{"doi":"10.1111/trf.70026","title":"Suppression of <scp>RBC</scp> alloimmunization and regulation of <scp> CD4 <sup>+</sup> T </scp> cell dependence by <scp>C3</scp> is not due to genetic confounders in mice","abstract":"Abstract Background Activation of complement protein C3 generally enhances antibody responses and C3‐null mice have decreased antibody‐based immunity. Mener et al. have reported a paradoxical suppressor function for C3 in alloimmunization to transfused RBCs as alloantibodies are increased in C3‐null mice. Moreover, C3 regulated the CD4 + T cell dependence of the immune response. However, the C3‐null mice used were on a mixed B6/129 genetic background. We have previously reported that 129 mice have significantly higher alloimmune responses to RBC transfusion and we mapped a genetic locus that contains C3 (amongst other genes). Given the surprising nature of Mener et al.'s findings and the potential confounding from 129 genetic elements, it is a necessary part of scientific rigor to suspect that contaminating 129 elements rather than the deletion of C3 caused the observed biology. Methods We used CRISPR/Cas9 to generate a new C3‐null mouse (C3Cr‐KO) directly in B6 mice lacking any 129 genetic elements. B6 and C3Cr‐KO mice were transfused with KEL‐K2 med RBCs with or without CD4 + T cell depletion and serum α‐KEL IgM and Igs were quantified by crossmatch. Results Identical to the findings of Mener et al., alloimmunization was increased in C3Cr‐KO mice compared to wild‐type B6 mice and CD4 + T cell dependence of the alloimmune response was reversed. Conclusions The current findings eliminate a common confounder present in murine knockout systems that has caused erroneous conclusions in other settings. Both the conclusion that the presence of the C3 gene decreases RBC alloimmunization and regulates CD4 + T cell dependence was confirmed.","journal":"Transfusion","year":2025,"id":584156,"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":0.9611,"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":297838,"name":"Ariel Hay","orcid":"0000-0002-9003-6415","position":1,"is_corresponding":false},{"id":1497048,"name":"James C. Zimring","orcid":"0000-0002-6365-8825","position":2,"is_corresponding":false},{"id":290789,"name":"Arijita Jash","orcid":"0000-0001-9613-4932","position":0,"is_corresponding":true}],"reference_count":39,"raw_metadata":null,"created_at":"2026-07-19T02:59:11.978098Z","pmid":"41342465","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":[]}