{"doi":"10.1002/eji.202451245","title":"A20 intrinsically influences human effector T‐cell survival and function by regulating both NF‐κB and JNK signaling","abstract":"A20 is a dual-function ubiquitin-editing enzyme that maintains immune homeostasis by restraining inflammation. Although A20 serves a similar negative feedback function for T-cell receptor (TCR) signaling, the molecular mechanisms utilized and their ultimate impact on human T-cell function remain unclear. TCR engagement triggers the assembly of the CARD11-BCL10-MALT1 (CBM) protein complex, a signaling platform that governs the activation of downstream transcription factors including NF-κB and c-Jun/AP-1. Utilizing WT and A20 knockout Jurkat T cells, we found that A20 is required to negatively regulate NF-κB and JNK. Utilizing a novel set of A20 mutants in NF-κB and AP-1-driven reporter systems, we discovered the ZnF7 domain is crucial for negative regulatory capacity, while deubiquitinase activity is dispensable. Successful inactivation of A20 in human primary effector T cells congruently conferred sustained NF-κB and JNK signaling, including enhanced upregulation of activation markers, and increased secretion of several cytokines including IL-9. Finally, loss of A20 in primary human T cells resulted in decreased sensitivity to restimulation-induced cell death and increased sensitivity to cytokine withdrawal-induced death. These findings demonstrate the importance of A20 in maintaining T-cell homeostasis via negative regulation of both NF-κB and JNK signaling.","journal":"European Journal of Immunology","year":2024,"id":458509,"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":5,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9543,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":299368,"name":"Allison Ruchinskas","orcid":"0000-0002-8412-1082","position":1,"is_corresponding":false},{"id":997211,"name":"Melissa A. Kallarakal","orcid":"0009-0000-9948-3871","position":2,"is_corresponding":false},{"id":1103690,"name":"Katherine P. Lee","orcid":null,"position":3,"is_corresponding":false},{"id":720899,"name":"Bradly M. Bauman","orcid":"0000-0002-4471-0966","position":4,"is_corresponding":false},{"id":1103242,"name":"Benjamin Epstein","orcid":"0000-0002-5129-9044","position":5,"is_corresponding":false},{"id":1284795,"name":"Hongli Yin","orcid":"0000-0002-2043-5066","position":6,"is_corresponding":false},{"id":754581,"name":"Daniel Krappmann","orcid":"0000-0001-7640-3234","position":7,"is_corresponding":false},{"id":454793,"name":"Brian C. Schaefer","orcid":"0000-0001-8877-3507","position":8,"is_corresponding":false},{"id":241321,"name":"Andrew L. Snow","orcid":"0000-0002-8728-6691","position":9,"is_corresponding":false},{"id":1285307,"name":"Gina Dabbah‐Krancher","orcid":null,"position":0,"is_corresponding":true}],"reference_count":82,"raw_metadata":null,"created_at":"2026-07-19T02:03:50.608887Z","pmid":"39359035","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":[]}