Abstract
Natural killer (NK) cells provide important host defense and can generate long-lived memory NK cells. 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- 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.
© 2016 Nabekura and Lanier.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, N.I.H., Extramural
MeSH terms
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Alleles
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Animals
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Antineoplastic Agents / pharmacology
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Cell Differentiation / drug effects
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Cell Lineage* / drug effects
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Cell Tracking / methods*
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Cytokines / pharmacology*
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Cytomegalovirus Infections / immunology*
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Cytomegalovirus Infections / pathology
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Cytomegalovirus Infections / virology*
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Epitopes / drug effects
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Epitopes / immunology*
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Immunologic Memory / drug effects
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Integrases / metabolism
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Killer Cells, Natural / cytology*
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Killer Cells, Natural / drug effects
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Killer Cells, Natural / immunology
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Listeria monocytogenes / drug effects
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Listeriosis / immunology
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Listeriosis / microbiology
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Listeriosis / pathology
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Mice, Inbred C57BL
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Mice, Transgenic
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Muromegalovirus / drug effects
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Muromegalovirus / physiology*
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NK Cell Lectin-Like Receptor Subfamily A / metabolism
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Natural Cytotoxicity Triggering Receptor 1 / metabolism
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Signal Transduction / drug effects
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Tamoxifen / administration & dosage
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Tamoxifen / pharmacology
Substances
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Antineoplastic Agents
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Cytokines
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Epitopes
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NK Cell Lectin-Like Receptor Subfamily A
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Natural Cytotoxicity Triggering Receptor 1
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Tamoxifen
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Cre recombinase
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Integrases