{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T08:30:52Z","timestamp":1791361852723,"version":"4.3.1"},"reference-count":41,"publisher":"Springer Science and Business Media LLC","issue":"4","license":[{"start":{"date-parts":[[2019,8,30]],"date-time":"2019-08-30T00:00:00Z","timestamp":1567123200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/www.springer.com\/tdm"},{"start":{"date-parts":[[2019,8,30]],"date-time":"2019-08-30T00:00:00Z","timestamp":1567123200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/www.springer.com\/tdm"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cell Mol Immunol"],"published-print":{"date-parts":[[2020,4]]},"DOI":"10.1038\/s41423-019-0277-2","type":"journal-article","created":{"date-parts":[[2019,8,30]],"date-time":"2019-08-30T08:03:54Z","timestamp":1567152234000},"page":"347-355","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":67,"title":["NK cell detachment from target cells is regulated by successful cytotoxicity and influences cytokine production"],"prefix":"10.1038","volume":"17","author":[{"given":"Moritz","family":"Anft","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Petra","family":"Netter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Doris","family":"Urlaub","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabel","family":"Prager","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samantha","family":"Schaffner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5195-0995","authenticated-orcid":false,"given":"Carsten","family":"Watzl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,8,30]]},"reference":[{"key":"277_CR1","doi-asserted-by":"publisher","first-page":"461","DOI":"10.1182\/blood-2007-09-077438","volume":"112","author":"MA Caligiuri","year":"2008","unstructured":"Caligiuri, M. A. Human natural killer cells. Blood 112, 461\u2013469 (2008).","journal-title":"Blood"},{"key":"277_CR2","doi-asserted-by":"publisher","first-page":"503","DOI":"10.1038\/ni1582","volume":"9","author":"E Vivier","year":"2008","unstructured":"Vivier, E., Tomasello, E., Baratin, M., Walzer, T. & Ugolini, S. Functions of natural killer cells. Nat. Immunol. 9, 503\u2013510 (2008).","journal-title":"Nat. Immunol."},{"key":"277_CR3","doi-asserted-by":"crossref","first-page":"3845","DOI":"10.4049\/jimmunol.137.12.3845","volume":"137","author":"L London","year":"1986","unstructured":"London, L., Perussia, B. & Trinchieri, G. Induction of proliferation in vitro of resting human natural killer cells: IL 2 induces into cell cycle most peripheral blood NK cells, but only a minor subset of low density T cells. J. Immunol. 137, 3845\u20133854 (1986).","journal-title":"J. Immunol."},{"key":"277_CR4","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1038\/35040504","volume":"408","author":"J Parrish-Novak","year":"2000","unstructured":"Parrish-Novak, J. et al. Interleukin 21 and its receptor are involved in NK cell expansion and regulation of lymphocyte function. Nature 408, 57\u201363 (2000).","journal-title":"Nature"},{"key":"277_CR5","doi-asserted-by":"publisher","first-page":"771","DOI":"10.1084\/jem.191.5.771","volume":"191","author":"MK Kennedy","year":"2000","unstructured":"Kennedy, M. K. et al. Reversible defects in natural killer and memory CD8 T cell lineages in interleukin 15-deficient mice. J. Exp. Med. 191, 771\u2013780 (2000).","journal-title":"J. Exp. Med."},{"key":"277_CR6","doi-asserted-by":"publisher","first-page":"15062","DOI":"10.1073\/pnas.96.26.15062","volume":"96","author":"DM Davis","year":"1999","unstructured":"Davis, D. M. et al. The human natural killer cell immune synapse. Proc. Natl Acad. Sci. USA 96, 15062\u201315067 (1999).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"277_CR7","doi-asserted-by":"publisher","first-page":"2757","DOI":"10.4049\/jimmunol.1002867","volume":"186","author":"SC Hoffmann","year":"2011","unstructured":"Hoffmann, S. C., Cohnen, A., Ludwig, T. & Watzl, C. 2B4 engagement mediates rapid LFA-1 and actin-dependent NK cell adhesion to tumor cells as measured by single cell force spectroscopy. J. Immunol. 186, 2757\u20132764 (2011).","journal-title":"J. Immunol."},{"key":"277_CR8","doi-asserted-by":"publisher","first-page":"1944","DOI":"10.4049\/jimmunol.1601004","volume":"198","author":"D Urlaub","year":"2017","unstructured":"Urlaub, D., Hofer, K., Muller, M. L. & Watzl, C. LFA-1 activation in NK cells and their subsets: influence of receptors, maturation, and cytokine stimulation. J. Immunol. 198, 1944\u20131951 (2017).","journal-title":"J. Immunol."},{"key":"277_CR9","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1016\/B978-0-12-800147-9.00005-4","volume":"124","author":"C Watzl","year":"2014","unstructured":"Watzl, C. How to trigger a killer: modulation of natural killer cell reactivity on many levels. Adv. Immunol. 124, 137\u2013170 (2014).","journal-title":"Adv. Immunol."},{"key":"277_CR10","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1038\/icb.2013.96","volume":"92","author":"EM Mace","year":"2014","unstructured":"Mace, E. M. et al. Cell biological steps and checkpoints in accessing NK cell cytotoxicity. Immunol. Cell Biol. 92, 245\u2013255 (2014).","journal-title":"Immunol. Cell Biol."},{"key":"277_CR11","doi-asserted-by":"crossref","unstructured":"Prager, I. & Watzl, C. Mechanisms of natural killer cell-mediated cellular cytotoxicity. J. Leukoc. Biol. 105, 1319\u20131329 (2019).","DOI":"10.1002\/JLB.MR0718-269R"},{"key":"277_CR12","doi-asserted-by":"publisher","first-page":"1411","DOI":"10.1182\/blood-2012-07-441832","volume":"122","author":"A Cohnen","year":"2013","unstructured":"Cohnen, A. et al. Surface CD107a\/LAMP-1 protects natural killer cells from degranulation-associated damage. Blood 122, 1411\u20131418 (2013).","journal-title":"Blood"},{"key":"277_CR13","doi-asserted-by":"publisher","first-page":"6488","DOI":"10.1073\/pnas.1221312110","volume":"110","author":"PJ Choi","year":"2013","unstructured":"Choi, P. J. & Mitchison, T. J. Imaging burst kinetics and spatial coordination during serial killing by single natural killer cells. Proc. Natl Acad. Sci. USA 110, 6488\u20136493 (2013).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"277_CR14","doi-asserted-by":"publisher","first-page":"1326","DOI":"10.1182\/blood-2012-06-439851","volume":"121","author":"B Vanherberghen","year":"2013","unstructured":"Vanherberghen, B. et al. Classification of human natural killer cells based on migration behavior and cytotoxic response. Blood 121, 1326\u20131334 (2013).","journal-title":"Blood"},{"key":"277_CR15","doi-asserted-by":"publisher","first-page":"e326","DOI":"10.1371\/journal.pone.0000326","volume":"2","author":"R Bhat","year":"2007","unstructured":"Bhat, R. & Watzl, C. Serial killing of tumor cells by human natural killer cells-enhancement by therapeutic antibodies. PLoS ONE 2, e326 (2007).","journal-title":"PLoS ONE"},{"key":"277_CR16","doi-asserted-by":"publisher","unstructured":"Prager, I. et al. NK cells switch from granzyme B to death receptor-mediated cytotoxicity during serial killing. J. Exp. Med. 216, (2019). https:\/\/doi.org\/10.1084\/jem.20181454 .","DOI":"10.1084\/jem.20181454"},{"key":"277_CR17","doi-asserted-by":"publisher","first-page":"293","DOI":"10.1016\/j.mehy.2010.10.027","volume":"76","author":"P Li","year":"2011","unstructured":"Li, P., Katirai, F., Zheng, F. & Gong, F. Recycling and reutilization of cytotoxic molecules, a new type of energy conservation of NK cells? Med. Hypotheses 76, 293\u2013295 (2011).","journal-title":"Med. Hypotheses"},{"key":"277_CR18","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1073\/pnas.0405737102","volume":"102","author":"D Liu","year":"2005","unstructured":"Liu, D. et al. Rapid biogenesis and sensitization of secretory lysosomes in NK cells mediated by target-cell recognition. Proc. Natl. Acad. Sci. USA 102, 123\u2013127 (2005).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"277_CR19","doi-asserted-by":"publisher","first-page":"2528","DOI":"10.4049\/jimmunol.1700394","volume":"199","author":"P Netter","year":"2017","unstructured":"Netter, P., Anft, M. & Watzl, C. Termination of the activating NK cell immunological synapse is an active and regulated process. J. Immunol. 199, 2528\u20132535 (2017).","journal-title":"J. Immunol."},{"key":"277_CR20","doi-asserted-by":"publisher","first-page":"307","DOI":"10.1084\/jem.20140964","volume":"212","author":"MR Jenkins","year":"2015","unstructured":"Jenkins, M. R. et al. Failed CTL\/NK cell killing and cytokine hypersecretion are directly linked through prolonged synapse time. J. Exp. Med. 212, 307\u2013317 (2015).","journal-title":"J. Exp. Med."},{"key":"277_CR21","doi-asserted-by":"publisher","first-page":"257","DOI":"10.1111\/j.1365-2567.2010.03299.x","volume":"131","author":"S Konjar","year":"2010","unstructured":"Konjar, S. et al. Human and mouse perforin are processed in part through cleavage by the lysosomal cysteine proteinase cathepsin L. Immunology 131, 257\u2013267 (2010).","journal-title":"Immunology"},{"key":"277_CR22","doi-asserted-by":"crossref","first-page":"3938","DOI":"10.4049\/jimmunol.153.9.3938","volume":"153","author":"T Kataoka","year":"1994","unstructured":"Kataoka, T. et al. Acidification is essential for maintaining the structure and function of lytic granules of CTL. Effect of concanamycin A, an inhibitor of vacuolar type H(+)-ATPase, on CTL-mediated cytotoxicity. J. Immunol. 153, 3938\u20133947 (1994).","journal-title":"J. Immunol."},{"key":"277_CR23","doi-asserted-by":"crossref","first-page":"3678","DOI":"10.4049\/jimmunol.156.10.3678","volume":"156","author":"T Kataoka","year":"1996","unstructured":"Kataoka, T. et al. Concanamycin A, a powerful tool for characterization and estimation of contribution of perforin- and Fas-based lytic pathways in cell-mediated cytotoxicity. J. Immunol. 156, 3678\u20133686 (1996).","journal-title":"J. Immunol."},{"key":"277_CR24","doi-asserted-by":"publisher","first-page":"6387","DOI":"10.1128\/MCB.18.11.6387","volume":"18","author":"CH Bird","year":"1998","unstructured":"Bird, C. H. et al. Selective regulation of apoptosis: the cytotoxic lymphocyte serpin proteinase inhibitor 9 protects against granzyme B-mediated apoptosis without perturbing the Fas cell death pathway. Mol. Cell Biol. 18, 6387\u20136398 (1998).","journal-title":"Mol. Cell Biol."},{"key":"277_CR25","doi-asserted-by":"publisher","first-page":"3268","DOI":"10.1002\/eji.200636146","volume":"36","author":"MM Sandusky","year":"2006","unstructured":"Sandusky, M. M., Messmer, B. & Watzl, C. Regulation of 2B4 (CD244)-mediated NK cell activation by ligand-induced receptor modulation. Eur. J. Immunol. 36, 3268\u20133276 (2006).","journal-title":"Eur. J. Immunol."},{"key":"277_CR26","doi-asserted-by":"publisher","first-page":"690","DOI":"10.1038\/nri2152","volume":"7","author":"S Feske","year":"2007","unstructured":"Feske, S. Calcium signalling in lymphocyte activation and disease. Nat. Rev. Immunol. 7, 690\u2013702 (2007).","journal-title":"Nat. Rev. Immunol."},{"key":"277_CR27","doi-asserted-by":"publisher","first-page":"8426","DOI":"10.1074\/jbc.M413303200","volume":"280","author":"I Voskoboinik","year":"2005","unstructured":"Voskoboinik, I. et al. Calcium-dependent plasma membrane binding and cell lysis by perforin are mediated through its C2 domain: a critical role for aspartate residues 429, 435, 483, and 485 but not 491. J. Biol. Chem. 280, 8426\u20138434 (2005).","journal-title":"J. Biol. Chem."},{"key":"277_CR28","doi-asserted-by":"publisher","first-page":"2492","DOI":"10.1016\/j.molimm.2010.06.001","volume":"47","author":"T Praper","year":"2010","unstructured":"Praper, T. et al. Human perforin permeabilizing activity, but not binding to lipid membranes, is affected by pH. Mol. Immunol. 47, 2492\u20132504 (2010).","journal-title":"Mol. Immunol."},{"key":"277_CR29","doi-asserted-by":"publisher","first-page":"482","DOI":"10.1038\/nature05768","volume":"447","author":"BK Kaiser","year":"2007","unstructured":"Kaiser, B. K. et al. Disulphide-isomerase-enabled shedding of tumour-associated NKG2D ligands. Nature 447, 482\u2013486 (2007).","journal-title":"Nature"},{"key":"277_CR30","doi-asserted-by":"publisher","first-page":"49","DOI":"10.4049\/jimmunol.182.1.49","volume":"182","author":"P Boutet","year":"2009","unstructured":"Boutet, P. et al. Cutting edge: the metalloproteinase ADAM17\/TNF-alpha-converting enzyme regulates proteolytic shedding of the MHC class I-related chain B protein. J. Immunol. 182, 49\u201353 (2009).","journal-title":"J. Immunol."},{"key":"277_CR31","doi-asserted-by":"publisher","first-page":"734","DOI":"10.1038\/nature01112","volume":"419","author":"V Groh","year":"2002","unstructured":"Groh, V., Wu, J., Yee, C. & Spies, T. Tumour-derived soluble MIC ligands impair expression of NKG2D and T-cell activation. Nature 419, 734\u2013738 (2002).","journal-title":"Nature"},{"key":"277_CR32","doi-asserted-by":"publisher","first-page":"6368","DOI":"10.1158\/0008-5472.CAN-07-6768","volume":"68","author":"I Waldhauer","year":"2008","unstructured":"Waldhauer, I. et al. Tumor-associated MICA is shed by ADAM proteases. Cancer Res. 68, 6368\u20136376 (2008).","journal-title":"Cancer Res."},{"key":"277_CR33","doi-asserted-by":"publisher","first-page":"3429","DOI":"10.1158\/0008-5472.CAN-13-3017","volume":"74","author":"E Schlecker","year":"2014","unstructured":"Schlecker, E. et al. Metalloprotease-mediated tumor cell shedding of B7-H6, the ligand of the natural killer cell-activating receptor NKp30. Cancer Res. 74, 3429\u20133440 (2014).","journal-title":"Cancer Res."},{"key":"277_CR34","doi-asserted-by":"publisher","first-page":"3267","DOI":"10.1083\/jcb.201712085","volume":"217","author":"K Srpan","year":"2018","unstructured":"Srpan, K. et al. Shedding of CD16 disassembles the NK cell immune synapse and boosts serial engagement of target cells. J. Cell Biol. 217, 3267\u20133283 (2018).","journal-title":"J. Cell Biol."},{"key":"277_CR35","doi-asserted-by":"publisher","first-page":"339","DOI":"10.1146\/annurev.immunol.021908.132554","volume":"27","author":"CL Abram","year":"2009","unstructured":"Abram, C. L. & Lowell, C. A. The ins and outs of leukocyte integrin signaling. Annu. Rev. Immunol. 27, 339\u2013362 (2009).","journal-title":"Annu. Rev. Immunol."},{"key":"277_CR36","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1016\/S1074-7613(01)00112-1","volume":"14","author":"SC Bunnell","year":"2001","unstructured":"Bunnell, S. C., Kapoor, V., Trible, R. P., Zhang, W. & Samelson, L. E. Dynamic actin polymerization drives T cell receptor-induced spreading: a role for the signal transduction adaptor LAT. Immunity 14, 315\u2013329 (2001).","journal-title":"Immunity"},{"issue":"Pt 1","key":"277_CR37","doi-asserted-by":"publisher","first-page":"187","DOI":"10.1242\/jcs.00220","volume":"116","author":"R Furukawa","year":"2003","unstructured":"Furukawa, R. et al. Calcium regulation of actin crosslinking is important for function of the actin cytoskeleton in Dictyostelium. J. Cell Sci. 116(Pt 1), 187\u2013196 (2003).","journal-title":"J. Cell Sci."},{"key":"277_CR38","doi-asserted-by":"publisher","first-page":"2918","DOI":"10.1182\/blood.V78.11.2918.2918","volume":"78","author":"JI Henter","year":"1991","unstructured":"Henter, J. I. et al. Hypercytokinemia in familial hemophagocytic lymphohistiocytosis. Blood 78, 2918\u20132922 (1991).","journal-title":"Blood"},{"key":"277_CR39","doi-asserted-by":"publisher","first-page":"1330","DOI":"10.1038\/s41590-018-0251-7","volume":"19","author":"X Michelet","year":"2018","unstructured":"Michelet, X. et al. Metabolic reprogramming of natural killer cells in obesity limits antitumor responses. Nat. Immunol. 19, 1330\u20131340 (2018).","journal-title":"Nat. Immunol."},{"key":"277_CR40","doi-asserted-by":"publisher","first-page":"376","DOI":"10.1038\/ni.3120","volume":"16","author":"FM Wensveen","year":"2015","unstructured":"Wensveen, F. M. et al. NK cells link obesity-induced adipose stress to inflammation and insulin resistance. Nat. Immunol. 16, 376\u2013385 (2015).","journal-title":"Nat. Immunol."},{"key":"277_CR41","doi-asserted-by":"publisher","first-page":"4646","DOI":"10.4049\/jimmunol.176.8.4646","volume":"176","author":"B Messmer","year":"2006","unstructured":"Messmer, B., Eissmann, P., Stark, S. & Watzl, C. CD48 stimulation by 2B4 (CD244)-expressing targets activates human NK cells. J. Immunol. 176, 4646\u20134650 (2006).","journal-title":"J. Immunol."}],"container-title":["Cellular & Molecular Immunology"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/www.nature.com\/articles\/s41423-019-0277-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/www.nature.com\/articles\/s41423-019-0277-2","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/www.nature.com\/articles\/s41423-019-0277-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,19]],"date-time":"2023-09-19T17:24:56Z","timestamp":1695144296000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41423-019-0277-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,8,30]]},"references-count":41,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2020,4]]}},"alternative-id":["277"],"URL":"https:\/\/doi.org\/10.1038\/s41423-019-0277-2","relation":{},"ISSN":["1672-7681","2042-0226"],"issn-type":[{"value":"1672-7681","type":"print"},{"value":"2042-0226","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,8,30]]},"assertion":[{"value":"26 February 2019","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"7 August 2019","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"30 August 2019","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}