{"doi":"10.1093/jimmun/vkaf283.620","title":"Epididymal tertiary lymphoid structure formation after Treg depletion sustains male subfertility 2733","abstract":"Abstract Description Tregs are vital for maintaining immune tolerance in the testis and epididymis, where spermatozoa reside. Our previous studies showed that 2 weeks after Treg depletion, autoimmune orchitis, and epididymitis, characterized by anti-sperm antibody (ASA) production, reduced sperm count and motility, leading to subfertility. Here, we investigated the long-term effects of Treg depletion by injecting diphtheria toxin (DT, i.p.) in WT and Foxp3-DTR mice. Flow Cytometry showed that 8 weeks after Treg depletion, the myeloid cell infiltration had resolved, and T and B lymphocytes had increased in the testis and epididymis. ELISA detected elevated serum and tissue antibody levels against sperm and reproductive tract antigens. Confocal microscopy revealed organized T- and B-cell aggregates forming tertiary lymphoid structures (TLS). Soluble mediators associated with TLS formation and maintenance were upregulated in the Treg-depleted epididymis. Proteomic analysis revealed immune-related and fertility-associated sperm proteins targeted by serum and epididymal fluid autoantibodies. Sperm count and fertility were compromised, as evidenced by reduced litter size. Treg depletion induces a persistent proinflammatory response in the male reproductive tract, leading to TLS formation and chronic subfertility. These findings may aid in developing new treatments for male infertility and immuno-contraceptive strategies. Funding Sources NIH HD104672-01 MGH Physician/Scientist Development and Claflin Distinguished Scholar Award Lalor Foundation Fellowship Topic Categories Mucosal and Regional Immunology (MUC)","journal":"The Journal of Immunology","year":2025,"id":582562,"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":0.9538,"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":1409160,"name":"Maria C. Avenatti","orcid":"0009-0004-3658-0390","position":1,"is_corresponding":false},{"id":845884,"name":"Ferran Barrachina","orcid":"0000-0003-3138-4142","position":2,"is_corresponding":false},{"id":1409161,"name":"Isinsu Bastepe","orcid":"0009-0000-4985-2448","position":3,"is_corresponding":false},{"id":699641,"name":"Angela Chen","orcid":"0000-0003-0214-8482","position":4,"is_corresponding":false},{"id":279518,"name":"María Agustina Battistone","orcid":"0000-0003-0490-9548","position":5,"is_corresponding":false},{"id":316745,"name":"Maia Lina Elizagaray","orcid":"0000-0002-4570-172X","position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":null,"created_at":"2026-07-19T02:58:59.653747Z","pmid":null,"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":[]}