{"doi":"10.1073/pnas.2414792121","title":"MR1 presents vitamin B6–related compounds for recognition by MR1-reactive T cells","abstract":"The major histocompatibility complex class I related protein (MR1) presents microbially derived vitamin B2 precursors to mucosal-associated invariant T (MAIT) cells. MR1 can also present other metabolites to activate MR1-restricted T cells expressing more diverse T cell receptors (TCRs), some with anti-tumor reactivity. However, knowledge of the range of the antigen(s) that can activate diverse MR1-reactive T cells remains incomplete. Here, we identify pyridoxal (vitamin B6) as a naturally presented MR1 ligand using unbiased mass spectrometry analyses of MR1-bound metabolites. Pyridoxal, and the related compound, pyridoxal 5-phosphate bound to MR1 and enabled cell surface upregulation of wild type MR1*01 and MR1 expressing the Arg9His polymorphism associated with the MR1*04 allotype in a manner dependent on Lys43-mediated Schiff-base formation. Crystal structures of MR1*01 in complex with pyridoxal and pyridoxal 5-phosphate showed how these ligands were accommodated within the A-pocket of MR1. T cell lines transduced with the 7.G5 TCR, which has reported \"pan-cancer\" specificity, were specifically activated by pyridoxal presented by antigen-presenting cells expressing MR1*01 and MR1 allotypes bearing the less common Arg9His polymorphism. 7.G5 T cells also recognized, to a lesser extent, pyridoxal 5-phosphate and, importantly, recognition of both vitamers was blocked by an anti-MR1 antibody. 7.G5 TCR reactivity toward pyridoxal was enhanced when presented by the Arg9His polymorphism-bearing MR1 allotypes. Vitamin B6, and vitamers thereof, have been associated with various cancers, and here we describe a link between this ligand, MR1, and its allomorphs, and the pan-cancer 7.G5 TCR. This work identifies an MR1 ligand that can activate a diverse MR1-restricted TCR.","journal":"Proceedings of the National Academy of Sciences","year":2024,"id":422741,"datarank":0.4943755299006494,"base_score":3.295836866004329,"endowment":3.295836866004329,"self_citation_contribution":0.4943755299006494,"citation_network_contribution":0.0,"self_endowment_contribution":0.4943755299006494,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":26,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9502,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":292887,"name":"Wael Awad","orcid":"0000-0002-7597-2133","position":1,"is_corresponding":false},{"id":584662,"name":"Michael N. T. Souter","orcid":"0000-0002-1459-7923","position":2,"is_corresponding":false},{"id":1217705,"name":"Yang Kang","orcid":null,"position":3,"is_corresponding":false},{"id":877573,"name":"Carl J. H. Wang","orcid":"0000-0003-4564-3125","position":4,"is_corresponding":false},{"id":1217706,"name":"Kean Chan Yew Poa","orcid":null,"position":5,"is_corresponding":false},{"id":1217138,"name":"Mohamed R. Abdelaal","orcid":"0000-0001-9804-1510","position":6,"is_corresponding":false},{"id":1217707,"name":"Ngoc H. Le","orcid":null,"position":7,"is_corresponding":false},{"id":1217139,"name":"Chloe M. Shepherd","orcid":"0000-0002-0149-7448","position":8,"is_corresponding":false},{"id":1217708,"name":"Conor McNeice","orcid":null,"position":9,"is_corresponding":false},{"id":867088,"name":"Lucy J. Meehan","orcid":"0000-0001-8638-644X","position":10,"is_corresponding":false},{"id":654814,"name":"Adam G. Nelson","orcid":"0000-0002-5897-791X","position":11,"is_corresponding":false},{"id":735243,"name":"Jeremy M. Raynes","orcid":"0000-0002-2564-7893","position":12,"is_corresponding":false},{"id":293172,"name":"Jeffrey Y. W. Mak","orcid":"0000-0002-8011-4539","position":13,"is_corresponding":false},{"id":256187,"name":"James McCluskey","orcid":"0000-0002-8597-815X","position":14,"is_corresponding":false},{"id":654819,"name":"Zhenjun Chen","orcid":"0000-0003-1205-683X","position":15,"is_corresponding":false},{"id":1217140,"name":"Ching‐Seng Ang","orcid":"0000-0001-7861-6719","position":16,"is_corresponding":false},{"id":293174,"name":"David P. Fairlie","orcid":"0000-0002-7856-8566","position":17,"is_corresponding":false},{"id":293171,"name":"Jérôme Le Nours","orcid":"0000-0002-2221-7636","position":18,"is_corresponding":false},{"id":663779,"name":"Patricia T. Illing","orcid":"0000-0002-3870-0796","position":19,"is_corresponding":false},{"id":256186,"name":"Jamie Rossjohn","orcid":"0000-0002-2020-7522","position":20,"is_corresponding":false},{"id":287873,"name":"Anthony W. Purcell","orcid":"0000-0003-0532-8331","position":21,"is_corresponding":false},{"id":1217137,"name":"Mitchell P. McInerney","orcid":"0009-0001-1411-3650","position":0,"is_corresponding":true}],"reference_count":65,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T01:57:51.642883Z","pmid":"39589872","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}