Biology:Mucosal associated invariant T cell
Mucosal associated invariant T cells (MAIT 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 B 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.
MAIT cells constitute a subset of αβ T lymphocytes characterized by a semi-invariant T cell receptor alpha (TCRα) chain. The TCRα originates from the rearrangement of TCRα variable (V) and joining (J) gene segments TRAV1-2/TRAJ12/20/33 during VDJ recombination in the nucleus. However, TRAJ33 is expressed more often than TRAJ12 and TRAJ20. With little diversity in the TCRα chain, the TCR is more conserved in MAIT cells than in other T cell subsets. In addition, the TCRα chain can combine with a restricted number of possible TCRβ chains to form a functional MAIT cell TCR, further limiting TCR diversity.
MAIT cells were initially specified as T cells that do not express the TCR co-receptors CD4 or CD8 on the cell surface. However, CD8+ MAIT cells have been recently observed. In humans, MAIT cells express high levels of CD161, interleukin-18 (IL-18) receptor, and chemokine receptors CCR5, CXCR6, and CCR6 on the cell surface. Additionally, as an indication of their memory-like phenotype in the periphery, mature MAIT cells express a CD44+, CD45RO+, CCR7−, CD62Llo phenotype.
Development & presence in the body
Like all T cell subsets, MAIT cells develop in the thymus. Here, T cells rearrange their TCRs and are subjected to TCR affinity tests as a part of positive selection and negative selection. However, rather than undergoing selection on MHC class I or II molecules, MAIT cells interact with the MHC class I-like molecule, MR1, on thymocytes. MR1 also serves as the antigen-presenting molecule outside of the thymus that binds to TCR and activates MAIT cells. MAIT cells display effector-like qualities before leaving the thymus, which is why they are often described as innate-like T cells in the peripheral tissue. This thymic development process is found in both mice and human MAIT cell populations.
In healthy humans, MAIT cells are found in the lungs, liver, joints, blood, and mucosal tissues, such as the intestinal mucosa. In total, MAIT cells make up roughly 5% of the peripheral T cell population. MAIT cells are most common in the liver, where they usually comprise 20-40% of the T lymphocyte population. The total murine MAIT cell population is roughly ten times smaller than the human MAIT cell population.
While MAIT cells display effector characteristics immediately out of the thymus, they may also undergo clonal expansion in the periphery and establish antigen memory. In this way, MAIT cells display both innate and adaptive characteristics.
MAIT cell activation
MAIT cells can be activated in ways that involve, and do not involve, MR1-mediated antigen presentation. However, MR1-independent and MR1-dependent activation elicit separate MAIT cell functions as part of an immune response. During MR1-independent activation against Mycobacteria, MAIT cells bind extracellular IL-12, which is often secreted by stressed macrophages. In response to IL-12, MAIT cells produce and secrete interferon-gamma (IFN-γ), a cytokine that activate macrophages, assists in the maturation of dendritic cells, and promotes the expression of MHC class II on antigen presenting cells. MAIT cells also secrete IL-17, an important pro-inflammatory cytokine, after binding IL-23.
MAIT cells are also activated in a MR1-dependent manner, in which a MAIT cell's semi-invariant TCR binds to the MR1 protein presenting antigen. While most T cell subsets have TCRs that recognize peptide or lipid-based antigens in association with MHC or CD1, MAIT cells are unique in that they recognize small molecules created through the process of vitamin B2 (riboflavin) and B9 (folic acid) biosynthesis. The vitamin B2 related molecules that activate MAIT cells are chemically unstable, and undergo spontaneous degradation in water, although they have now been successfully chemically synthesised and isolated. Riboflavin and folic acid are both crucial components of the metabolic pathways in bacteria. When MR1 associates with these small molecules and becomes expressed on the surface of antigen-presenting cells, MAIT cell TCRs then bind to MR1, leading to MAIT cell activation, clonal expansion, memory, and an array of antimicrobial responses. While protective against some pathogens, MAIT cell activation can produce inflammatory cytokines that augment immunopathology and gastritis in chronic infection by Helicobacter pylori.
MAIT cell antigens
MAIT cells are activated by compounds derived from bacterial vitamin B2 (riboflavin) biosynthesis. In 2014, the exact identity of the antigens were found to be the compounds 5-OP-RU (5-(2-oxopropylideneamino)-6-D-ribitylaminouracil) and 5-OE-RU (5-(2-oxoethylideneamino)-6-D-ribitylaminouracil). Both compounds are highly potent in activating MAIT cells, but are chemically unstable. Both have been chemically synthesised, stabilised and characterised in the solvent DMSO, allowing for the unstable compounds to be used as reagents for the study of MAIT cells.
A chemically stable antigen that is functionally similar to 5-OP-RU has also been created.
A 2017 study also found that some common drugs and drug-like molecules can modulate MAIT cell function in mammals.
Like MHC class I, MR1 is found in all a large variety of cells and associates with β2-microglobulin. However, it remains to be understood whether certain cell types, such as myeloid or epithelial cells, more commonly display antigen to MAIT. While MHC class I alleles are extremely diverse in human populations, MR1 is non-polymorphic and highly conserved. In fact, when comparing the genetic content of humans and mice to each other, there is a 90% similarity in MR1 coding sequences. Furthermore, the ligand-binding grooves of MR1 molecules differ from those of MHC class I molecules in that they are smaller in size and specifically bind metabolic products of bacteria.
MR1 is found intracellularly in the endoplasmic reticulum and interacts with some of the common MHC loading complex components and chaperone proteins (e.g. TAP, ERp57, and tapasin). The loading of vitamin B metabolic molecules onto MR1 occurs in a way that is different from peptide loading onto MHC class I. Yet the specifics of this process must be further looked into.
In healthy cells, MR1 is sparsely exhibited on the cell surface. However, MR1 expression is upregulated on the surface after cell infection or the introduction of a bacterially-produced MR1 ligand. Once expressed on the surface, MR1, with its antigen ligand covalently-attached, binds to the appropriate MAIT cell TCR.
MAIT cells display effector-like qualities, allowing them to directly respond to microbial pathogens immediately following activation. In a MR1-dependent manner, MAIT cells respond to bacteria by producing cytokines and strengthening their cytotoxic functions. After TCR binding and activation, MAIT cells secrete several cytokines, including tumor necrosis factor alpha (TNF-α), IFN-γ, and IL-17. These cytokines are pro-inflammatory and activate important cells in the immune response, such as macrophages and dendritic cells. After activation, MAIT cells also produce cytolytic molecules perforin and granzyme B, which form pores in the bacterially-infected cells, leading to apoptosis and the elimination of dangerous microbes from the body.
MAIT cells can target a wide variety of microbes, including Staphylococcus aureus, Escherichia coli Mycobacterium tuberculosis, Candida albicans, and Salmonella enterica, to name a few. However, some types of bacteria, including strains of Listeria and Enterobacter, may escape MAIT cell targeting. These strains avoid MAIT cell-mediated elimination because they have unusual riboflavin metabolic pathways that do not produce viable ligands for MR1 molecules.
While MAIT cells have not been found to target viruses in a TCR-dependent manner, they can respond against viruses upon stimulation with IL-18 and other cytokines, such as IL-12 and IFN-α/β. After receiving these cytokine signals, MAIT cells secrete anti-viral cytotoxic molecules and cytokines that aid the immune response.
Role in autoimmunity
While MAIT cells play a crucial role in the immune system by targeting bacterially-infected cells and other pathogens, they may also attack healthy cells and play a role in certain autoimmune diseases.
For individuals with the autoimmune disease multiple sclerosis (MS), the immune system attacks the myelin sheaths covering nerves, causing impaired nerve signaling. While T helper 1 (Th1) and T helper 17 (Th17) cells have been reported as contributors to MS by increasing inflammation at myelin sites, human MAIT cells have also been observed at these sites. In addition, during periods of myelin degeneration, MAIT cell levels in the peripheral blood have been found to decrease, suggesting their tendency to migrate to sites of MS-related inflammation. At these sites, MAIT cells further contribute to the autoimmune response by secreting pro-inflammatory cytokines. However, in contrast to these findings, MAIT cells have also been found to display a protective role in MS by limiting Th1 cell secretion of IFN-γ at sites of inflammation. To explain these findings, the role of MAIT cells in MS must be further explored.
Inflammatory bowel disease
In autoimmune-related inflammatory bowel disease, the immune system initiates a response against healthy parts of the gastrointestinal tract, such as the mucosal microbiome. During relapse periods of certain types of inflammatory bowel disease, such as Crohn’s disease, MAIT cells have been found to migrate to sites of inflammation, triggering the harmful responses of other immune cells through the expression of NKG2D and increasing inflammation by secreting IL-17.
In systematic autoimmune rheumatic diseases, such as rheumatoid arthritis and systemic lupus erythematosus (SLE), MAIT cells are activated through TCR-independent signaling. Stimulated by IL-12, IL-18, and IL-23, MAIT cells can produce and secrete pro-inflammatory cytokines, drawing immune cells into areas of the autoimmune attack. In this way, MAIT cells facilitate and intensify the harmful effects of systematic autoimmune rheumatic diseases.
- Napier, Ruth J.; Adams, Erin J.; Gold, Marielle C.; Lewinsohn, David M. (2015-07-06). "The Role of Mucosal Associated Invariant T Cells in Antimicrobial Immunity". Frontiers in Immunology 6: 344. doi:10.3389/fimmu.2015.00344. ISSN 1664-3224. PMID 26217338.
- Gold, Marielle C.; Lewinsohn, David M. (2017-02-12). "Mucosal associated invariant T cells and the immune response to infection". Microbes and Infection / Institut Pasteur 13 (8–9): 742–748. doi:10.1016/j.micinf.2011.03.007. ISSN 1286-4579. PMID 21458588.
- Eckle, Sidonia B. G.; Corbett, Alexandra J.; Keller, Andrew N.; Chen, Zhenjun; Godfrey, Dale I.; Liu, Ligong; Mak, Jeffrey Y. W.; Fairlie, David P. et al. (2015-12-18). "Recognition of Vitamin B Precursors and Byproducts by Mucosal Associated Invariant T Cells". The Journal of Biological Chemistry 290 (51): 30204–30211. doi:10.1074/jbc.R115.685990. ISSN 0021-9258. PMID 26468291.
- Ussher, James E.; Klenerman, Paul; Willberg, Chris B. (2014-10-08). "Mucosal-Associated Invariant T-Cells: New Players in Anti-Bacterial Immunity". Frontiers in Immunology 5: 450. doi:10.3389/fimmu.2014.00450. ISSN 1664-3224. PMID 25339949.
- Howson, Lauren J.; Salio, Mariolina; Cerundolo, Vincenzo (2015-06-16). "MR1-Restricted Mucosal-Associated Invariant T Cells and Their Activation during Infectious Diseases". Frontiers in Immunology 6: 303. doi:10.3389/fimmu.2015.00303. ISSN 1664-3224. PMID 26136743.
- Hinks, Timothy S. C. (2016). "Mucosal‐associated invariant T cells in autoimmunity, immune‐mediated diseases and airways, disease". Immunology 148 (1): 1–12. doi:10.1111/imm.12582. ISSN 0019-2805. PMID 26778581.
- Bianchini, Elena; De Biasi, Sara; Simone, Anna Maria; Ferraro, Diana; Sola, Patrizia; Cossarizza, Andrea; Pinti, Marcello (2017-03-01). "Invariant natural killer T cells and mucosal-associated invariant T cells in multiple sclerosis". Immunology Letters 183: 1–7. doi:10.1016/j.imlet.2017.01.009. PMID 28119072.
- Treiner, Emmanuel; Duban, Livine; Bahram, Seiamak; Radosavljevic, Mirjana; Wanner, Valerie; Tilloy, Florence; Affaticati, Pierre; Gilfillan, Susan et al. (2003-03-13). "Selection of evolutionarily conserved mucosal-associated invariant T cells by MR1" (in en). Nature 422 (6928): 164–169. doi:10.1038/nature01433. ISSN 0028-0836. PMID 12634786.
- Lepore, Marco; Kalinicenko, Artem; Colone, Alessia; Paleja, Bhairav; Singhal, Amit; Tschumi, Andreas; Lee, Bernett; Poidinger, Michael et al. (2014-05-15). "Parallel T-cell cloning and deep sequencing of human MAIT cells reveal stable oligoclonal TCRβ repertoire" (in en). Nature Communications 5: 3866. doi:10.1038/ncomms4866. ISSN 2041-1723. PMID 24832684.
- Porcelli, S.; Yockey, C. E.; Brenner, M. B.; Balk, S. P. (1993-07-01). "Analysis of T cell antigen receptor (TCR) expression by human peripheral blood CD4-8- alpha/beta T cells demonstrates preferential use of several V beta genes and an invariant TCR alpha chain." (in en). Journal of Experimental Medicine 178 (1): 1–16. doi:10.1084/jem.178.1.1. ISSN 0022-1007. PMID 8391057.
- Sakala, Isaac G.; Kjer-Nielsen, Lars; Eickhoff, Christopher S.; Wang, Xiaoli; Blazevic, Azra; Liu, Ligong; Fairlie, David P.; Rossjohn, Jamie et al. (2015-07-15). "Functional heterogeneity and anti-mycobacterial effects of mouse mucosal associated invariant T (MAIT) cells specific for riboflavin metabolites". Journal of Immunology 195 (2): 587–601. doi:10.4049/jimmunol.1402545. ISSN 0022-1767. PMID 26063000.
- Rahimpour, Azad; Koay, Hui Fern; Enders, Anselm; Clanchy, Rhiannon; Eckle, Sidonia B.G.; Meehan, Bronwyn; Chen, Zhenjun; Whittle, Belinda et al. (2015-06-29). "Identification of phenotypically and functionally heterogeneous mouse mucosal-associated invariant T cells using MR1 tetramers". The Journal of Experimental Medicine 212 (7): 1095–1108. doi:10.1084/jem.20142110. ISSN 0022-1007. PMID 26101265.
- Chua, Wei-Jen; Truscott, Steven M.; Eickhoff, Christopher S.; Blazevic, Azra; Hoft, Daniel F.; Hansen, Ted H. (2017-02-25). "Polyclonal Mucosa-Associated Invariant T Cells Have Unique Innate Functions in Bacterial Infection". Infection and Immunity 80 (9): 3256–3267. doi:10.1128/IAI.00279-12. ISSN 0019-9567. PMID 22778103.
- Boehm, U.; Klamp, T.; Groot, M.; Howard, J. C. (1997-01-01). "Cellular responses to interferon-gamma". Annual Review of Immunology 15: 749–795. doi:10.1146/annurev.immunol.15.1.749. ISSN 0732-0582. PMID 9143706.
- Chiba, Asako; Tajima, Ryohsuke; Tomi, Chiharu; Miyazaki, Yusei; Yamamura, Takashi; Miyake, Sachiko (2012-01-01). "Mucosal-associated invariant T cells promote inflammation and exacerbate disease in murine models of arthritis" (in en). Arthritis & Rheumatism 64 (1): 153–161. doi:10.1002/art.33314. ISSN 1529-0131. PMID 21904999.
- Corbett, Alexandra J.; Eckle, Sidonia B. G.; Birkinshaw, Richard W.; Liu, Ligong; Patel, Onisha; Mahony, Jennifer; Chen, Zhenjun; Reantragoon, Rangsima et al. (2014). "T-cell activation by transitory neo-antigens derived from distinct microbial pathways". Nature 509 (7500): 361–365. doi:10.1038/nature13160. PMID 24695216.
- Kjer-Nielsen, Lars; Patel, Onisha; Corbett, Alexandra J.; Nours, Jérôme Le; Meehan, Bronwyn; Liu, Ligong; Bhati, Mugdha; Chen, Zhenjun et al. (2012). "MR1 presents microbial vitamin B metabolites to MAIT cells". Nature 491 (7426): 717–723. doi:10.1038/nature11605. PMID 23051753. https://espace.library.uq.edu.au/view/UQ:284808/UQ284808_OA.pdf.
- Mak, Jeffrey Y. W.; Xu, Weijun; Reid, Robert C.; Corbett, Alexandra J.; Meehan, Bronwyn S.; Wang, Huimeng; Chen, Zhenjun; Rossjohn, Jamie et al. (2017-03-08). "Stabilizing short-lived Schiff base derivatives of 5-aminouracils that activate mucosal-associated invariant T cells" (in en). Nature Communications 8: 14599. doi:10.1038/ncomms14599. ISSN 2041-1723. PMID 28272391.
- D’Souza, Criselle; Pediongco, Troi; Wang, Huimeng; Scheerlinck, Jean-Pierre Y.; Kostenko, Lyudmila; Esterbauer, Robyn; Stent, Andrew W.; Eckle, Sidonia B. G. et al. (2018-03-01). "Mucosal-Associated Invariant T Cells Augment Immunopathology and Gastritis in Chronic Helicobacter pylori Infection" (in en). The Journal of Immunology 200 (5): 1901–1916. doi:10.4049/jimmunol.1701512. ISSN 0022-1767. PMID 29378910. http://orca.cf.ac.uk/110478/1/110478%20%20%20MucosalAssociated%20Inva%20Tcell%20%20%20Rossjohn.pdf.
- Keller, Andrew N; Eckle, Sidonia B G; Xu, Weijun; Liu, Ligong; Hughes, Victoria A; Mak, Jeffrey Y W; Meehan, Bronwyn S; Pediongco, Troi et al. (2017). "Drugs and drug-like molecules can modulate the function of mucosal-associated invariant T cells". Nature Immunology 18 (4): 402–411. doi:10.1038/ni.3679. PMID 28166217. http://orca.cf.ac.uk/99998/1/99998%20%20%20Drugs%20druglike%20molecules%20Rossjohn-Keller%20FIGS.pdf.
- Yamaguchi, Hisateru; Hashimoto, Keiichiro (2002-01-18). "Association of MR1 protein, an MHC class I-related molecule, with beta(2)-microglobulin". Biochemical and Biophysical Research Communications 290 (2): 722–729. doi:10.1006/bbrc.2001.6277. ISSN 0006-291X. PMID 11785959.
- Yamaguchi, H.; Hirai, M.; Kurosawa, Y.; Hashimoto, K. (1997-09-29). "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. ISSN 0006-291X. PMID 9325151.
- Miley, Michael J.; Truscott, Steven M.; Yu, Yik Yeung Lawrence; Gilfillan, Susan; Fremont, Daved H.; Hansen, Ted H.; Lybarger, Lonnie (2003-06-15). "Biochemical Features of the MHC-Related Protein 1 Consistent with an Immunological Function" (in en). The Journal of Immunology 170 (12): 6090–6098. doi:10.4049/jimmunol.170.12.6090. ISSN 0022-1767. PMID 12794138.
- Gold, Marielle C.; Cerri, Stefania; Smyk-Pearson, Susan; Cansler, Meghan E.; Vogt, Todd M.; Delepine, Jacob; Winata, Ervina; Swarbrick, Gwendolyn M. et al. (2010-06-29). "Human Mucosal Associated Invariant T Cells Detect Bacterially Infected Cells". PLOS Biology 8 (6): e1000407. doi:10.1371/journal.pbio.1000407. ISSN 1545-7885. PMID 20613858.
- van Wilgenburg, Bonnie; Scherwitzl, Iris; Hutchinson, Edward C.; Leng, Tianqi; Kurioka, Ayako; Kulicke, Corinna; de Lara, Catherine; Cole, Suzanne et al. (2016-06-23). "MAIT cells are activated during human viral infections". Nature Communications 7: 11653. doi:10.1038/ncomms11653. ISSN 2041-1723. PMID 27337592.
- Karussis, Dimitrios (2014-02-01). "The diagnosis of multiple sclerosis and the various related demyelinating syndromes: a critical review". Journal of Autoimmunity 48–49: 134–142. doi:10.1016/j.jaut.2014.01.022. ISSN 1095-9157. PMID 24524923.
- Miyazaki, Y.; Miyake, S.; Chiba, A.; Lantz, O.; Yamamura, T. (2011-09-01). "Mucosal-associated invariant T cells regulate Th1 response in multiple sclerosis" (in en). International Immunology 23 (9): 529–535. doi:10.1093/intimm/dxr047. ISSN 0953-8178. PMID 21712423.
- Baumgart, Daniel C; Carding, Simon R (2007-05-18). "Inflammatory bowel disease: cause and immunobiology". The Lancet 369 (9573): 1627–1640. doi:10.1016/S0140-6736(07)60750-8. PMID 17499605.
Original source: https://en.wikipedia.org/wiki/ Mucosal associated invariant T cell. Read more