{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T14:29:56Z","timestamp":1778509796660,"version":"3.51.4"},"reference-count":30,"publisher":"Rockefeller University Press","issue":"1","content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2009,1,16]]},"abstract":"<jats:p>The in vivo requirements for human natural killer (NK) cell development and differentiation into cytotoxic effectors expressing inhibitory receptors for self\u2013major histocompatability complex class I (MHC-I; killer Ig-like receptors [KIRs]) remain undefined. Here, we dissect the role of interleukin (IL)-15 in human NK cell development using Rag2\u2212\/\u2212\u03b3c\u2212\/\u2212 mice transplanted with human hematopoietic stem cells. Human NK cell reconstitution was intrinsically low in this model because of the poor reactivity to mouse IL-15. Although exogenous human IL-15 (hIL-15) alone made little improvement, IL-15 coupled to IL-15 receptor \u03b1 (IL-15R\u03b1) significantly augmented human NK cells. IL-15\u2013IL-15R\u03b1 complexes induced extensive NK cell proliferation and differentiation, resulting in accumulation of CD16+KIR+ NK cells, which was not uniquely dependent on enhanced survival or preferential responsiveness of this subset to IL-15. Human NK cell differentiation in vivo required hIL-15 and progressed in a linear fashion from CD56hiCD16\u2212KIR\u2212 to CD56loCD16+KIR\u2212, and finally to CD56loCD16+KIR+. These data provide the first evidence that IL-15 trans-presentation regulates human NK cell homeostasis. Use of hIL-15 receptor agonists generates a robust humanized immune system model to study human NK cells in vivo. IL-15 receptor agonists may provide therapeutic tools to improve NK cell reconstitution after bone marrow transplants, enhance graft versus leukemia effects, and increase the pool of IL-15\u2013responsive cells during immunotherapy strategies.<\/jats:p>","DOI":"10.1084\/jem.20082013","type":"journal-article","created":{"date-parts":[[2008,12,23]],"date-time":"2008-12-23T01:48:58Z","timestamp":1229996938000},"page":"25-34","update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":497,"title":["IL-15 trans-presentation promotes human NK cell development and differentiation in vivo"],"prefix":"10.1084","volume":"206","author":[{"given":"Nicholas D.","family":"Huntington","sequence":"first","affiliation":[{"name":"Cytokine and Lymphoid Development Unit, Immunology Department 1 , 2 , 3"},{"name":"Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale (INSERM) U668 1 , 2 , 3"},{"name":"INSERM U883, Unit\u00e9 de R\u00e9gulation Immunitaire et Vaccinologie, Institut Pasteur, Paris 75724, France 1 , 2 , 3"},{"name":"Cytokine and Lymphoid Development Unit, Immunology Department 1 , 2 , 3"},{"name":"Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale (INSERM) U668 1 , 2 , 3"},{"name":"INSERM U883, Unit\u00e9 de R\u00e9gulation Immunitaire et Vaccinologie, Institut Pasteur, Paris 75724, France 1 , 2 , 3"}]},{"given":"Nicolas","family":"Legrand","sequence":"additional","affiliation":[{"name":"Academic Medical Center, University of Amsterdam, 1100 DD, Amsterdam, Netherlands 4"}]},{"given":"Nuno L.","family":"Alves","sequence":"additional","affiliation":[{"name":"Cytokine and Lymphoid Development Unit, Immunology Department 1 , 2 , 3"},{"name":"Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale (INSERM) U668 1 , 2 , 3"},{"name":"INSERM U883, Unit\u00e9 de R\u00e9gulation Immunitaire et Vaccinologie, Institut Pasteur, Paris 75724, France 1 , 2 , 3"},{"name":"Cytokine and Lymphoid Development Unit, Immunology Department 1 , 2 , 3"},{"name":"Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale (INSERM) U668 1 , 2 , 3"},{"name":"INSERM U883, Unit\u00e9 de R\u00e9gulation Immunitaire et Vaccinologie, Institut Pasteur, Paris 75724, France 1 , 2 , 3"}]},{"given":"Barbara","family":"Jaron","sequence":"additional","affiliation":[{"name":"Cytokine and Lymphoid Development Unit, Immunology Department 1 , 2 , 3"},{"name":"Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale (INSERM) U668 1 , 2 , 3"},{"name":"INSERM U883, Unit\u00e9 de R\u00e9gulation Immunitaire et Vaccinologie, Institut Pasteur, Paris 75724, France 1 , 2 , 3"}]},{"given":"Kees","family":"Weijer","sequence":"additional","affiliation":[{"name":"Academic Medical Center, University of Amsterdam, 1100 DD, Amsterdam, Netherlands 4"}]},{"given":"Ariane","family":"Plet","sequence":"additional","affiliation":[{"name":"INSERM U892, Groupe de Recherche Cytokines et R\u00e9cepteurs, Institut de Biologie, Nantes F-44093, France 5"}]},{"given":"Erwan","family":"Corcuff","sequence":"additional","affiliation":[{"name":"Cytokine and Lymphoid Development Unit, Immunology Department 1 , 2 , 3"},{"name":"Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale (INSERM) U668 1 , 2 , 3"},{"name":"INSERM U883, Unit\u00e9 de R\u00e9gulation Immunitaire et Vaccinologie, Institut Pasteur, Paris 75724, France 1 , 2 , 3"},{"name":"Cytokine and Lymphoid Development Unit, Immunology Department 1 , 2 , 3"},{"name":"Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale (INSERM) U668 1 , 2 , 3"},{"name":"INSERM U883, Unit\u00e9 de R\u00e9gulation Immunitaire et Vaccinologie, Institut Pasteur, Paris 75724, France 1 , 2 , 3"}]},{"given":"Erwan","family":"Mortier","sequence":"additional","affiliation":[{"name":"INSERM U892, Groupe de Recherche Cytokines et R\u00e9cepteurs, Institut de Biologie, Nantes F-44093, France 5"}]},{"given":"Yannick","family":"Jacques","sequence":"additional","affiliation":[{"name":"INSERM U892, Groupe de Recherche Cytokines et R\u00e9cepteurs, Institut de Biologie, Nantes F-44093, France 5"}]},{"given":"Hergen","family":"Spits","sequence":"additional","affiliation":[{"name":"Academic Medical Center, University of Amsterdam, 1100 DD, Amsterdam, Netherlands 4"}]},{"given":"James P.","family":"Di Santo","sequence":"additional","affiliation":[{"name":"Cytokine and Lymphoid Development Unit, Immunology Department 1 , 2 , 3"},{"name":"Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale (INSERM) U668 1 , 2 , 3"},{"name":"INSERM U883, Unit\u00e9 de R\u00e9gulation Immunitaire et Vaccinologie, Institut Pasteur, Paris 75724, France 1 , 2 , 3"},{"name":"Cytokine and Lymphoid Development Unit, Immunology Department 1 , 2 , 3"},{"name":"Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale (INSERM) U668 1 , 2 , 3"},{"name":"INSERM U883, Unit\u00e9 de R\u00e9gulation Immunitaire et Vaccinologie, Institut Pasteur, Paris 75724, France 1 , 2 , 3"}]}],"member":"291","published-online":{"date-parts":[[2008,12,22]]},"reference":[{"key":"2023072919542970000_bib1","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1038\/nri2154","article-title":"Developmental pathways that generate natural-killer-cell diversity in mice and humans","volume":"7","author":"Huntington","year":"2007","journal-title":"Nat. Rev. Immunol."},{"key":"2023072919542970000_bib2","doi-asserted-by":"crossref","first-page":"3239","DOI":"10.1182\/blood.V79.12.3239.bloodjournal79123239","article-title":"CD16- CD56+ natural killer cells after bone marrow transplantation","volume":"79","author":"Jacobs","year":"1992","journal-title":"Blood."},{"key":"2023072919542970000_bib3","first-page":"259","article-title":"Two populations of CD56 (Leu-19)+\/CD16+ cells in bone marrow transplant recipients","volume":"5","author":"Gottschalk","year":"1990","journal-title":"Bone Marrow Transplant."},{"key":"2023072919542970000_bib4","doi-asserted-by":"crossref","first-page":"89","DOI":"10.4049\/jimmunol.179.1.89","article-title":"CD56bright human NK cells differentiate into CD56dim cells: role of contact with peripheral fibroblasts","volume":"179","author":"Chan","year":"2007","journal-title":"J. Immunol."},{"key":"2023072919542970000_bib5","doi-asserted-by":"crossref","first-page":"4947","DOI":"10.4049\/jimmunol.178.8.4947","article-title":"CD56brightCD16- killer Ig-like receptor- NK cells display longer telomeres and acquire features of CD56dim NK cells upon activation","volume":"178","author":"Romagnani","year":"2007","journal-title":"J. Immunol."},{"key":"2023072919542970000_bib6","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1016\/j.immuni.2006.06.013","article-title":"Human NK cell education by inhibitory receptors for MHC class I","volume":"25","author":"Anfossi","year":"2006","journal-title":"Immunity."},{"key":"2023072919542970000_bib7","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1126\/science.7517574","article-title":"Homozygous human TAP peptide transporter mutation in HLA class I deficiency","volume":"265","author":"de la Salle","year":"1994","journal-title":"Science."},{"key":"2023072919542970000_bib8","first-page":"225","article-title":"The impact of variation at the KIR gene cluster on human disease","volume":"298","author":"Carrington","year":"2006","journal-title":"Curr. Top. Microbiol. Immunol."},{"key":"2023072919542970000_bib9","doi-asserted-by":"crossref","first-page":"1213","DOI":"10.1084\/jem.20071913","article-title":"IL-15R\u03b1 chaperones IL-15 to stable dendritic cell membrane complexes that activate NK cells via trans presentation","volume":"205","author":"Mortier","year":"2008","journal-title":"J. Exp. Med."},{"key":"2023072919542970000_bib10","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1146\/annurev.immunol.24.021605.090727","article-title":"Diverse functions of IL-2, IL-15, and IL-7 in lymphoid homeostasis","volume":"24","author":"Ma","year":"2006","journal-title":"Annu. Rev. Immunol."},{"key":"2023072919542970000_bib11","doi-asserted-by":"crossref","first-page":"9166","DOI":"10.1073\/pnas.0600240103","article-title":"Converting IL-15 to a superagonist by binding to soluble IL-15R{alpha}","volume":"103","author":"Rubinstein","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA."},{"key":"2023072919542970000_bib12","doi-asserted-by":"crossref","first-page":"6072","DOI":"10.4049\/jimmunol.177.9.6072","article-title":"Combined IL-15\/IL-15Ralpha immunotherapy maximizes IL-15 activity in vivo","volume":"177","author":"Stoklasek","year":"2006","journal-title":"J. Immunol."},{"key":"2023072919542970000_bib13","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1146\/annurev.immunol.22.012703.104614","article-title":"Molecular defects in human severe combined immunodeficiency and approaches to immune reconstitution","volume":"22","author":"Buckley","year":"2004","journal-title":"Annu. Rev. Immunol."},{"key":"2023072919542970000_bib14","doi-asserted-by":"crossref","first-page":"877","DOI":"10.1182\/blood.V98.3.877","article-title":"Defective expression of the interleukin-2\/interleukin-15 receptor beta subunit leads to a natural killer cell-deficient form of severe combined immunodeficiency","volume":"98","author":"Gilmour","year":"2001","journal-title":"Blood."},{"key":"2023072919542970000_bib15","doi-asserted-by":"crossref","first-page":"3886","DOI":"10.1182\/blood-2004-02-0656","article-title":"Monitoring the effect of gene silencing by RNA interference in human CD34+ cells injected into newborn RAG2\u2212\/\u2212 gammac\u2212\/\u2212 mice: functional inactivation of p53 in developing T cells","volume":"104","author":"Gimeno","year":"2004","journal-title":"Blood."},{"key":"2023072919542970000_bib16","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1126\/science.1093933","article-title":"Development of a human adaptive immune system in cord blood cell-transplanted mice","volume":"304","author":"Traggiai","year":"2004","journal-title":"Science."},{"key":"2023072919542970000_bib17","doi-asserted-by":"crossref","first-page":"1421","DOI":"10.1084\/jem.20042294","article-title":"A requirement for CD45 distinguishes Ly49D-mediated cytokine and chemokine production from killing in primary natural killer cells","volume":"201","author":"Huntington","year":"2005","journal-title":"J. Exp. Med."},{"key":"2023072919542970000_bib18","doi-asserted-by":"crossref","first-page":"856","DOI":"10.1038\/ni1487","article-title":"Interleukin 15-mediated survival of natural killer cells is determined by interactions among Bim, Noxa and Mcl-1","volume":"8","author":"Huntington","year":"2007","journal-title":"Nat. Immunol."},{"key":"2023072919542970000_bib19","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1182\/blood.V97.1.14","article-title":"Interleukin 15: biology and relevance to human disease","volume":"97","author":"Fehniger","year":"2001","journal-title":"Blood."},{"key":"2023072919542970000_bib20","doi-asserted-by":"crossref","first-page":"1612","DOI":"10.1074\/jbc.M508624200","article-title":"Soluble interleukin-15 receptor alpha (IL-15R alpha)-sushi as a selective and potent agonist of IL-15 action through IL-15R beta\/gamma. Hyperagonist IL-15 x IL-15R alpha fusion proteins","volume":"281","author":"Mortier","year":"2006","journal-title":"J. Biol. Chem."},{"key":"2023072919542970000_bib21","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.jmb.2008.07.019","article-title":"The exon-3-encoded domain of IL-15ralpha contributes to IL-15 high-affinity binding and is crucial for the IL-15 antagonistic effect of soluble IL-15Ralpha","volume":"382","author":"Bouchaud","year":"2008","journal-title":"J. Mol. Biol."},{"key":"2023072919542970000_bib22","doi-asserted-by":"crossref","first-page":"937","DOI":"10.1172\/JCI119258","article-title":"A potential role for interleukin-15 in the regulation of human natural killer cell survival","volume":"99","author":"Carson","year":"1997","journal-title":"J. Clin. Invest."},{"key":"2023072919542970000_bib23","doi-asserted-by":"crossref","first-page":"2559","DOI":"10.1016\/j.molimm.2008.01.001","article-title":"Bcl-xL is associated with the anti-apoptotic effect of IL-15 on the survival of CD56(dim) natural killer cells","volume":"45","author":"Zheng","year":"2008","journal-title":"Mol. Immunol."},{"key":"2023072919542970000_bib24","doi-asserted-by":"crossref","first-page":"798","DOI":"10.1016\/j.immuni.2007.04.010","article-title":"Acquisition of murine NK cell cytotoxicity requires the translation of a pre-existing pool of granzyme B and perforin mRNAs","volume":"26","author":"Fehniger","year":"2007","journal-title":"Immunity."},{"key":"2023072919542970000_bib25","doi-asserted-by":"crossref","first-page":"1395","DOI":"10.1084\/jem.180.4.1395","article-title":"Interleukin (IL) 15 is a novel cytokine that activates human natural killer cells via components of the IL-2 receptor","volume":"180","author":"Carson","year":"1994","journal-title":"J. Exp. Med."},{"key":"2023072919542970000_bib26","doi-asserted-by":"crossref","first-page":"578","DOI":"10.1182\/blood-2006-07-036228","article-title":"A subpopulation of human peripheral blood NK cells that lacks inhibitory receptors for self-MHC is developmentally immature","volume":"110","author":"Cooley","year":"2007","journal-title":"Blood."},{"key":"2023072919542970000_bib27","doi-asserted-by":"crossref","first-page":"2302","DOI":"10.1182\/blood-2005-01-0064","article-title":"Membrane-bound and soluble IL-15\/IL-15Ralpha complexes display differential signaling and functions on human hematopoietic progenitors","volume":"106","author":"Giron-Michel","year":"2005","journal-title":"Blood."},{"key":"2023072919542970000_bib28","doi-asserted-by":"crossref","first-page":"2637","DOI":"10.1182\/blood.V94.8.2637.420k22_2637_2646","article-title":"Genetic modification of human B-cell development: B-cell development is inhibited by the dominant negative helix loop helix factor Id3","volume":"94","author":"Jaleco","year":"1999","journal-title":"Blood."},{"key":"2023072919542970000_bib29","doi-asserted-by":"crossref","first-page":"1597","DOI":"10.1084\/jem.186.9.1597","article-title":"Inhibition of T cell and promotion of natural killer cell development by the dominant negative helix loop helix factor Id3","volume":"186","author":"Heemskerk","year":"1997","journal-title":"J. Exp. Med."},{"key":"2023072919542970000_bib30","doi-asserted-by":"crossref","first-page":"1405","DOI":"10.1089\/hum.1996.7.12-1405","article-title":"Episomal vectors rapidly and stably produce high-titer recombinant retrovirus","volume":"7","author":"Kinsella","year":"1996","journal-title":"Hum. Gene Ther."}],"container-title":["Journal of Experimental Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/rupress.org\/jem\/article-pdf\/206\/1\/25\/1908889\/20082013.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/rupress.org\/jem\/article-pdf\/206\/1\/25\/1908889\/20082013.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,7,29]],"date-time":"2023-07-29T19:55:04Z","timestamp":1690660504000},"score":1,"resource":{"primary":{"URL":"https:\/\/rupress.org\/jem\/article\/206\/1\/25\/54173\/IL-15-trans-presentation-promotes-human-NK-cell"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2008,12,22]]},"references-count":30,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2009,1,16]]}},"URL":"https:\/\/doi.org\/10.1084\/jem.20082013","relation":{},"ISSN":["1540-9538","0022-1007"],"issn-type":[{"value":"1540-9538","type":"electronic"},{"value":"0022-1007","type":"print"}],"subject":[],"published":{"date-parts":[[2008,12,22]]}}}