| MR1 | |||||||||||||||||||||||||||||||||||||||||||||||||||
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| Aliases | MR1 , HLALS, Major histocompatibility complex, class I-related | ||||||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | OMIM: 600764; MGI: 1195463; HomoloGene: 123981; GeneCards: MR1; OMA:MR1 - orthologs | ||||||||||||||||||||||||||||||||||||||||||||||||||
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Major histocompatibility complex class I-related gene protein (MR1) is a non-classical MHC class I protein, that binds vitamine metabolites (intermediates of riboflavin synthesis) produced in certain types of bacteria. MR1 interacts with mucosal associated invariant T cells (MAIT). [5] [6]
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 17, human chromosome 6) 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 17 (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.
Many human cells can present antigens via MR1 with varying efficiency. [10] [11] [12] 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. [13] 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. [14] 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. [14] After antigen binding MR1 undergoes conformational change, associate with β2 microglobulin and is directed to the cell membrane. [15] [5] [13]
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 majority of MR1 ligands are uracil analogues, but some non-uracil drug-like molecules [16] also weakly bind to MR1. [17] [18] 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. [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 other antigens. MR1 was able to stimulate T lymphocytes in the presence of Streptococcus 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. [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 MR1 T lymphocytes (MC.7.G5) were able to kill various cancer cells in vivo and in 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 bacterial antigens are known as indirect tumor growth promoters with low cytotoxic activity. On the contrary, self-reactive MR1-restricted T cells (described above) not only promote inflammation 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 of IFNγ 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 impaired NK and CD8+ 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 in antigen presentation. In several studies it has been shown that MR1 uses more than one pathway to capture and traffic metabolite antigen depending on its source. [21]
As gut microbiota is modified in patients with diabetes, [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 during obesity and Type 2 diabetes (T2D), specifically in adipose tissue and guts. [26] The study showed that mice lacking MR1 had a significantly decreased transcript level of cytokines/chemokines known to be associated with inflammation, such as Ccl2, Ccl5, Il1β, Il6, Il17a, Ifnγ , and Tnfα . In contrast, the transcript level of regulatory factors ( Foxp3 , Il5 , and Il13 ) was increased. [26]
Situation is a bit different when it comes to Type 1 diabetes (T1D). Both in patients with T1D and in non-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 of dendritic cells which led to pancreatic islet destruction. These mice had overall exacerbated diabetes in comparison to the control group. [27]
Some studies show that MAIT cells infiltrate the colon in patients with ulcerative colitis. Haga et al. have previously reported that these cells also play an important role in pathogenesis of inflammatory 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]
Both ankylosing spondylitis (AS) and rheumatoid arthritis (RA) are chronic inflammatory diseases affecting mostly bones and joints. Both of these diseases are also known as autoimmune or autoinflammatory diseases due to the presence of specific autoantibodies. It is also worth mentioning that they are often associated with other diseases such as IBD or psoriasis. [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 in synovial fluid. Also some phenotypical changes have been shown. For example, activation of MAIT cells positively correlated with AS progression in patients. There was also higher production of IL-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]
In immunology, an antigen (Ag) is a molecule, moiety, foreign particulate matter, or an allergen, such as pollen, that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune response.
T cells are one of the important types of white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell receptor (TCR) on their cell surface.
A cytotoxic T cell (also known as TC, cytotoxic T lymphocyte, CTL, T-killer cell, cytolytic T cell, CD8+ T-cell or killer T cell) is a T lymphocyte (a type of white blood cell) that kills cancer cells, cells that are infected by intracellular pathogens (such as viruses or bacteria), or cells that are damaged in other ways.
The major histocompatibility complex (MHC) is a large locus on vertebrate DNA containing a set of closely linked polymorphic genes that code for cell surface proteins essential for the adaptive immune system. These cell surface proteins are called MHC molecules.
An antigen-presenting cell (APC) or accessory cell is a cell that displays an antigen bound by major histocompatibility complex (MHC) proteins on its surface; this process is known as antigen presentation. T cells may recognize these complexes using their T cell receptors (TCRs). APCs process antigens and present them to T cells.
MHC class I molecules are one of two primary classes of major histocompatibility complex (MHC) molecules and are found on the cell surface of all nucleated cells in the bodies of vertebrates. They also occur on platelets, but not on red blood cells. Their function is to display peptide fragments of proteins from within the cell to cytotoxic T cells; this will trigger an immediate response from the immune system against a particular non-self antigen displayed with the help of an MHC class I protein. Because MHC class I molecules present peptides derived from cytosolic proteins, the pathway of MHC class I presentation is often called cytosolic or endogenous pathway.
The T-cell receptor (TCR) is a protein complex found on the surface of T cells, or T lymphocytes, that is responsible for recognizing fragments of antigen as peptides bound to major histocompatibility complex (MHC) molecules. The binding between TCR and antigen peptides is of relatively low affinity and is degenerate: that is, many TCRs recognize the same antigen peptide and many antigen peptides are recognized by the same TCR.
CD1 is a family of glycoproteins expressed on the surface of various human antigen-presenting cells. CD1 glycoproteins are structurally related to the class I MHC molecules, however, in contrast to MHC class 1 proteins, they present lipids, glycolipids and small molecules antigens, from both endogenous and pathogenic proteins, to T cells and activate an immune response. Both αβ and γδ T cells recognise CD1 molecules.
β2 microglobulin (B2M) is a component of MHC class I molecules. MHC class I molecules have α1, α2, and α3 proteins which are present on all nucleated cells. In humans, the β2 microglobulin protein is encoded by the B2M gene.
CD1D is the human gene that encodes the protein CD1d, a member of the CD1 family of glycoproteins expressed on the surface of various human antigen-presenting cells. They are non-classical MHC proteins, related to the class I MHC proteins, and are involved in the presentation of lipid antigens to T cells. CD1d is the only member of the group 2 CD1 molecules.
Antigen presentation is a vital immune process that is essential for T cell immune response triggering. Because T cells recognize only fragmented antigens displayed on cell surfaces, antigen processing must occur before the antigen fragment can be recognized by a T-cell receptor. Specifically, the fragment, bound to the major histocompatibility complex (MHC), is transported to the surface of the antigen-presenting cell, a process known as presentation. If there has been an infection with viruses or bacteria, the cell antigen-presenting cell will present an endogenous or exogenous peptide fragment derived from the antigen by MHC molecules. There are two types of MHC molecules which differ in the behaviour of the antigens: MHC class I molecules (MHC-I) bind peptides from the cell cytosol, while peptides generated in the endocytic vesicles after internalisation are bound to MHC class II (MHC-II). Cellular membranes separate these two cellular environments - intracellular and extracellular. Each T cell can only recognize tens to hundreds of copies of a unique sequence of a single peptide among thousands of other peptides presented on the same cell, because an MHC molecule in one cell can bind to quite a large range of peptides. Predicting which antigens will be presented to the immune system by a certain MHC/HLA type is difficult, but the technology involved is improving.
MHC Class II molecules are a class of major histocompatibility complex (MHC) molecules normally found only on professional antigen-presenting cells such as dendritic cells, macrophages, some endothelial cells, thymic epithelial cells, and B cells. These cells are important in initiating immune responses.
Cluster of Differentiation 86 is a protein constitutively expressed on dendritic cells, Langerhans cells, macrophages, B-cells, and on other antigen-presenting cells. Along with CD80, CD86 provides costimulatory signals necessary for T cell activation and survival. Depending on the ligand bound, CD86 can signal for self-regulation and cell-cell association, or for attenuation of regulation and cell-cell disassociation.
Understanding of the antitumor immunity role of CD4+ T cells has grown substantially since the late 1990s. CD4+ T cells (mature T-helper cells) play an important role in modulating immune responses to pathogens and tumor cells, and are important in orchestrating overall immune responses.
NKG2 also known as CD159 is a receptor for natural killer cells. There are 7 NKG2 types: A, B, C, D, E, F and H. NKG2D is an activating receptor on the NK cell surface. NKG2A dimerizes with CD94 to make an inhibitory receptor (CD94/NKG2).
HLA class I histocompatibility antigen, alpha chain F is a protein that in humans is encoded by the HLA-F gene. It is an empty intracellular molecule that encodes a non-classical heavy chain anchored to the membrane and forming a heterodimer with a β-2 microglobulin light chain. It belongs to the HLA class I heavy chain paralogues that separate from most of the HLA heavy chains. HLA-F is localized in the endoplasmic reticulum and Golgi apparatus, and is also unique in the sense that it exhibits few polymorphisms in the human population relative to the other HLA genes; however, there have been found different isoforms from numerous transcript variants found for the HLA-F gene. Its pathways include IFN-gamma signaling and CDK-mediated phosphorylation and removal of the Saccharomycescerevisiae Cdc6 protein, which is crucial for functional DNA replication.
Lymphocyte-activation gene 3, also known as LAG-3, is a protein which in humans is encoded by the LAG3 gene. LAG3, which was discovered in 1990 and was designated CD223 after the Seventh Human Leucocyte Differentiation Antigen Workshop in 2000, is a cell surface molecule with diverse biological effects on T cell function but overall has an immune inhibitory effect. It is an immune checkpoint receptor and as such is the target of various drug development programs by pharmaceutical companies seeking to develop new treatments for cancer and autoimmune disorders. In soluble form it is also being developed as a cancer drug in its own right.
Immunoevasins are proteins expressed by some viruses that enable the virus to evade immune recognition by interfering with MHC I complexes in the infected cell, therefore blocking the recognition of viral protein fragments by CD8+ cytotoxic T lymphocytes. Less frequently, MHC II antigen presentation and induced-self molecules may also be targeted. Some viral immunoevasins block peptide entry into the endoplasmic reticulum (ER) by targeting the TAP transporters. Immunoevasins are particularly abundant in viruses that are capable of establishing long-term infections of the host, such as herpesviruses.
Mucosal-associated invariant T cells make up a subset of T cells in the immune system that display innate, effector-like qualities. In humans, MAIT cells are found in the blood, liver, lungs, and mucosa, defending against microbial activity and infection. The MHC class I-like protein, MR1, is responsible for presenting bacterially-produced vitamin B2 and B9 metabolites to MAIT cells. After the presentation of foreign antigen by MR1, MAIT cells secrete pro-inflammatory cytokines and are capable of lysing bacterially-infected cells. MAIT cells can also be activated through MR1-independent signaling. In addition to possessing innate-like functions, this T cell subset supports the adaptive immune response and has a memory-like phenotype. Furthermore, MAIT cells are thought to play a role in autoimmune diseases, such as multiple sclerosis, arthritis and inflammatory bowel disease, although definitive evidence is yet to be published.
Group 1 CD1-restricted T cells are a heterogeneous group of unconventional T cells defined by their ability to recognize antigens bound on group 1 CD1 molecules with their TCR. Natural killer T (NKT) cells are a similar population with affinity to CD1d. Both groups recognize lipid antigens in contrast to the conventional peptide antigens presented on MHC class 1 and 2 proteins. Most identified T-cells that bind group 1 CD1 proteins are αβ T cells and some are γδ T cells. Both foreign and endogenous lipid antigens activate these cells.
