{"doi":"10.1172/jci173602","title":"Induced CD8α identifies human NK cells with enhanced proliferative fitness and modulates NK cell activation","abstract":"The surface receptor CD8α is present on 20%-80% of human (but not mouse) NK cells, yet its function on NK cells remains poorly understood. CD8α expression on donor NK cells was associated with a lack of therapeutic responses in patients with leukemia in prior studies, thus, we hypothesized that CD8α may affect critical NK cell functions. Here, we discovered that CD8α- NK cells had improved control of leukemia in xenograft models compared with CD8α+ NK cells, likely due to an enhanced capacity for proliferation. Unexpectedly, we found that CD8α expression was induced on approximately 30% of previously CD8α- NK cells following IL-15 stimulation. These induced CD8α+ (iCD8α+) NK cells had the greatest proliferation, responses to IL-15 signaling, and metabolic activity compared with those that sustained existing CD8α expression (sustained CD8α+) or those that remained CD8α- (persistent CD8α-). These iCD8α+ cells originated from an IL-15Rβhi NK cell population, with CD8α expression dependent on the transcription factor RUNX3. Moreover, CD8A CRISPR/Cas9 deletion resulted in enhanced responses through the activating receptor NKp30, possibly by modulating KIR inhibitory function. Thus, CD8α status identified human NK cell capacity for IL-15-induced proliferation and metabolism in a time-dependent fashion, and its presence had a suppressive effect on NK cell-activating receptors.","journal":"Journal of Clinical Investigation","year":2024,"id":433053,"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":14,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9541,"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":260029,"name":"Pamela Wong","orcid":"0000-0002-6856-2603","position":1,"is_corresponding":false},{"id":403002,"name":"Hannah K. Dorando","orcid":"0000-0002-9600-588X","position":2,"is_corresponding":false},{"id":260036,"name":"Jennifer A. Foltz","orcid":"0000-0001-9158-3464","position":3,"is_corresponding":false},{"id":646693,"name":"Jennifer Tran","orcid":"0000-0001-5339-1218","position":4,"is_corresponding":false},{"id":314100,"name":"Lynne Marsala","orcid":"0000-0002-5499-5627","position":5,"is_corresponding":false},{"id":314099,"name":"Nancy D. Marín","orcid":"0000-0002-2626-3349","position":6,"is_corresponding":false},{"id":806190,"name":"Mark Foster","orcid":null,"position":7,"is_corresponding":false},{"id":260032,"name":"Timothy Schappe","orcid":"0000-0003-4067-1573","position":8,"is_corresponding":false},{"id":985960,"name":"Hijab Fatima","orcid":null,"position":9,"is_corresponding":false},{"id":260035,"name":"Michelle Becker‐Hapak","orcid":"0000-0003-0323-7233","position":10,"is_corresponding":false},{"id":105185,"name":"Alice Y. Zhou","orcid":"0000-0002-3916-8666","position":11,"is_corresponding":false},{"id":1208817,"name":"Kimberly Hwang","orcid":"0009-0003-4034-5177","position":12,"is_corresponding":false},{"id":646695,"name":"Miriam T. Jacobs","orcid":"0000-0002-8831-7592","position":13,"is_corresponding":false},{"id":626354,"name":"David A. Russler‐Germain","orcid":"0000-0003-1009-2247","position":14,"is_corresponding":false},{"id":225937,"name":"Emily M. Mace","orcid":"0000-0003-0226-7393","position":15,"is_corresponding":false},{"id":260026,"name":"Melissa M. Berrien-Elliott","orcid":"0000-0002-7319-9159","position":16,"is_corresponding":false},{"id":403004,"name":"Jacqueline E. Payton","orcid":"0000-0001-8832-3661","position":17,"is_corresponding":false},{"id":260043,"name":"Todd A. Fehniger","orcid":"0000-0002-8705-2887","position":18,"is_corresponding":false},{"id":260027,"name":"Celia C. Cubitt","orcid":"0000-0003-0037-9324","position":0,"is_corresponding":true}],"reference_count":81,"raw_metadata":null,"created_at":"2026-07-19T01:59:44.444627Z","pmid":"38805302","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":[]}