{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T09:11:36Z","timestamp":1790413896665,"version":"4.1.0"},"reference-count":49,"publisher":"American Society for Microbiology","issue":"15","license":[{"start":{"date-parts":[[2015,8,1]],"date-time":"2015-08-01T00:00:00Z","timestamp":1438387200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["J Virol"],"published-print":{"date-parts":[[2015,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>Natural killer (NK) cells provide a first line of defense against infection via the production of antiviral cytokines and direct lysis of target cells. Cytokines such as interleukin 12 (IL-12) and IL-18 are critical regulators of NK cell activation, but much remains to be learned about how cytokines interact to regulate NK cell function. Here, we have examined cytokine-mediated activation of NK cells during infection with two natural mouse pathogens, lymphocytic choriomeningitis virus (LCMV) and murine cytomegalovirus (MCMV). Using a systematic screen of 1,849 cytokine pairs, we identified the most potent combinations capable of eliciting gamma interferon (IFN-\u03b3) production in NK cells. We observed that NK cell responses to cytokine stimulation were reduced 8 days after acute LCMV infection but recovered to preinfection levels by 60 days postinfection. In contrast, during MCMV infection, NK cell responses to cytokines remained robust at all time points examined. Ly49H-positive (Ly49H<jats:sup>+<\/jats:sup>) NK cells recognizing viral ligand m157 showed preferential proliferation during early MCMV infection. A population of these cells was still detected beyond 60 days postinfection, but these divided cells did not demonstrate enhanced IFN-\u03b3 production in response to innate cytokine stimulation. Instead, the maturation state of the NK cells (as determined by CD11b or CD27 surface phenotype) was predictive of responsiveness to cytokines, regardless of Ly49H expression. These results help define cytokine interactions that regulate NK cell activation and highlight variations in NK cell function during two unrelated viral infections.<\/jats:p><jats:p><jats:bold>IMPORTANCE<\/jats:bold>Natural killer cells play an important role in immunity to many viral infections. From an initial screen of 1,849 cytokine pairs, we identified the most stimulatory cytokine combinations capable of inducing IFN-\u03b3 production by NK cells. Ly49H<jats:sup>+<\/jats:sup>NK cells, which can be directly activated by MCMV protein m157, preferentially proliferated during MCMV infection but did not show enhanced IFN-\u03b3 production following direct<jats:italic>ex vivo<\/jats:italic>cytokine stimulation. Instead, mature CD11b<jats:sup>+<\/jats:sup>and\/or CD27<jats:sup>+<\/jats:sup>NK cells responded similarly to innate cytokine stimulation regardless of Ly49H expression. Collectively, our data provide a better foundation for understanding cytokine-mediated NK cell activation during viral infection.<\/jats:p>","DOI":"10.1128\/jvi.00199-15","type":"journal-article","created":{"date-parts":[[2015,5,21]],"date-time":"2015-05-21T02:41:33Z","timestamp":1432176093000},"page":"7922-7931","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":62,"title":["Cytokine-Mediated Activation of NK Cells during Viral Infection"],"prefix":"10.1128","volume":"89","author":[{"given":"Bailey E.","family":"Freeman","sequence":"first","affiliation":[{"name":"Division of Neuroscience, Oregon National Primate Research Center, Beaverton, Oregon, USA"},{"name":"Department of Molecular Microbiology and Immunology, Oregon Health &amp; Science University, Portland, Oregon, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hans-Peter","family":"Rau\u00e9","sequence":"additional","affiliation":[{"name":"Division of Neuroscience, Oregon National Primate Research Center, Beaverton, Oregon, USA"},{"name":"Department of Molecular Microbiology and Immunology, Oregon Health &amp; Science University, Portland, Oregon, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ann B.","family":"Hill","sequence":"additional","affiliation":[{"name":"Department of Molecular Microbiology and Immunology, Oregon Health &amp; Science University, Portland, Oregon, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark K.","family":"Slifka","sequence":"additional","affiliation":[{"name":"Division of Neuroscience, Oregon National Primate Research Center, Beaverton, Oregon, USA"},{"name":"Department of Molecular Microbiology and Immunology, Oregon Health &amp; Science University, Portland, Oregon, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.coi.2006.05.002"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/S095279150200002X"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0065-230X(03)90004-2"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1120528109"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.79.1.661-667.2005"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.coviro.2011.10.017"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.virol.2012.10.005"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature10624"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.06042-11"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.0030123"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20091193"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-065X.2006.00465.x"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2008-10-187179"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2567.2011.03446.x"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1038\/icb.2010.78"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.immunol.17.1.189"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1038\/ni1581"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.168.3.1146"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1099\/vir.0.19120-0"},{"key":"e_1_3_2_21_2","doi-asserted-by":"crossref","first-page":"1138","DOI":"10.4049\/jimmunol.156.3.1138","article-title":"An absolute and restricted requirement for IL-12 in natural killer cell IFN-gamma production and antiviral defense. Studies of natural killer and T cell responses in contrasting viral infections","volume":"156","author":"Orange JS","year":"1996","unstructured":"Orange JS, Biron CA. 1996. An absolute and restricted requirement for IL-12 in natural killer cell IFN-gamma production and antiviral defense. Studies of natural killer and T cell responses in contrasting viral infections. J Immunol 156:1138\u20131142.","journal-title":"J Immunol"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.164.2.994"},{"key":"e_1_3_2_23_2","first-page":"112","article-title":"Demonstration of the antiviral role of natural killer cells in vivo with a natural killer cell-specific monoclonal antibody (NK 1.1)","volume":"9","author":"Welsh RM","year":"1990","unstructured":"Welsh RM, Dundon PL, Eynon EE, Brubaker JO, Koo GC, O'Donnell CL. 1990. Demonstration of the antiviral role of natural killer cells in vivo with a natural killer cell-specific monoclonal antibody (NK 1.1). Nat Immun Cell Growth Regul 9:112\u2013120.","journal-title":"Nat Immun Cell Growth Regul"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.092258599"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1070884"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1038\/ni714"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00251-008-0313-3"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1007\/3-540-27743-9_10"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1060042"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1155\/2011\/641702"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1203543109"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature04606"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1093\/intimm\/dxf020"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1078\/0171-2985-00219"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1201528"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.171.1.173"},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2013.07.015"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1198687"},{"key":"e_1_3_2_39_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-065X.2010.00900.x"},{"key":"e_1_3_2_40_2","doi-asserted-by":"publisher","DOI":"10.1002\/eji.200939435"},{"key":"e_1_3_2_41_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0813192106"},{"key":"e_1_3_2_42_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1003035"},{"key":"e_1_3_2_43_2","doi-asserted-by":"publisher","DOI":"10.1038\/nri3044"},{"key":"e_1_3_2_44_2","doi-asserted-by":"publisher","DOI":"10.1038\/ni796"},{"key":"e_1_3_2_45_2","doi-asserted-by":"publisher","DOI":"10.1038\/nri2692"},{"key":"e_1_3_2_46_2","doi-asserted-by":"publisher","DOI":"10.1093\/intimm\/dxn060"},{"key":"e_1_3_2_47_2","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.01978-14"},{"key":"e_1_3_2_48_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00658-14"},{"key":"e_1_3_2_49_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature07665"},{"key":"e_1_3_2_50_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2004-07-2833"}],"container-title":["Journal of Virology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/JVI.00199-15","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/JVI.00199-15","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,10]],"date-time":"2023-08-10T19:25:06Z","timestamp":1691695506000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/JVI.00199-15"}},"subtitle":[],"editor":[{"given":"L.","family":"Hutt-Fletcher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2015,8]]},"references-count":49,"journal-issue":{"issue":"15","published-print":{"date-parts":[[2015,8]]}},"alternative-id":["10.1128\/JVI.00199-15"],"URL":"https:\/\/doi.org\/10.1128\/jvi.00199-15","relation":{},"ISSN":["0022-538X","1098-5514"],"issn-type":[{"value":"0022-538X","type":"print"},{"value":"1098-5514","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,8]]},"assertion":[{"value":"2015-01-30","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2015-05-15","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2015-07-08","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}