{"doi":"10.1073/pnas.2312039120","title":"Deletion of Vβ3 + CD4 + T cells by endogenous mouse mammary tumor virus 3 prevents type 1 diabetes induction by autoreactive CD8 + T cells","abstract":"In both humans and NOD mice, type 1 diabetes (T1D) develops from the autoimmune destruction of pancreatic beta cells by T cells. Interactions between both helper CD4 + and cytotoxic CD8 + T cells are essential for T1D development in NOD mice. Previous work has indicated that pathogenic T cells arise from deleterious interactions between relatively common genes which regulate aspects of T cell activation/effector function ( Ctla4, Tnfrsf9, Il2/Il21 ), peptide presentation ( H2-A g7 , B2m ), and T cell receptor (TCR) signaling ( Ptpn22 ). Here, we used a combination of subcongenic mapping and a CRISPR/Cas9 screen to identify the NOD-encoded mammary tumor virus ( Mtv )3 provirus as a genetic element affecting CD4 + /CD8 + T cell interactions through an additional mechanism, altering the TCR repertoire. Mtv3 encodes a superantigen (SAg) that deletes the majority of Vβ3 + thymocytes in NOD mice. Ablating Mtv3 and restoring Vβ3 + T cells has no effect on spontaneous T1D development in NOD mice. However, transferring Mtv3 to C57BL/6 (B6) mice congenic for the NOD H2 g7 MHC haplotype (B6. H2 g7 ) completely blocks their normal susceptibility to T1D mediated by transferred CD8 + T cells transgenically expressing AI4 or NY8.3 TCRs. The entire genetic effect is manifested by Vβ3 + CD4 + T cells, which unless deleted by Mtv3 , accumulate in insulitic lesions triggering in B6 background mice the pathogenic activation of diabetogenic CD8 + T cells. Our findings provide evidence that endogenous Mtv SAgs can influence autoimmune responses. Furthermore, since most common mouse strains have gaps in their TCR Vβ repertoire due to Mtvs , it raises questions about the role of Mtvs in other mouse models designed to reflect human immune disorders.","journal":"Proceedings of the National Academy of Sciences","year":2023,"id":381311,"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":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.955,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1147275,"name":"Sadie Clements","orcid":null,"position":1,"is_corresponding":false},{"id":1146846,"name":"Weihong Gu","orcid":"0000-0002-0111-9949","position":2,"is_corresponding":false},{"id":286498,"name":"Aron M. Geurts","orcid":"0000-0002-4347-2505","position":3,"is_corresponding":false},{"id":389036,"name":"Clayton E. Mathews","orcid":"0000-0002-8817-6355","position":4,"is_corresponding":false},{"id":312736,"name":"David Serreze","orcid":null,"position":5,"is_corresponding":false},{"id":302506,"name":"Yi-Guang Chen","orcid":"0000-0001-9616-8841","position":6,"is_corresponding":false},{"id":397274,"name":"John P. Driver","orcid":"0000-0002-6714-3335","position":7,"is_corresponding":false},{"id":445508,"name":"Cheng Ye","orcid":"0009-0003-1113-6990","position":0,"is_corresponding":true}],"reference_count":71,"raw_metadata":null,"created_at":"2026-07-19T01:17:08.831117Z","pmid":"38015847","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":[]}