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Immunol."],"abstract":"<jats:p>\n                    Mucosal-associated invariant T (MAIT) cells recognize metabolite-derived ligands, but the identity of such ligands in the context of cancer remains poorly defined. Herein, we demonstrate that the tumor-derived metabolite 5-formyl tetrahydrofolate (5-formyl THF), which is an intermediate of the folate metabolism pathway, induces T cell receptor (TCR)-dependent activation of mouse mucosal-associated invariant T (MAIT) cells. The activity was weaker than that of a potent MAIT cell agonist 5-(2-oxopropylideneamino)-6-d-ribitylaminouracil (5-OP-RU).\n                    <jats:italic>Amino methyltransferase<\/jats:italic>\n                    (\n                    <jats:italic>Amt<\/jats:italic>\n                    ), an enzyme that is necessary for the generation of 5-formyl THF from tumor cells, was essential for the activation of mouse MAIT cells. Genetic deletion of\n                    <jats:italic>Amt<\/jats:italic>\n                    in the tumor resulted in impaired activation of mouse MAIT cells. In contrast,\n                    <jats:italic>Amt<\/jats:italic>\n                    overexpression in the tumor led to an enhancement in the agonistic activity of the MAIT cells. The introduction of mouse MAIT TCRs to primary T cells from MAIT cell-deficient mice also conferred reactivity to 5-formyl THF. Using single-cell TCR sequencing analysis, a 5-formyl THF-reactive MAIT cell clonotype was identified in humans. These results demonstrate that 5-formyl THF is the first tumor-derived ligand recognized by MAIT cells in both humans and mice. However, the functional relevance of this pathway\n                    <jats:italic>in vivo<\/jats:italic>\n                    remains to be determined.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2026.1797918","type":"journal-article","created":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T05:55:15Z","timestamp":1782280515000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Mucosal-associated invariant T cells recognize a tumor-derived metabolite in the DNA synthesis pathway"],"prefix":"10.3389","volume":"17","author":[{"given":"Yanqi","family":"Xue","sequence":"first","affiliation":[{"name":"Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University","place":["Fukuoka, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuka","family":"Yamada","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Graduate School of Medicine, Yamaguchi University","place":["Ube, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rikako","family":"Suzuki","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Graduate School of Medicine, Yamaguchi University","place":["Ube, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brenda","family":"Luong","sequence":"additional","affiliation":[{"name":"School of Chemical and Physical Sciences, Victoria University of Wellington","place":["Wellington, New Zealand"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shotaro","family":"Fujii","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Graduate School of Medicine, Yamaguchi University","place":["Ube, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keisuke","family":"Nakata","sequence":"additional","affiliation":[{"name":"Division of Metabolomics, Medical Research Center for High Depth Omics, Medical Institute of Bioregulation, Kyushu University","place":["Fukuoka, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masatomo","family":"Takahashi","sequence":"additional","affiliation":[{"name":"Division of Metabolomics, Medical Research Center for High Depth Omics, Medical Institute of Bioregulation, Kyushu University","place":["Fukuoka, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshihiro","family":"Izumi","sequence":"additional","affiliation":[{"name":"Division of Metabolomics, Medical Research Center for High Depth Omics, Medical Institute of Bioregulation, Kyushu University","place":["Fukuoka, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chihiro","family":"Fukui","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University","place":["Fukuoka, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryosuke","family":"Takasaki","sequence":"additional","affiliation":[{"name":"Graduate School of Pharmaceutical Sciences, Kyoto University","place":["Kyoto, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francois","family":"Legoux","sequence":"additional","affiliation":[{"name":"INSERM ERL1305, CNRS UMR6290, Institut de G\u00e9n\u00e9tique et D\u00e9veloppement de Rennes, Universit\u00e9 de Rennes","place":["Rennes, France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shinsuke","family":"Inuki","sequence":"additional","affiliation":[{"name":"Graduate School of Pharmaceutical Sciences, Kyoto University","place":["Kyoto, Japan"]},{"name":"Graduate School of Biomedical Sciences, Tokushima University","place":["Tokushima, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daisuke","family":"Motooka","sequence":"additional","affiliation":[{"name":"NGS core facility, Bioinformatics Center, Research Institute for Microbial Diseases, Osaka University","place":["Suita, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emi","family":"Ito","sequence":"additional","affiliation":[{"name":"Department of Molecular Immunology, Research Institute for Microbial Diseases, Osaka University","place":["Suita, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bridget L.","family":"Stocker","sequence":"additional","affiliation":[{"name":"School of Chemical and Physical Sciences, Victoria University of Wellington","place":["Wellington, New Zealand"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mattie S. 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