{"doi":"10.1016/j.jbc.2025.110416","title":"A molecular basis underpinning TRBV28+ T-cell receptor recognition of MR1–antigen","abstract":"Mucosal-associated invariant T (MAIT) cells express a TRAV1-2 + T cell receptor (TCR) that recognises microbial vitamin B2-derivatives presented by the MHC class I-related molecule, MR1. Most MAIT TCRs incorporate a biased TCR-β repertoire, predominantly TRBV20-1 and TRBV6, but some utilise other TRBV genes, including TRBV28. A second conserved, albeit less frequent TRAV36 + TRBV28 + T cell population exhibits MAIT-like phenotypic features but use a markedly distinct mode of MR1-antigen-recognition compared to MAIT TCR-MR1 binding. Nevertheless, our understanding of how differing TCR gene usage results in altered MR1 binding modes remains incomplete. Here, binding studies demonstrated differential affinities and antigen-specificities between TRBV6 + and TRBV28 + MR1-restricted TCRs. Alanine-scanning mutagenesis on the TRAV36-TRBV28 TCR, revealed a strong dependence on germline-encoded residues within the highly selected CDR3α loop, similar to TRAV1-2- TRBV6 TCRs, and further alanine-scanning mutagenesis experiments demonstrate differential energetic footprints by these TCRs atop MR1. We determined the crystal structure of a MAIT TRAV1-2-TRBV28 + TCR-MR1-5-OP-RU ternary complex. This structure revealed a docking mode conserved amongst other TRAV1-2 + MAIT TCRs, with the TRBV28 -encoded TCR-β chain adopting highly distinct docking modes between the TRAV1-2 + and TRAV36 + TCRs. This indicates that the TCR-α chain dictates the positioning and role of the TCR-β chain. Taken together, these findings provide new molecular insights into MR1-Ag driven selection of paired TCR-α and TCR-β chains.","journal":"Journal of Biological Chemistry","year":2025,"id":568965,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9487,"is_data_producer":true,"deposit_databanks":{"PDB":["9BYS"]},"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":675821,"name":"Nicholas A. Gherardin","orcid":"0000-0003-4690-2571","position":1,"is_corresponding":false},{"id":1076103,"name":"Lisa Ciacchi","orcid":"0000-0001-9130-7718","position":2,"is_corresponding":false},{"id":1473668,"name":"Andrew N. Keller","orcid":"0000-0002-0578-0152","position":3,"is_corresponding":false},{"id":293173,"name":"Ligong Liu","orcid":"0000-0002-2693-1896","position":4,"is_corresponding":false},{"id":293174,"name":"David P. Fairlie","orcid":"0000-0002-7856-8566","position":5,"is_corresponding":false},{"id":256187,"name":"James McCluskey","orcid":"0000-0002-8597-815X","position":6,"is_corresponding":false},{"id":675832,"name":"Dale I. Godfrey","orcid":"0000-0002-3009-5472","position":7,"is_corresponding":false},{"id":256186,"name":"Jamie Rossjohn","orcid":"0000-0002-2020-7522","position":8,"is_corresponding":false},{"id":292887,"name":"Wael Awad","orcid":"0000-0002-7597-2133","position":0,"is_corresponding":true}],"reference_count":42,"raw_metadata":null,"created_at":"2026-07-19T02:56:55.795846Z","pmid":"40570962","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":[]}