RU are compounds derived fromriboflavin biosynthesis that bind MR1 for presentation to MAIT cells for activation.[7] They are chemically unstable, but have been synthesised as chemical tools for studying MR1 biology.[19] 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 otherantigens. MR1 was able to stimulateT lymphocytes in the presence ofStreptococcus pyogenes, that is unable to synthesiseriboflavin. MR1 is important in the immune fight againstcancer, because MR1T lymphocytes were able to selectively kill variouscancer cells.[20]
Since the MR1 molecule is involved in presentation of cancer specific antigens and plays a role in tumor immunosurveillance, it has potential use in immunotherapy.[21]
Specific clones of MR1T lymphocytes (MC.7.G5) were able to kill various cancer cellsin vivo andin vitro and were inert to noncancerous cells. The MR1 expression on cancer cells is basal and appeared to be independent of bacterial load and MR1-ligand binding. Interestingly, cancer cell lines lacking a surface expression of MR1 weren't killed by MR1 T lymphocytes. Same result was shown in reaction to healthy but stressed or damaged cells, which were unable to activate MR1 T lymphocytes. This again suggests that some MR1 T lymphocytes can specifically react to a cancer cell derived ligand presented on the MR1 molecule.[22]
MAIT cells reactive to bacterialantigens are known as indirect tumor growth promoters with lowcytotoxic activity. On the contrary, self-reactive MR1-restricted T cells (described above) not only promoteinflammation and have much higher cytotoxic activity but also directly recognize tumor antigens presented on MR1 of cancer cells. This direct contact results in secretion of apoptosis-inducing factors and in death of a cancer cell.[23]
Taken together, immune response triggered by MR1-TCR interaction depends on the antigen presented on the MR1 receptor. As MAIT cells are enriched in mucosal sites like lungs or intestine, we can more likely expect a bacterial antigen presentation, which results in a different reaction of MAIT cells. It is shown that these cells inhibit NK cell and CD8+ T cell effector activity and the production ofIFNγ in the response to bacterial antigens presented on MR1.[24] As a result, we should be careful when manipulating with MR1 molecule as a therapeutic target. On one hand its depletion can prevent unpreferable polarization of immune cells and impairedNK andCD8+ T cells activity. On the other hand, as described earlier, cancer cells lacking MR1 had better survival rate as they were not recognized by MR1 T lymphocytes (lower immune surveillance of cancer). To make MR1 molecule truly clinically significant we need to get a better understanding of mechanisms and differences inantigen presentation. In several studies it has been shown that MR1 uses more than one pathway to capture and trafficmetabolite antigen depending on its source.[21]
As gutmicrobiota is modified in patients withdiabetes,[25] it is expected that MR1-TCR interaction will have an impact on the disease progression.
MR1, as has been shown in some studies, plays an important role in promoting inflammation duringobesity and Type 2 diabetes (T2D), specifically inadipose tissue andguts.[26] The study showed that mice lacking MR1 had a significantly decreasedtranscript level ofcytokines/chemokines known to be associated with inflammation, such asCcl2,Ccl5,Il1β,Il6,Il17a,Ifnγ, andTnfα. In contrast, the transcript level of regulatory factors (Foxp3,Il5, andIl13) was increased.[26]
Situation is a bit different when it comes to Type 1 diabetes (T1D). Both in patients with T1D and innon-obese diabetic (NOD) mice an alteration in frequency and functions of MAIT cells was detected. On the other hand, NOD mice lacking MR1 had greater anti-islet autoreactive T cell response and local activation ofdendritic cells which led topancreaticislet destruction. These mice had overall exacerbated diabetes in comparison to the control group.[27]
Some studies show that MAIT cells infiltrate thecolon in patients withulcerative colitis. Hagaet al. have previously reported that these cells also play an important role in pathogenesis ofinflammatory bowel diseases.[28] An important role of MR1-TCR interaction in ulcerative colitis has been shown on MR1-deficient mouse model. Interestingly, both deficient and control mice developed colitis, though survival rate in deficient mice was much higher, than in control group. This deficiency decreased overall inflammation in the colon and reduced colitis severity.[29][30]
Bothankylosing spondylitis (AS) andrheumatoid arthritis (RA) are chronic inflammatory diseases affecting mostlybones andjoints. Both of these diseases are also known asautoimmune orautoinflammatory diseases due to the presence of specificautoantibodies. It is also worth mentioning that they are often associated with other diseases such as IBD orpsoriasis.[31] As microbiome is changed in both IBD and psoriasis, it is expected that MAIT cells will again play an important role in overall pathogenesis of all these conditions. In both AS and RA systemic frequency of MAIT cells was decreased.[32] On the contrary, it was highly elevated insynovial fluid. Also somephenotypical changes have been shown. For example, activation of MAIT cells positively correlated with AS progression in patients. There was also higher production ofIL-17 by MAIT cells in peripheral blood and even higher in synovial fluid (none of these appeared in RA). Interestingly, it was observed only in male patients.[30][33][34]
^McWilliam HE, Villadangos JA (September 2017). "How MR1 Presents a Pathogen Metabolic Signature to Mucosal-Associated Invariant T (MAIT) Cells".Trends in Immunology.38 (9):679–689.doi:10.1016/j.it.2017.06.005.PMID28688841.
Maruyama K, Sugano S (January 1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides".Gene.138 (1–2):171–174.doi:10.1016/0378-1119(94)90802-8.PMID8125298.
Yamaguchi H, Hirai M, Kurosawa Y, Hashimoto K (September 1997). "A highly conserved major histocompatibility complex class I-related gene in mammals".Biochemical and Biophysical Research Communications.238 (3):697–702.doi:10.1006/bbrc.1997.7379.PMID9325151.
Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S (October 1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library".Gene.200 (1–2):149–156.doi:10.1016/S0378-1119(97)00411-3.PMID9373149.
Parra-Cuadrado JF, Navarro P, Mirones I, Setién F, Oteo M, Martínez-Naves E (August 2000). "A study on the polymorphism of human MHC class I-related MR1 gene and identification of an MR1-like pseudogene".Tissue Antigens.56 (2):170–172.doi:10.1034/j.1399-0039.2000.560211.x.PMID11019920.
Hempelmann A, Kumar S, Muralitharan S, Sander T (July 2006). "Myofibrillogenesis regulator 1 gene (MR-1) mutation in an Omani family with paroxysmal nonkinesigenic dyskinesia".Neuroscience Letters.402 (1–2):118–120.doi:10.1016/j.neulet.2006.03.048.PMID16632198.S2CID22214392.
