{"doi":"10.3389/fimmu.2025.1519128","title":"Recognition of MR1-antigen complexes by TCR Vγ9Vδ2","abstract":"The TCR-mediated activation of T cells expressing the TCR Vγ9Vδ2 relies on an innate-like mechanism involving the butyrophilin 3A1, 3A2 and 2A1 molecules and phospho-antigens, without the participation of classical antigen-presenting molecules. Whether TCR Vγ9Vδ2 cells also recognize complexes composed of antigens and antigen-presenting molecules in an adaptive-like manner is unknown. Here, we identify MR1-autoreactive cells expressing the TCR Vγ9Vδ2. This MR1-restricted response is antigen- and CDR3δ-dependent and butyrophilin-independent. TCR gene transfer reconstitutes MR1-antigen recognition, and engineered TCR Vγ9Vδ2 tetramers interact with soluble MR1-antigen complexes in an antigen-dependent manner. These cells are present in healthy individuals with low frequency and are mostly CD8 + or CD4-CD8 double negative. We also describe a patient with autoimmune symptoms and TCR γδ lymphocytosis in which ~10% of circulating T cells are MR1-self-reactive and express a TCR Vγ9Vδ2. These cells release pro-inflammatory cytokines, suggesting a possible participation in disease pathogenesis. Thus, MR1-self-antigen complexes can interact with some TCRs Vγ9Vδ2, promoting full cell activation and potentially contributing to diseases.","journal":"Frontiers in Immunology","year":2025,"id":551733,"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":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9554,"is_data_producer":false,"deposit_databanks":null,"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":1042525,"name":"Alessandro Vacchini","orcid":"0000-0001-5473-9693","position":1,"is_corresponding":false},{"id":1042517,"name":"Giuliano Berloffa","orcid":"0000-0003-3152-9858","position":2,"is_corresponding":false},{"id":1447775,"name":"Ján Deván","orcid":"0009-0009-1544-7511","position":3,"is_corresponding":false},{"id":1042527,"name":"Verena Schaefer","orcid":"0000-0001-7507-5435","position":4,"is_corresponding":false},{"id":1042515,"name":"Vladimir Nosi","orcid":"0009-0007-3759-9116","position":5,"is_corresponding":false},{"id":1042518,"name":"Rodrigo Colombo","orcid":"0009-0002-8641-6252","position":6,"is_corresponding":false},{"id":1042516,"name":"Aisha Beshirova","orcid":"0000-0001-9434-3423","position":7,"is_corresponding":false},{"id":1448061,"name":"Giulia Montanelli","orcid":null,"position":8,"is_corresponding":false},{"id":1223647,"name":"B. Meyer","orcid":"0000-0002-9307-9736","position":9,"is_corresponding":false},{"id":1447776,"name":"Timothy Sharpe","orcid":"0000-0002-4980-1330","position":10,"is_corresponding":false},{"id":242875,"name":"Andrew Chancellor","orcid":"0000-0001-9658-4124","position":11,"is_corresponding":false},{"id":536845,"name":"Mike Recher","orcid":"0000-0002-9121-6936","position":12,"is_corresponding":false},{"id":1042534,"name":"Lucia Mori","orcid":"0000-0002-5522-4648","position":13,"is_corresponding":false},{"id":1042536,"name":"Gennaro De Libero","orcid":"0000-0003-0853-7868","position":14,"is_corresponding":false},{"id":926735,"name":"José Pedro Loureiro","orcid":"0000-0002-1744-6135","position":0,"is_corresponding":true}],"reference_count":66,"raw_metadata":null,"created_at":"2026-07-19T02:54:29.318076Z","pmid":"40040716","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":[]}