{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T04:07:49Z","timestamp":1773979669222,"version":"3.50.1"},"reference-count":37,"publisher":"American Society of Hematology","issue":"7","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2003,10,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Recent studies in mice have shown that although interleukin 15 (IL-15) plays an important role in regulating homeostasis of memory CD8+ T cells, it has no apparent function in controlling homeostatic proliferation of naive T cells. We here assessed the influence of IL-15 on antigen-independent expansion and differentiation of human CD8+ T cells. Both naive and primed human T cells divided in response to IL-15. In this process, naive CD8+ T cells successively down-regulated CD45RA and CD28 but maintained CD27 expression. Concomitant with these phenotypic changes, naive cells acquired the ability to produce interferon \u03b3 (IFN-\u03b3) and tumor necrosis factor \u03b1 (TNF-\u03b1), expressed perforin and granzyme B, and acquired cytotoxic properties. Primed CD8+ T cells, from both noncytotoxic (CD45RA-CD27+) and cytotoxic (CD45RA+CD27-) subsets, responded to IL-15 and yielded ample numbers of cytokine-secreting and cytotoxic effector cells. In summary, all human CD8+ T-cell subsets had the ability to respond to IL-15, which suggests a generic influence of this cytokine on CD8+ T-cell homeostasis in man. (Blood. 2003;102:2541-2546)<\/jats:p>","DOI":"10.1182\/blood-2003-01-0183","type":"journal-article","created":{"date-parts":[[2003,6,16]],"date-time":"2003-06-16T20:34:45Z","timestamp":1055795685000},"page":"2541-2546","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":135,"title":["IL-15 induces antigen-independent expansion and differentiation of human naive CD8+ T cells in vitro"],"prefix":"10.1182","volume":"102","author":[{"given":"Nuno L.","family":"Alves","sequence":"first","affiliation":[{"name":"From the Laboratory for Experimental Immunology, Academic Medical Center, Amsterdam, the Netherlands; Laboratory of Molecular Immunology, Institute for Molecular and Cell Biology, Porto, Portugal; and Sanquin Research, Amsterdam, the Netherlands."}]},{"given":"Berend","family":"Hooibrink","sequence":"additional","affiliation":[{"name":"From the Laboratory for Experimental Immunology, Academic Medical Center, Amsterdam, the Netherlands; Laboratory of Molecular Immunology, Institute for Molecular and Cell Biology, Porto, Portugal; and Sanquin Research, Amsterdam, the Netherlands."}]},{"given":"Fernando A.","family":"Arosa","sequence":"additional","affiliation":[{"name":"From the Laboratory for Experimental Immunology, Academic Medical Center, Amsterdam, the Netherlands; Laboratory of Molecular Immunology, Institute for Molecular and Cell Biology, Porto, Portugal; and Sanquin Research, Amsterdam, the Netherlands."}]},{"given":"Rene\u0301 A. W.","family":"van Lier","sequence":"additional","affiliation":[{"name":"From the Laboratory for Experimental Immunology, Academic Medical Center, Amsterdam, the Netherlands; Laboratory of Molecular Immunology, Institute for Molecular and Cell Biology, Porto, Portugal; and Sanquin Research, Amsterdam, the Netherlands."}]}],"member":"234","reference":[{"key":"2020021222393440200_REF1","doi-asserted-by":"crossref","unstructured":"Michie CA, McLean A, Alcock C, Beverley PC. Lifespan of human lymphocyte subsets defined by CD45 isoforms. Nature. 1992;360: 264-265.","DOI":"10.1038\/360264a0"},{"key":"2020021222393440200_REF2","doi-asserted-by":"crossref","unstructured":"Lodolce JP, Burkett PR, Boone DL, Chien M, Ma A. T cell-independent interleukin 15Ralpha signals are required for bystander proliferation. J Exp Med. 2001;194: 1187-1194.","DOI":"10.1084\/jem.194.8.1187"},{"key":"2020021222393440200_REF3","doi-asserted-by":"crossref","unstructured":"Tan JT, Dudl E, LeRoy E, et al. IL-7 is critical for homeostatic proliferation and survival of naive T cells. Proc Natl Acad Sci U S A. 2001;98: 8732-8737.","DOI":"10.1073\/pnas.161126098"},{"key":"2020021222393440200_REF4","doi-asserted-by":"crossref","unstructured":"Fry TJ, Mackall CL. Interleukin-7: master regulator of peripheral T-cell homeostasis? Trends Immunol. 2001;22: 564-571.","DOI":"10.1016\/S1471-4906(01)02028-2"},{"key":"2020021222393440200_REF5","doi-asserted-by":"crossref","unstructured":"Schluns KS, Kieper WC, Jameson SC, Lefrancois L. Interleukin-7 mediates the homeostasis of naive and memory CD8 T cells in vivo. Nat Immunol. 2000;1: 426-432.","DOI":"10.1038\/80868"},{"key":"2020021222393440200_REF6","doi-asserted-by":"crossref","unstructured":"Zhang X, Sun S, Hwang I, Tough DF, Sprent J. Potent and selective stimulation of memory-phenotype CD8+ T cells in vivo by IL-15. Immunity. 1998;8: 591-599.","DOI":"10.1016\/S1074-7613(00)80564-6"},{"key":"2020021222393440200_REF7","doi-asserted-by":"crossref","unstructured":"Schluns KS, Williams K, Ma A, Zheng XX, Lefrancois L. Cutting edge: requirement for IL-15 in the generation of primary and memory antigen-specific CD8 T cells. J Immunol. 2002;168: 4827-4831.","DOI":"10.4049\/jimmunol.168.10.4827"},{"key":"2020021222393440200_REF8","doi-asserted-by":"crossref","unstructured":"Prlic M, Lefrancois L, Jameson SC. Multiple choices: regulation of memory CD8 T cell generation and homeostasis by interleukin (IL)-7 and IL-15. J Exp Med. 2002;195: F49-F52.","DOI":"10.1084\/jem.20020767"},{"key":"2020021222393440200_REF9","doi-asserted-by":"crossref","unstructured":"Goldrath AW, Sivakumar PV, Glaccum M, et al. Cytokine requirements for acute and Basal homeostatic proliferation of naive and memory CD8+ T cells. J Exp Med. 2002;195: 1515-1522.","DOI":"10.1084\/jem.20020033"},{"key":"2020021222393440200_REF10","doi-asserted-by":"crossref","unstructured":"Tan JT, Ernst B, Kieper WC, LeRoy E, Sprent J, Surh CD. Interleukin (IL)-15 and IL-7 jointly regulate homeostatic proliferation of memory phenotype CD8+ cells but are not required for memory phenotype CD4+ cells. J Exp Med. 2002;195: 1523-1532.","DOI":"10.1084\/jem.20020066"},{"key":"2020021222393440200_REF11","doi-asserted-by":"crossref","unstructured":"Kennedy MK, Glaccum M, Brown SN, et al. Reversible defects in natural killer and memory CD8 T cell lineages in interleukin 15-deficient mice. J Exp Med. 2000;191: 771-780.","DOI":"10.1084\/jem.191.5.771"},{"key":"2020021222393440200_REF12","doi-asserted-by":"crossref","unstructured":"Lodolce JP, Boone DL, Chai S, et al. IL-15 receptor maintains lymphoid homeostasis by supporting lymphocyte homing and proliferation. Immunity. 1998;9: 669-676.","DOI":"10.1016\/S1074-7613(00)80664-0"},{"key":"2020021222393440200_REF13","doi-asserted-by":"crossref","unstructured":"Marks-Konczalik J, Dubois S, Losi JM, et al. IL-2-induced activation-induced cell death is inhibited in IL-15 transgenic mice. Proc Natl Acad Sci U S A. 2000;97: 11445-11450.","DOI":"10.1073\/pnas.200363097"},{"key":"2020021222393440200_REF14","doi-asserted-by":"crossref","unstructured":"Geginat J, Sallusto F, Lanzavecchia A. Cytokine-driven proliferation and differentiation of human naive, central memory, and effector memory CD4(+) T cells. J Exp Med. 2001;194: 1711-1719.","DOI":"10.1084\/jem.194.12.1711"},{"key":"2020021222393440200_REF15","doi-asserted-by":"crossref","unstructured":"Kanegane H, Tosato G. Activation of naive and memory T cells by interleukin-15. Blood. 1996;88: 230-235.","DOI":"10.1182\/blood.V88.1.230.230"},{"key":"2020021222393440200_REF16","doi-asserted-by":"crossref","unstructured":"Hamann D, Baars PA, Rep MH, et al. Phenotypic and functional separation of memory and effector human CD8+ T cells. J Exp Med. 1997;186: 1407-1418.","DOI":"10.1084\/jem.186.9.1407"},{"key":"2020021222393440200_REF17","doi-asserted-by":"crossref","unstructured":"Sandberg JK, Fast NM, Nixon DF. Functional heterogeneity of cytokines and cytolytic effector molecules in human CD8+ T lymphocytes. J Immunol. 2001;167: 181-187.","DOI":"10.4049\/jimmunol.167.1.181"},{"key":"2020021222393440200_REF18","doi-asserted-by":"crossref","unstructured":"Hamann D, Roos MT, van Lier RA. Faces and phases of human CD8 T-cell development. Immunol Today. 1999;20: 177-180.","DOI":"10.1016\/S0167-5699(99)01444-9"},{"key":"2020021222393440200_REF19","doi-asserted-by":"crossref","unstructured":"He X, Janeway CA Jr, Levine M, et al. Dual receptor T cells extend the immune repertoire for foreign antigens. Nat Immunol. 2002;3: 127-134.","DOI":"10.1038\/ni751"},{"key":"2020021222393440200_REF20","doi-asserted-by":"crossref","unstructured":"Liu K, Catalfamo M, Li Y, Henkart PA, Weng NP. IL-15 mimics T cell receptor crosslinking in the induction of cellular proliferation, gene expression, and cytotoxicity in CD8+ memory T cells. Proc Natl Acad Sci U S A. 2002;99: 6192-6197.","DOI":"10.1073\/pnas.092675799"},{"key":"2020021222393440200_REF21","doi-asserted-by":"crossref","unstructured":"Sallusto F, Lenig D, Forster R, Lipp M, Lanzavecchia A. Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature. 1999;401: 708-712.","DOI":"10.1038\/44385"},{"key":"2020021222393440200_REF22","doi-asserted-by":"crossref","unstructured":"Grabstein KH, Eisenman J, Shanebeck K, et al. Cloning of a T cell growth factor that interacts with the beta chain of the interleukin-2 receptor. Science. 1994;264: 965-968.","DOI":"10.1126\/science.8178155"},{"key":"2020021222393440200_REF23","doi-asserted-by":"crossref","unstructured":"Carson WE, Giri JG, Lindemann MJ, et al. Interleukin (IL) 15 is a novel cytokine that activates human natural killer cells via components of the IL-2 receptor. J Exp Med. 1994;180: 1395-1403.","DOI":"10.1084\/jem.180.4.1395"},{"key":"2020021222393440200_REF24","doi-asserted-by":"crossref","unstructured":"Bamford RN, Grant AJ, Burton JD, et al. The interleukin (IL) 2 receptor beta chain is shared by IL-2 and a cytokine, provisionally designated IL-T, that stimulates T-cell proliferation and the induction of lymphokine-activated killer cells. Proc Natl Acad Sci U S A. 1994;91: 4940-4944.","DOI":"10.1073\/pnas.91.11.4940"},{"key":"2020021222393440200_REF25","doi-asserted-by":"crossref","unstructured":"Kim YJ, Brutkiewicz RR, Broxmeyer HE. Role of 4-1BB (CD137) in the functional activation of cord blood CD28(-) CD8(+) T cells. Blood. 2002;100: 3253-3260.","DOI":"10.1182\/blood-2001-11-0136"},{"key":"2020021222393440200_REF26","doi-asserted-by":"crossref","unstructured":"Niedbala W, Wei X, Liew FY. IL-15 induces type 1 and type 2 CD4+ and CD8+ T cells proliferation but is unable to drive cytokine production in the absence of TCR activation or IL-12\/IL-4 stimulation in vitro. Eur J Immunol. 2002;32: 341-347.","DOI":"10.1002\/1521-4141(200202)32:2<341::AID-IMMU341>3.0.CO;2-X"},{"key":"2020021222393440200_REF27","doi-asserted-by":"crossref","unstructured":"Carson WE, Ross ME, Baiocchi RA, et al. Endogenous production of interleukin 15 by activated human monocytes is critical for optimal production of interferon-gamma by natural killer cells in vitro. J Clin Invest. 1995;96: 2578-2582.","DOI":"10.1172\/JCI118321"},{"key":"2020021222393440200_REF28","doi-asserted-by":"crossref","unstructured":"Fehniger TA, Caligiuri MA. Interleukin 15: biology and relevance to human disease. Blood. 2001;97: 14-32.","DOI":"10.1182\/blood.V97.1.14"},{"key":"2020021222393440200_REF29","doi-asserted-by":"crossref","unstructured":"Reinecker HC, MacDermott RP, Mirau S, Dignass A, Podolsky DK. Intestinal epithelial cells both express and respond to interleukin 15. Gastroenterology. 1996;111: 1706-1713.","DOI":"10.1016\/S0016-5085(96)70036-7"},{"key":"2020021222393440200_REF30","doi-asserted-by":"crossref","unstructured":"Briard D, Brouty-Boye D, Azzarone B, Jasmin C. Fibroblasts from human spleen regulate NK cell differentiation from blood CD34(+) progenitors via cell surface IL-15. J Immunol. 2002;168: 4326-4332.","DOI":"10.4049\/jimmunol.168.9.4326"},{"key":"2020021222393440200_REF31","doi-asserted-by":"crossref","unstructured":"Dubois S, Mariner J, Waldmann TA, Tagaya Y. IL-15Ralpha recycles and presents IL-15 In trans to neighboring cells. Immunity. 2002;17: 537-547.","DOI":"10.1016\/S1074-7613(02)00429-6"},{"key":"2020021222393440200_REF32","doi-asserted-by":"crossref","unstructured":"Cooper MA, Fehniger TA, Caligiuri MA. The biology of human natural killer-cell subsets. Trends Immunol. 2001;22: 633-640.","DOI":"10.1016\/S1471-4906(01)02060-9"},{"key":"2020021222393440200_REF33","doi-asserted-by":"crossref","unstructured":"Cho BK, Rao VP, Ge Q, Eisen HN, Chen J. Homeostasis-stimulated proliferation drives naive T cells to differentiate directly into memory T cells. J Exp Med. 2000;192: 549-556.","DOI":"10.1084\/jem.192.4.549"},{"key":"2020021222393440200_REF34","doi-asserted-by":"crossref","unstructured":"Goldrath AW, Bogatzki LY, Bevan MJ. Naive T cells transiently acquire a memory-like phenotype during homeostasis-driven proliferation. J Exp Med. 2000;192: 557-564.","DOI":"10.1084\/jem.192.4.557"},{"key":"2020021222393440200_REF35","doi-asserted-by":"crossref","unstructured":"Murali-Krishna K, Ahmed R. Cutting edge: naive T cells masquerading as memory cells. J Immunol. 2000;165: 1733-1737.","DOI":"10.4049\/jimmunol.165.4.1733"},{"key":"2020021222393440200_REF36","doi-asserted-by":"crossref","unstructured":"Kieper WC, Tan JT, Bondi-Boyd B, et al. Overexpression of interleukin (IL)-7 leads to IL-15-independent generation of memory phenotype CD8+ T cells. J Exp Med. 2002;195: 1533-1539.","DOI":"10.1084\/jem.20020067"},{"key":"2020021222393440200_REF37","doi-asserted-by":"crossref","unstructured":"Richter A, Lohning M, Radbruch A. Instruction for cytokine expression in T helper lymphocytes in relation to proliferation and cell cycle progression. J Exp Med. 1999;190: 1439-1450.","DOI":"10.1084\/jem.190.10.1439"}],"container-title":["Blood"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/ashpublications.org\/blood\/article-pdf\/102\/7\/2541\/1691782\/h81903002541.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/ashpublications.org\/blood\/article-pdf\/102\/7\/2541\/1691782\/h81903002541.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,2,12]],"date-time":"2020-02-12T22:39:47Z","timestamp":1581547187000},"score":1,"resource":{"primary":{"URL":"https:\/\/ashpublications.org\/blood\/article\/102\/7\/2541\/18000\/IL15-induces-antigenindependent-expansion-and"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2003,10,1]]},"references-count":37,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2003,10,1]]}},"URL":"https:\/\/doi.org\/10.1182\/blood-2003-01-0183","relation":{},"ISSN":["0006-4971","1528-0020"],"issn-type":[{"value":"0006-4971","type":"print"},{"value":"1528-0020","type":"electronic"}],"subject":[],"published":{"date-parts":[[2003,10,1]]}}}