{"doi":"10.1093/jimmun/vkaf189","title":"Direct-in-NOD genetic ablation of <i>Bcl3</i> leads to complete type 1 diabetes protection","abstract":"It was previously reported that genetic ablation of the NF-κB atypical inhibitor Bcl3 through congenic introduction of a 129P2-embryo derived knockout allele (Bcl3tm1Ver) accelerated autoimmune diabetes in the NOD mouse model. Conversely, we found that direct CRISPR-mediated ablation of this gene in the NOD/ShiLtDvs substrain completely inhibited diabetes development. Our CRISPR approach excised exons 3-7 within the NOD Bcl3 gene. These new NOD-Bcl3-/- mice had very low levels of insulitis, indicating protective mechanisms elicited early in the disease process. Dissimilar to reports of Bcl3 ablation in nonautoimmune C57BL/6-background mice, we found that splenic and lymph node B cells were not reduced. However, splenic T2 and MZ cells were increased with a disruption of B-cell follicle formation. Diabetes protection was associated with elevated splenic and lymph node regulatory T cells, and increases in CD4 effector and CD8 central memory T cells in pancreatic lymph nodes. Diabetes protection was overridden by anti-PD-1 administration. Previous studies suggested that Bcl3 may influence diabetes development downstream of Nfkbid, another atypical NF-κB inhibitor. Indeed, co-introduction of this Bcl3 knockout allele also completely blocked diabetes in NOD-Nfkbid-/- mice normally characterized by accelerated disease. Collectively these findings support the possibility that prior findings may have been driven by congenic introduction of linked modifier genes from non-NOD background strains and initiate a critical reevaluation of the role of Bcl3 in type 1 diabetes pathogenesis.","journal":"The Journal of Immunology","year":2025,"id":545996,"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":0.9609,"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":935747,"name":"Jennifer R. Dwyer","orcid":"0000-0002-5893-6026","position":1,"is_corresponding":false},{"id":531145,"name":"Harold D. Chapman","orcid":null,"position":2,"is_corresponding":false},{"id":1437232,"name":"Amy Bell","orcid":"0000-0002-7584-6321","position":3,"is_corresponding":false},{"id":533061,"name":"Raymond F. Robledo","orcid":"0000-0003-3606-3073","position":4,"is_corresponding":false},{"id":312736,"name":"David Serreze","orcid":null,"position":5,"is_corresponding":false},{"id":530417,"name":"Jeremy J. Racine","orcid":"0000-0001-5514-3074","position":0,"is_corresponding":true}],"reference_count":46,"raw_metadata":null,"created_at":"2026-07-19T02:53:27.751050Z","pmid":"40796308","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":[]}