{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nMR1 is a highly conserved, monomorphic major histocompatibility complex class I–related molecule that uniquely binds small‐molecule metabolites—primarily intermediates from microbial vitamin B biosynthetic pathways—and presents them to innate‐like T cells known as mucosal‐associated invariant T (MAIT) cells. Structural studies have revealed that the antigen‐binding cleft of MR1 is distinct from classical MHC and CD1 molecules, providing an ideal pocket for vitamin B2 (riboflavin) and vitamin B9 (folate) derivative ligands. These MR1–ligand complexes are recognized by semi‐invariant MAIT cell receptors, which, despite their limited TCR diversity, mediate robust responses to bacterial and fungal infections by sensing conserved microbial metabolic products."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its specialized ligand‐binding properties, MR1 displays a dynamic intracellular trafficking pathway that is tightly regulated to ensure appropriate antigen presentation. Under steady‐state conditions, MR1 predominantly resides in the endoplasmic reticulum in a ligand‐receptive conformation and only transits to the cell surface upon binding vitamin B metabolites—often via the formation of a Schiff base—and accessory chaperones assist in its proper folding and loading. Moreover, a cadre of intracellular trafficking molecules (including components identified in endosomal and recycling‐pathways) and signals from innate immune receptors (such as those engaged by Toll‐like receptor 9 agonists) modulate MR1 surface expression and endocytic recycling. These mechanisms together ensure that MR1 rapidly samples the intracellular milieu for microbial antigens while preventing inappropriate activation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "11"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its role in microbial antigen presentation, MR1 has emerged as a critical immunomodulatory nexus with clinical implications across infection, cancer, autoimmunity, and even neuroinflammatory disorders. Genetic studies have linked MR1 expression with susceptibility to infections such as tuberculosis, while in tumor models MR1‐mediated MAIT cell activation can paradoxically suppress cytolytic cells and promote tumor progression. In parallel, alternative splicing of the MR1 gene and differential ligand capture influence the diversity and responsiveness of the MR1‐restricted T cell repertoire, including unconventional responses by γδ T cells. Collectively, these findings support a model in which MR1 not only serves as a sensor for microbial vitamin metabolites but also integrates signals from cellular trafficking, innate cytokine networks, and genetic variation to modulate MAIT cell function in diverse pathophysiologic contexts ranging from inflammatory skin disorders to central nervous system diseases."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "12", "end_ref": "22"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Shouxiong Huang, Emmanuel Martin, Sojung Kim, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MR1 antigen presentation to mucosal-associated invariant T cells was highly conserved in evolution."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.0903196106"}], "href": "https://doi.org/10.1073/pnas.0903196106"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19416870"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19416870"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Rangsima Reantragoon, Lars Kjer-Nielsen, Onisha Patel, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "MAITs, MR1 and vitamin B metabolites."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Curr Opin Immunol (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.coi.2013.09.007"}], "href": "https://doi.org/10.1016/j.coi.2013.09.007"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24556396"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24556396"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Ildiko Van Rhijn, Dale I Godfrey, Jamie Rossjohn, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "The intracellular pathway for the presentation of vitamin B-related antigens by the antigen-presenting molecule MR1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Immunol (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ni.3416"}], "href": "https://doi.org/10.1038/ni.3416"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27043408"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27043408"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Caroline Boulouis, Jean-Baptiste Gorin, Joana Dias, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Rab6 regulates recycling and retrograde trafficking of MR1 molecules."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Sci Rep (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41598-020-77563-4"}], "href": "https://doi.org/10.1038/s41598-020-77563-4"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33247182"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33247182"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Hui Jing Lim, Jacinta M Wubben, Cristian Pinero Garcia, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A specialized tyrosine-based endocytosis signal in MR1 controls antigen presentation to MAIT cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Biol (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1083/jcb.202110125"}], "href": "https://doi.org/10.1083/jcb.202110125"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "36129434"}], "href": "https://pubmed.ncbi.nlm.nih.gov/36129434"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Beatriz Gozalbo-López, Manuel Gómez del Moral, Yolanda Campos-Martín, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The MHC-related protein 1 (MR1) is expressed by a subpopulation of CD38+, IgA+ cells in the human intestinal mucosa."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Histol Histopathol (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.14670/HH-24.1439"}], "href": "https://doi.org/10.14670/HH-24.1439"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19760593"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19760593"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Chunwei Wang, Hua Xiang, Huiyuan Si, et al. "}, {"type": "b", "children": [{"type": "t", "text": "High expression of myofibrillogenesis regulator-1 predicts poor prognosis for patients with hepatocellular carcinoma after curative hepatectomy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Clin Exp Pathol (2015)"}]}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26823810"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26823810"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "James E Ussher, Bonnie van Wilgenburg, Rachel F Hannaway, et al. "}, {"type": "b", "children": [{"type": "t", "text": "TLR signaling in human antigen-presenting cells regulates MR1-dependent activation of MAIT cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Eur J Immunol (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/eji.201545969"}], "href": "https://doi.org/10.1002/eji.201545969"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27105778"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27105778"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "C Seshadri, N T T Thuong, N T H Mai, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A polymorphism in human MR1 is associated with mRNA expression and susceptibility to tuberculosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Genes Immun (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/gene.2016.41"}], "href": "https://doi.org/10.1038/gene.2016.41"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27881839"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27881839"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "Sara Suliman, Melissa Murphy, Munyaradzi Musvosvi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MR1-Independent Activation of Human Mucosal-Associated Invariant T Cells by Mycobacteria."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Immunol (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.4049/jimmunol.1900674"}], "href": "https://doi.org/10.4049/jimmunol.1900674"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31611259"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31611259"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "Brian P McSharry, Carolyn Samer, Hamish E G McWilliam, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Virus-Mediated Suppression of the Antigen Presentation Molecule MR1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Rep (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.celrep.2020.02.017"}], "href": "https://doi.org/10.1016/j.celrep.2020.02.017"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32130899"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32130899"}]}, {"type": "r", "ref": 18, "children": [{"type": "t", "text": "Gitanjali A Narayanan, Abhinav Nellore, Jessica Tran, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Alternative splicing of MR1 regulates antigen presentation to MAIT cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Sci Rep (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41598-020-72394-9"}], "href": "https://doi.org/10.1038/s41598-020-72394-9"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32963314"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32963314"}]}, {"type": "r", "ref": 19, "children": [{"type": "t", "text": "Michael T Rice, Anouk von Borstel, Priyanka Chevour, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Recognition of the antigen-presenting molecule MR1 by a Vδ3"}, {"type": "a", "children": [{"type": "t", "text": "sup"}], "href": "sup"}, {"type": "t", "text": "+"}, {"type": "a", "children": [{"type": "t", "text": "/sup"}], "href": "/sup"}, {"type": "t", "text": " γδ T cell receptor."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.2110288118"}], "href": "https://doi.org/10.1073/pnas.2110288118"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34845016"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34845016"}]}, {"type": "r", "ref": 20, "children": [{"type": "t", "text": "Hamish E G McWilliam, Jose A Villadangos "}, {"type": "b", "children": [{"type": "t", "text": "MR1 antigen presentation to MAIT cells and other MR1-restricted T cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Rev Immunol (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41577-023-00934-1"}], "href": "https://doi.org/10.1038/s41577-023-00934-1"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "37773272"}], "href": "https://pubmed.ncbi.nlm.nih.gov/37773272"}]}, {"type": "r", "ref": 21, "children": [{"type": "t", "text": "Maja Jirouš Drulak, Zvonimir Grgić, Vera Plužarić, et al. 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