Tracking the fate of antigen-specific versus cytokine-activated natural killer cells after cytomegalovirus infection

J Exp Med. 2016 Nov 14;213(12):2745-2758. doi: 10.1084/jem.20160726. Epub 2016 Oct 24.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Alleles
  • Animals
  • Antineoplastic Agents / pharmacology
  • Cell Differentiation / drug effects
  • Cell Lineage* / drug effects
  • Cell Tracking / methods*
  • Cytokines / pharmacology*
  • Cytomegalovirus Infections / immunology*
  • Cytomegalovirus Infections / pathology
  • Cytomegalovirus Infections / virology*
  • Epitopes / drug effects
  • Epitopes / immunology*
  • Immunologic Memory / drug effects
  • Integrases / metabolism
  • Killer Cells, Natural / cytology*
  • Killer Cells, Natural / drug effects
  • Killer Cells, Natural / immunology
  • Listeria monocytogenes / drug effects
  • Listeriosis / immunology
  • Listeriosis / microbiology
  • Listeriosis / pathology
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Muromegalovirus / drug effects
  • Muromegalovirus / physiology*
  • NK Cell Lectin-Like Receptor Subfamily A / metabolism
  • Natural Cytotoxicity Triggering Receptor 1 / metabolism
  • Signal Transduction / drug effects
  • Tamoxifen / administration & dosage
  • Tamoxifen / pharmacology


  • Antineoplastic Agents
  • Cytokines
  • Epitopes
  • NK Cell Lectin-Like Receptor Subfamily A
  • Natural Cytotoxicity Triggering Receptor 1
  • Tamoxifen
  • Cre recombinase
  • Integrases