{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T18:40:42Z","timestamp":1790793642703,"version":"4.1.0"},"reference-count":37,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2020,11,1]],"date-time":"2020-11-01T00:00:00Z","timestamp":1604188800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100000054","name":"National Institutes of Health\/National Cancer Institute","doi-asserted-by":"publisher","award":["CA199447"],"award-info":[{"award-number":["CA199447"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Institutes of Health\/National Cancer Institute","doi-asserted-by":"publisher","award":["CA208353"],"award-info":[{"award-number":["CA208353"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Institutes of Health\/National Cancer Institute","doi-asserted-by":"publisher","award":["CA068458"],"award-info":[{"award-number":["CA068458"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Institutes of Health\/National Cancer Institute","doi-asserted-by":"publisher","award":["CA236063"],"award-info":[{"award-number":["CA236063"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,11,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Human NK cells develop in tonsils through discrete NK cell developmental intermediates (NKDIs), yet the mechanistic regulation of this process is unclear. We demonstrate that Notch activation in human tonsil-derived stage 3 (CD34\u2212CD117+CD94\u2212NKp80\u2212) and 4A (CD34\u2212CD117+\/\u2212CD94+NKp80\u2212) NKDIs promoted non\u2013NK innate lymphoid cell differentiation at the expense of NK cell differentiation. In contrast, stage 4B (CD34\u2212CD117+\/\u2212CD94+NKp80+) NKDIs were NK cell lineage committed despite Notch activation. Interestingly, whereas NK cell functional maturation from stage 3 and 4A NKDIs was independent of Notch activation, the latter was required for high NKp80 expression and a stage 4B\u2013like phenotype by the NKDI-derived NK cells. The Notch-dependent effects required simultaneous engagement with OP9 stromal cells and were also stage-specific, with NOTCH1 and NOTCH2 receptors regulating stage 3 NKDIs and NOTCH1 primarily regulating stage 4A NKDIs. These data establish stage-specific and stromal-dependent roles for Notch in regulating human NK cell developmental plasticity and maturation.<\/jats:p>","DOI":"10.4049\/jimmunol.2000434","type":"journal-article","created":{"date-parts":[[2020,10,5]],"date-time":"2020-10-05T19:10:11Z","timestamp":1601925011000},"page":"2679-2693","source":"Crossref","is-referenced-by-count":27,"title":["Notch Regulates Innate Lymphoid Cell Plasticity during Human NK Cell Development"],"prefix":"10.1093","volume":"205","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5673-0203","authenticated-orcid":false,"given":"Ansel P","family":"Nalin","sequence":"first","affiliation":[{"name":"Comprehensive Cancer Center, The Ohio State University , Columbus, OH 43210"},{"name":"Medical Scientist Training Program, Biomedical Sciences Graduate Program, The Ohio State University , Columbus, OH 43210"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jesse J","family":"Kowalski","sequence":"additional","affiliation":[{"name":"Comprehensive Cancer Center, The Ohio State University , Columbus, OH 43210"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0880-6298","authenticated-orcid":false,"given":"Alexander C","family":"Sprague","sequence":"additional","affiliation":[{"name":"Comprehensive Cancer Center, The Ohio State University , Columbus, OH 43210"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1915-1899","authenticated-orcid":false,"given":"Blaire K","family":"Schumacher","sequence":"additional","affiliation":[{"name":"Comprehensive Cancer Center, The Ohio State University , Columbus, OH 43210"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9965-3914","authenticated-orcid":false,"given":"Adam G","family":"Gerhardt","sequence":"additional","affiliation":[{"name":"Comprehensive Cancer Center, The Ohio State University , Columbus, OH 43210"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Youssef","family":"Youssef","sequence":"additional","affiliation":[{"name":"Comprehensive Cancer Center, The Ohio State University , Columbus, OH 43210"},{"name":"Division of Hematology, Department of Internal Medicine, The Ohio State University , Columbus, OH 43210"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kiran V","family":"Vedantam","sequence":"additional","affiliation":[{"name":"Comprehensive Cancer Center, The Ohio State University , Columbus, OH 43210"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoli","family":"Zhang","sequence":"additional","affiliation":[{"name":"Comprehensive Cancer Center, The Ohio State University , Columbus, OH 43210"},{"name":"Department of Biomedical Informatics, The Ohio State University , Columbus, OH 43210"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian W","family":"Siebel","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology, Genentech Inc. , South San Francisco, CA 94080"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily M","family":"Mace","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Columbia University , New York, NY 10032"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4095-3020","authenticated-orcid":false,"given":"Michael A","family":"Caligiuri","sequence":"additional","affiliation":[{"name":"Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center , Duarte, CA 91010"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bethany L","family":"Mundy-Bosse","sequence":"additional","affiliation":[{"name":"Comprehensive Cancer Center, The Ohio State University , Columbus, OH 43210"},{"name":"Division of Hematology, Department of Internal Medicine, The Ohio State University , Columbus, OH 43210"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6086-1521","authenticated-orcid":false,"given":"Aharon G","family":"Freud","sequence":"additional","affiliation":[{"name":"Comprehensive Cancer Center, The Ohio State University , Columbus, OH 43210"},{"name":"Department of Pathology, The Ohio State University , Columbus, OH 43210"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2020,11,15]]},"reference":[{"key":"2025030417505613500_r1","doi-asserted-by":"crossref","first-page":"360","DOI":"10.3389\/fimmu.2017.00360","article-title":"Modeling human natural killer cell development in the era of innate lymphoid cells","volume":"8","author":"Scoville","year":"2017","journal-title":"Front. Immunol."},{"key":"2025030417505613500_r2","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1016\/j.smim.2014.02.008","article-title":"Human natural killer cell development in secondary lymphoid tissues","volume":"26","author":"Freud","year":"2014","journal-title":"Semin. Immunol."},{"key":"2025030417505613500_r3","doi-asserted-by":"crossref","first-page":"1086","DOI":"10.1016\/j.cell.2017.02.021","article-title":"Systemic human ILC precursors provide a substrate for tissue ILC differentiation","volume":"168","author":"Lim","year":"2017","journal-title":"Cell"},{"key":"2025030417505613500_r4","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1016\/j.immuni.2018.08.010","article-title":"CD56 expression marks human group 2 innate lymphoid cell divergence from a shared NK cell and group 3 innate lymphoid cell developmental pathway","volume":"49","author":"Chen","year":"2018","journal-title":"Immunity"},{"key":"2025030417505613500_r5","doi-asserted-by":"crossref","first-page":"1033","DOI":"10.1084\/jem.20052507","article-title":"Evidence for discrete stages of human natural killer cell differentiation in vivo","volume":"203","author":"Freud","year":"2006","journal-title":"J. Exp. Med."},{"key":"2025030417505613500_r6","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/j.bbmt.2008.11.031","article-title":"Activated notch supports development of cytokine producing NK cells which are hyporesponsive and fail to acquire NK cell effector functions","volume":"15","author":"Bachanova","year":"2009","journal-title":"Biol. Blood Marrow Transplant."},{"key":"2025030417505613500_r7","doi-asserted-by":"crossref","first-page":"2777","DOI":"10.4049\/jimmunol.1601711","article-title":"Fate decision between group 3 innate lymphoid and conventional NK cell lineages by notch signaling in human circulating hematopoietic progenitors","volume":"199","author":"Kyoizumi","year":"2017","journal-title":"J. Immunol."},{"key":"2025030417505613500_r8","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.imlet.2006.07.005","article-title":"The potential involvement of Notch signaling in NK cell development","volume":"107","author":"Rolink","year":"2006","journal-title":"Immunol. Lett."},{"key":"2025030417505613500_r9","doi-asserted-by":"crossref","first-page":"3593","DOI":"10.1242\/dev.063610","article-title":"Notch signaling: simplicity in design, versatility in function","volume":"138","author":"Andersson","year":"2011","journal-title":"Development"},{"key":"2025030417505613500_r10","doi-asserted-by":"crossref","first-page":"6168","DOI":"10.4049\/jimmunol.0803036","article-title":"Notch activation induces the generation of functional NK cells from human cord blood CD34-positive cells devoid of IL-15","volume":"182","author":"Haraguchi","year":"2009","journal-title":"J. Immunol."},{"key":"2025030417505613500_r11","doi-asserted-by":"crossref","first-page":"1026","DOI":"10.1016\/j.bbmt.2009.06.002","article-title":"The Notch ligands Jagged2, Delta1, and Delta4 induce differentiation and expansion of functional human NK cells from CD34+ cord blood hematopoietic progenitor cells","volume":"15","author":"Beck","year":"2009","journal-title":"Biol. Blood Marrow Transplant."},{"key":"2025030417505613500_r12","doi-asserted-by":"crossref","first-page":"3344","DOI":"10.4049\/jimmunol.1400534","article-title":"Notch signaling at later stages of NK cell development enhances KIR expression and functional maturation","volume":"193","author":"Felices","year":"2014","journal-title":"J. Immunol."},{"key":"2025030417505613500_r13","doi-asserted-by":"crossref","first-page":"12490","DOI":"10.1038\/srep12490","article-title":"Rapid column-free enrichment of mononuclear cells from solid tissues","volume":"5","author":"Scoville","year":"2015","journal-title":"Sci. Rep."},{"key":"2025030417505613500_r14","doi-asserted-by":"crossref","first-page":"1140","DOI":"10.1016\/j.immuni.2016.04.007","article-title":"A progenitor cell expressing transcription factor ROR\u03b3t generates all human innate lymphoid cell subsets","volume":"44","author":"Scoville","year":"2016","journal-title":"Immunity"},{"key":"2025030417505613500_r15","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1016\/S1074-7613(02)00474-0","article-title":"Induction of T cell development from hematopoietic progenitor cells by delta-like-1 in vitro","volume":"17","author":"Schmitt","year":"2002","journal-title":"Immunity"},{"key":"2025030417505613500_r16","doi-asserted-by":"crossref","first-page":"1052","DOI":"10.1038\/nature08878","article-title":"Therapeutic antibody targeting of individual Notch receptors","volume":"464","author":"Wu","year":"2010","journal-title":"Nature"},{"key":"2025030417505613500_r17","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1111\/imm.12357","article-title":"Dengue virus up-regulates expression of notch ligands Dll1 and Dll4 through interferon-\u03b2 signalling pathway","volume":"144","author":"Li","year":"2015","journal-title":"Immunology"},{"key":"2025030417505613500_r18","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1016\/j.celrep.2016.05.095","article-title":"NKp80 defines a critical step during human natural killer cell development","volume":"16","author":"Freud","year":"2016","journal-title":"Cell Rep."},{"key":"2025030417505613500_r19","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1089\/cell.2017.0009","article-title":"NOTCH signaling is essential for maturation, self-renewal, and tri-differentiation of in vitro derived human neural stem cells","volume":"19","author":"Venkatesh","year":"2017","journal-title":"Cell. Reprogram."},{"key":"2025030417505613500_r20","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1038\/ni.1668","article-title":"Human fetal lymphoid tissue-inducer cells are interleukin 17-producing precursors to RORC+ CD127+ natural killer-like cells","volume":"10","author":"Cupedo","year":"2009","journal-title":"Nat. Immunol."},{"key":"2025030417505613500_r21","doi-asserted-by":"crossref","first-page":"820","DOI":"10.1016\/j.immuni.2017.10.008","article-title":"The broad spectrum of human natural killer cell diversity","volume":"47","author":"Freud","year":"2017","journal-title":"Immunity"},{"key":"2025030417505613500_r22","doi-asserted-by":"crossref","first-page":"2696","DOI":"10.1182\/blood-2007-03-082206","article-title":"Notch signaling induces cytoplasmic CD3 epsilon expression in human differentiating NK cells","volume":"110","author":"De Smedt","year":"2007","journal-title":"Blood"},{"key":"2025030417505613500_r23","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1084\/jem.20091509","article-title":"Human NKp44+IL-22+ cells and LTi-like cells constitute a stable RORC+ lineage distinct from conventional natural killer cells","volume":"207","author":"Crellin","year":"2010","journal-title":"J. Exp. Med."},{"key":"2025030417505613500_r24","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1111\/j.1365-3083.2012.02673.x","article-title":"Notch signalling regulates cytokine production by CD8+ and CD4+ T cells","volume":"75","author":"Sauma","year":"2012","journal-title":"Scand. J. Immunol."},{"key":"2025030417505613500_r25","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1111\/imr.12725","article-title":"Emerging insights into human health and NK cell biology from the study of NK cell deficiencies","volume":"287","author":"Mace","year":"2019","journal-title":"Immunol. Rev."},{"key":"2025030417505613500_r26","doi-asserted-by":"crossref","first-page":"2616","DOI":"10.1182\/blood-2016-07-730564","article-title":"Haploidentical hematopoietic transplantation for the cure of leukemia: from its biology to clinical translation","volume":"128","author":"Mancusi","year":"2016","journal-title":"Blood"},{"key":"2025030417505613500_r27","doi-asserted-by":"crossref","first-page":"2097","DOI":"10.1126\/science.1068440","article-title":"Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants","volume":"295","author":"Ruggeri","year":"2002","journal-title":"Science"},{"key":"2025030417505613500_r28","doi-asserted-by":"crossref","first-page":"1609","DOI":"10.1084\/jem.20172310","article-title":"Peripheral PDGFR\u03b1+gp38+ mesenchymal cells support the differentiation of fetal liver-derived ILC2","volume":"215","author":"Koga","year":"2018","journal-title":"J. Exp. Med."},{"key":"2025030417505613500_r29","doi-asserted-by":"crossref","first-page":"1676","DOI":"10.1002\/stem.94","article-title":"Notch increases T\/NK potential of human hematopoietic progenitors and inhibits B cell differentiation at a pro-B stage","volume":"27","author":"Benne","year":"2009","journal-title":"Stem Cells"},{"key":"2025030417505613500_r30","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1016\/S1471-4906(01)02060-9","article-title":"The biology of human natural killer-cell subsets","volume":"22","author":"Cooper","year":"2001","journal-title":"Trends Immunol."},{"key":"2025030417505613500_r31","doi-asserted-by":"crossref","first-page":"486","DOI":"10.1016\/j.stem.2014.01.020","article-title":"Clonal tracking of rhesus macaque hematopoiesis highlights a distinct lineage origin for natural killer cells","volume":"14","author":"Wu","year":"2014","journal-title":"Cell Stem Cell"},{"key":"2025030417505613500_r32","doi-asserted-by":"crossref","first-page":"352","DOI":"10.4049\/jimmunol.0803183","article-title":"Notch ligands expressed by follicular dendritic cells protect germinal center B cells from apoptosis","volume":"183","author":"Yoon","year":"2009","journal-title":"J. Immunol."},{"key":"2025030417505613500_r33","doi-asserted-by":"crossref","first-page":"1403","DOI":"10.1172\/JCI46125","article-title":"Evidence for a stepwise program of extrathymic T cell development within the human tonsil","volume":"122","author":"McClory","year":"2012","journal-title":"J. Clin. Invest."},{"key":"2025030417505613500_r34","doi-asserted-by":"crossref","first-page":"803","DOI":"10.1016\/j.immuni.2010.06.007","article-title":"Interleukin-1beta selectively expands and sustains interleukin-22+ immature human natural killer cells in secondary lymphoid tissue","volume":"32","author":"Hughes","year":"2010","journal-title":"Immunity"},{"key":"2025030417505613500_r35","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1038\/nmeth.4258","article-title":"Progenitor T-cell differentiation from hematopoietic stem cells using Delta-like-4 and VCAM-1","volume":"14","author":"Shukla","year":"2017","journal-title":"Nat. Methods"},{"key":"2025030417505613500_r36","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0134026","article-title":"Modification of gene expression, proliferation, and function of OP9 stroma cells by bcr-Abl-expressing leukemia cells","volume":"10","author":"Supper","year":"2015","journal-title":"PLoS One"},{"key":"2025030417505613500_r37","doi-asserted-by":"crossref","first-page":"578","DOI":"10.1038\/onc.2013.592","article-title":"Opposing role of Notch1 and Notch2 in a Kras(G12D)-driven murine non-small cell lung cancer model","volume":"34","author":"Baumgart","year":"2015","journal-title":"Oncogene"}],"container-title":["The Journal of Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/205\/10\/2679\/61878789\/ji2000434.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/205\/10\/2679\/61878789\/ji2000434.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,4]],"date-time":"2025-03-04T18:27:35Z","timestamp":1741112855000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jimmunol\/article\/205\/10\/2679\/7931031"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,11]]},"references-count":37,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2020,11,15]]}},"URL":"https:\/\/doi.org\/10.4049\/jimmunol.2000434","relation":{},"ISSN":["0022-1767","1550-6606"],"issn-type":[{"value":"0022-1767","type":"print"},{"value":"1550-6606","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2020,11]]},"published":{"date-parts":[[2020,11]]}}}