{"doi":"10.4049/jimmunol.2000039","title":"IκBα Nuclear Export Enables 4-1BB–Induced cRel Activation and IL-2 Production to Promote CD8 T Cell Immunity","abstract":"Abstract Optimal CD8 T cell immunity is orchestrated by signaling events initiated by TCR recognition of peptide Ag in concert with signals from molecules such as CD28 and 4-1BB. The molecular mechanisms underlying the temporal and spatial signaling dynamics in CD8 T cells remain incompletely understood. In this study, we show that stimulation of naive CD8 T cells with agonistic CD3 and CD28 Abs, mimicking TCR and costimulatory signals, coordinately induces 4-1BB and cRel to enable elevated cytosolic cRel:IκBα complex formation and subsequent 4-1BB–induced IκBα degradation, sustained cRel activation, heightened IL-2 production and T cell expansion. NfkbiaNES/NES CD8 T cells harboring a mutated IκBα nuclear export sequence abnormally accumulate inactive cRel:IκBα complexes in the nucleus following stimulation with agonistic anti-CD3 and anti-CD28 Abs, rendering them resistant to 4-1BB induced signaling and a disrupted chain of events necessary for efficient T cell expansion. Consequently, CD8 T cells in NfkbiaNES/NES mice poorly expand during viral infection, and this can be overcome by exogenous IL-2 administration. Consistent with cell-based data, adoptive transfer experiments demonstrated that the antiviral CD8 T cell defect in NfkbiaNES/NES mice was cell intrinsic. Thus, these results reveal that IκBα, via its unique nuclear export function, enables, rather than inhibits 4-1BB–induced cRel activation and IL-2 production to facilitate optimal CD8 T cell immunity.","journal":"The Journal of Immunology","year":2020,"id":82899,"datarank":0.38474240361923057,"base_score":2.5649493574615367,"endowment":2.5649493574615367,"self_citation_contribution":0.38474240361923057,"citation_network_contribution":0.0,"self_endowment_contribution":0.38474240361923057,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":12,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9525,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":304199,"name":"Cheng Zhang","orcid":"0000-0003-3863-2866","position":1,"is_corresponding":false},{"id":427599,"name":"Melba Marie Tejera","orcid":null,"position":2,"is_corresponding":false},{"id":426890,"name":"Brandon Neldner","orcid":"0000-0003-4278-4045","position":3,"is_corresponding":false},{"id":321490,"name":"Jay W. Warrick","orcid":"0000-0002-4801-8897","position":4,"is_corresponding":false},{"id":427600,"name":"Shelly M. Wuerzberger‐Davis","orcid":null,"position":5,"is_corresponding":false},{"id":304204,"name":"Alexander Hoffmann","orcid":"0000-0002-5607-3845","position":6,"is_corresponding":false},{"id":426891,"name":"M. Suresh","orcid":"0000-0003-1794-3358","position":7,"is_corresponding":false},{"id":426892,"name":"Shigeki Miyamoto","orcid":"0000-0002-7827-3426","position":8,"is_corresponding":false},{"id":427598,"name":"Dominique N. Lisiero","orcid":null,"position":0,"is_corresponding":true}],"reference_count":62,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T21:53:48.608934Z","pmid":"32817348","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":[]}