Huang, W. C., Hsiao, Y. C., Wu, C. C., Hsu, Y. T. & Chang, C. L. Less circulating mucosal-associated invariant T cells in patients with cervical cancer. Taiwan. J. Obstet. Gynecol. 58, 117–121 (2019). Maekawa, T. et al. Low mucosal-associated invariant T-cell number in peripheral blood of patients with immune thrombocytopenia and their response to prednisolone. PLoS One 13, e0207149 (2018). Yamaguchi H, Hashimoto K (January 2002). "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. PMID 11785959. MAIT cells can be activated by two pathways as follows: via TCR signalling (MR1 dependent) or cytokine signalling alone (MR1 independent). Riboflavin derivatives presented by MR1 of antigen presenting cells (APCs) activate MAIT cells, while the folic acid product is a competitive inhibitor ( 31). Because riboflavin synthesis is broadly conserved among bacteria and fungi, MAIT cells respond to a diverse array of microbes, including known commensals ( 32, 33). Following MR1-mediated activation, MAIT cells rapidly produce a wide range of cytokines, including interferon (IFN)-γ, tumor necrosis factor (TNF), IL-17 and IL-22. These cytokines, either directly (IFN-γ, TNF and IL-17) or indirectly through cell proliferation (IL-22), promote cytolysis of the infected cells, thereby leading to the control of various infections ( 15, 32, 34, 35). MAIT cells can also be activated by inflammatory cytokines alone, such as IL-7, IL-12, IL-18, IL-15 and IFN-α/β, in a TCR-independent manner ( 19, 36, 37). MAIT cells are activated with no known antigens, for instance, during viral infections or sterile auto-immunities. Cytokine-dependent activation of MAIT cells leads to secretion of IFN-γ, TNF and granzyme B, which exert cytotoxic functions ( 36, 37). Transcriptomic analysis of E. coli- and TCR-activated MAIT cells has shown distinct transcriptional reprogramming, including altered pathways, transcription factors and effector molecules, which has been validated by proteomics and metabolomics ( 38). In E. coli -activated MAIT cells, the TWIST1 transcription factor has been identified as a key driver, showing high connectivity to cytokine and chemokine expression ( 38). MAIT Cells in Rheumatic Diseases Miley MJ, Truscott SM, Yu YY, Gilfillan S, Fremont DH, Hansen TH, Lybarger L (June 2003). "Biochemical features of the MHC-related protein 1 consistent with an immunological function". Journal of Immunology. 170 (12): 6090–6098. doi: 10.4049/jimmunol.170.12.6090. PMID 12794138.

Muttiah, B. et al. Peripheral loss of CD8 CD161 TCRVα7.2 MAIT cells in chronic HCV-infected patients. Eur. J. Clin. Invest. 46, 170–180 (2015). Solders, M. et al. Mucosal-associated invariant T cells display a poor reconstitution and altered phenotype after allogeneic hematopoietic stem cell transplantation. Front. Immunol. 8, 1861 (2017). Zumwalde, N. A., Haag, J. D., Gould, M. N. & Gumperz, J. E. Mucosal associated invariant T cells from human breast ducts mediate a Th17-skewed response to bacterially exposed breast carcinoma cells. Breast Cancer Res. 20, 111 (2018). Magalhaes, I. et al. Mucosal-associated invariant T cell alterations in obese and type 2 diabetic patients. J. Clin. Invest. 125, 1752–1762 (2015). MAIT cells are activated by compounds derived from bacterial vitamin B2 (riboflavin) biosynthesis. [4] [20] 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). [19] Both compounds are highly potent in activating MAIT cells, but are chemically unstable. [21] 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. [21]

Kwon, Y. S. et al. Mucosal-associated invariant T cells are numerically and functionally deficient in patients wi Chua, W. J. et al. Polyclonal mucosa-associated invariant T cells have unique innate functions in bacterial infection. Infect. Immun. 80, 3256–3267 (2012).

Treiner, E. et al. Selection of evolutionarily conserved mucosal-associated invariant T cells by MR1. Nature 422, 164–169 (2003). Ref. 5 defined MR1 as the restriction element for MAIT cells and also demonstrated their enrichment in mucosal tissues and coined the term ‘mucosal-associated invariant T cells’. Klenerman P, Hinks TS, Ussher JE (February 2021). "Biological functions of MAIT cells in tissues". Molecular Immunology. 130: 154–158. doi: 10.1016/j.molimm.2020.12.017. PMC 8021939. PMID 33358567. Kuric, E. et al. No evidence for presence of mucosal-associated invariant T cells in the insulitic lesions in patients recently diagnosed with type 1 diabetes. Am. J. Pathol. 188, 1744–1748 (2018). a b Hinks TS, Zhang XW (2020). "MAIT Cell Activation and Functions". Frontiers in Immunology. 11: 1014. doi: 10.3389/fimmu.2020.01014. PMC 7267072. PMID 32536923.Salio, M. et al. Activation of human mucosal-associated invariant T cells induces CD40L-dependent maturation of monocyte-derived and primary dendritic cells. J. Immunol. 199, 2631–2638 (2017). Beudeker, B. J. B. et al. Mucosal-associated invariant T-cell frequency and function in blood and liver of HCV mono- and HCV/HIV co-infected patients with advanced fibrosis. Liver Int. 38, 458–468 (2018). Gracey, E. et al. IL-7 primes IL-17 in mucosal-associated invariant T (MAIT) cells, which contribute to the Th17-axis in ankylosing spondylitis. Ann. Rheum. Dis. 75, 2124–2132 (2016). Lepore, M. et al. Parallel T-cell cloning and deep sequencing of human MAIT cells reveal stable oligoclonal TCRβ repertoire. Nat. Commun. 5, 3866 (2014).

Seach, N. et al. Double-positive thymocytes select mucosal-associated invariant T cells. J. Immunol. 191, 6002–6009 (2013). Zheng, C. et al. Landscape of infiltrating T cells in liver cancer revealed by single-cell sequencing. Cell 169, 1342–1356.e1316 (2017). Gherardin, N. A. et al. Enumeration, functional responses and cytotoxic capacity of MAIT cells in newly diagnosed and relapsed multiple myeloma. Sci. Rep. 8, 4159 (2018).Held, K. et al. αβ T-cell receptors from multiple sclerosis brain lesions show MAIT cell–related features. Neurol. Neuroimmunol. Neuroinflamm. 2, e107 (2015). Hengst, J. et al. Nonreversible MAIT cell-dysfunction in chronic hepatitis C virus infection despite successful interferon-free therapy. Eur. J. Immunol. 46, 2204–2210 (2016). a b Nel I, Bertrand L, Toubal A, Lehuen A (July 2021). "MAIT cells, guardians of skin and mucosa?". Mucosal Immunology. 14 (4): 803–814. doi: 10.1038/s41385-021-00391-w. PMC 7983967. PMID 33753874. MAIT cells can target a wide variety of microbes, including Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli Mycobacterium tuberculosis, Candida albicans, and Salmonella enterica, to name a few. [5] [29] 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. [3] [30]