Tracking the fate of antigen-specific versus cytokine-activated natural killer cells after cytomegalovirus infection.
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.
Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143.|Parker Institute for Cancer Immunotherapy, San Francisco, CA 94143.|Life Science Center, Tsukuba Advanced Research Alliance, University of Tsukuba, Ibaraki 305-8577, Japan.
Tsukasa
0000-0001-9954-1226
T
Nabekura
Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143 Lewis.Lanier@ucsf.edu.|Parker Institute for Cancer Immunotherapy, San Francisco, CA 94143.
Lewis L
0000-0003-1308-3952
LL
Lanier
D000483:Alleles; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D019070:Cell Lineage / Q000187:drug effects; D058948:Cell Tracking / Q000379:methods*; D016207:Cytokines / Q000494:pharmacology*; D003586:Cytomegalovirus Infections / Q000276:immunology* / Q000473:pathology / Q000821:virology*; D000939:Epitopes / Q000187:drug effects / Q000276:immunology*; D007156:Immunologic Memory / Q000187:drug effects; D019426:Integrases / Q000378:metabolism; D007694:Killer Cells, Natural / Q000166:cytology* / Q000187:drug effects / Q000276:immunology; D008089:Listeria monocytogenes / Q000187:drug effects; D008088:Listeriosis / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018146:Muromegalovirus / Q000187:drug effects / Q000502:physiology*; D055650:NK Cell Lectin-Like Receptor Subfamily A / Q000378:metabolism; D055627:Natural Cytotoxicity Triggering Receptor 1 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013629:Tamoxifen / Q000008:administration & dosage / Q000494:pharmacology
D000970:Antineoplastic Agents; D016207:Cytokines; D000939:Epitopes; D055650:NK Cell Lectin-Like Receptor Subfamily A; D055627:Natural Cytotoxicity Triggering Receptor 1; D013629:Tamoxifen; C045073:Cre recombinase; D019426:Integrases