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Here, by using novel transgenic mice carrying inducible Cre expressed under the control of Ncr1 gene, we demonstrated that two distinct long-lived NK cell subsets differentiate in a mouse model of cytomegalovirus (MCMV) infection. NK cells expressing the MCMV-specific Ly49H receptor differentiated into memory NK cells by an activating signaling through Ly49H and Ly49H\u2212 NK cells differentiated into cytokine-activated NK cells by exposure to inflammatory cytokines during infection. Interleukin-12 is indispensable for optimal generation of both antigen-specific memory NK cells and cytokine-activated NK cells. MCMV-specific memory NK cells show enhanced effector function and augmented antitumor activity in vivo as compared with cytokine-activated NK cells, whereas cytokine-activated NK cells exhibited a more robust response to IL-15 and persisted better in an MCMV-free environment. These findings reveal that NK cells are capable of differentiation into distinct long-lived subsets with different functional properties.<\/jats:p>","DOI":"10.1084\/jem.20160726","type":"journal-article","created":{"date-parts":[[2016,10,24]],"date-time":"2016-10-24T10:12:33Z","timestamp":1477303953000},"page":"2745-2758","update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":76,"title":["Tracking the fate of antigen-specific versus cytokine-activated natural killer cells after cytomegalovirus infection"],"prefix":"10.1084","volume":"213","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9954-1226","authenticated-orcid":false,"given":"Tsukasa","family":"Nabekura","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143 1"},{"name":"Parker Institute for Cancer Immunotherapy, San Francisco, CA 94143 2"},{"name":"Life Science Center, Tsukuba Advanced Research Alliance, University of Tsukuba, Ibaraki 305-8577, Japan 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1308-3952","authenticated-orcid":false,"given":"Lewis L.","family":"Lanier","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143 1"},{"name":"Parker Institute for Cancer Immunotherapy, San Francisco, CA 94143 2"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2016,10,24]]},"reference":[{"key":"2023072608521303800_bib1","doi-asserted-by":"publisher","first-page":"1323","DOI":"10.1126\/science.1070884","article-title":"Direct recognition of cytomegalovirus by activating and inhibitory NK cell receptors","volume":"296","author":"Arase","year":"2002","journal-title":"Science."},{"key":"2023072608521303800_bib2","author":"Brune","year":"2001"},{"key":"2023072608521303800_bib3","doi-asserted-by":"publisher","first-page":"7536","DOI":"10.1128\/JVI.78.14.7536-7544.2004","article-title":"Gain of virulence caused by loss of a gene in murine cytomegalovirus","volume":"78","author":"Bubi\u0107","year":"2004","journal-title":"J. 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