title: Cytomegalovirus generates long-lived antigen-specific NK cells with diminished bystander activation to heterologous infection.
abstract: Natural killer (NK) cells play a key role in the host response to cytomegalovirus (CMV) and can mediate an enhanced response to secondary challenge with CMV. We assessed the ability of mouse CMV (MCMV)-induced memory Ly49H(+) NK cells to respond to challenges with influenza, an acute viral infection localized to the lung, and Listeria monocytogenes, a systemic bacterial infection. MCMV-memory NK cells did not display enhanced activation or proliferation after infection with influenza or Listeria, as compared with naive Ly49H(+) or Ly49H(-) NK cells. Memory NK cells also showed impaired activation compared with naive cells when challenged with a mutant MCMV lacking m157, highlighting their antigen-specific response. Ex vivo, MCMV-memory NK cells displayed reduced phosphorylation of STAT4 and STAT1 in response to stimulation by IL-12 and type I interferon (IFN), respectively, and IFN-γ production was reduced in response to IL-12 + IL-18 compared with naive NK cells. However, costimulation of MCMV-memory NK cells with IL-12 and m157 antigen rescues their impaired response compared with cytokines alone. These findings reveal that MCMV-primed memory NK cells are diminished in their response to cytokine-driven bystander responses to heterologous infections as they become specialized and antigen-specific for the control of MCMV upon rechallenge.
authors.affiliation: Department of Microbiology and Immunology and Cancer Research Institute, University of California San Francisco, San Francisco, CA 94143 Department of Microbiology and Immunology and Cancer Research Institute, University of California San Francisco, San Francisco, CA 94143.
authors.forename: Gundula
authors.initials: G
authors.lastname: Min-Oo
authors.affiliation: Department of Microbiology and Immunology and Cancer Research Institute, University of California San Francisco, San Francisco, CA 94143 Department of Microbiology and Immunology and Cancer Research Institute, University of California San Francisco, San Francisco, CA 94143 Lewis.Lanier@ucsf.edu.
authors.forename: Lewis L
authors.initials: LL
authors.lastname: Lanier
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000956:Antigens, Viral / Q000276:immunology*; D024201:Bystander Effect / Q000276:immunology*; D049109:Cell Proliferation; D016207:Cytokines / Q000494:pharmacology; D004195:Disease Models, Animal; D004285:Dogs; D000939:Epitopes / Q000276:immunology*; D005260:Female; D006566:Herpesviridae Infections / Q000150:complications / Q000276:immunology* / Q000821:virology; D007156:Immunologic Memory / Q000276:immunology; D053118:Influenza A Virus, H1N1 Subtype / Q000502:physiology; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology*; D008088:Listeriosis / Q000150:complications / Q000276:immunology* / Q000821:virology; D008213:Lymphocyte Activation / Q000276:immunology; D061985:Madin Darby Canine Kidney Cells; D008810:Mice, Inbred C57BL; D018146:Muromegalovirus / Q000502:physiology*; D009154:Mutation / Q000235:genetics; D055650:NK Cell Lectin-Like Receptor Subfamily A / Q000378:metabolism; D009976:Orthomyxoviridae Infections / Q000150:complications / Q000276:immunology* / Q000821:virology; D018121:Receptors, Cytokine / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000956:Antigens, Viral; D016207:Cytokines; D000939:Epitopes; D055650:NK Cell Lectin-Like Receptor Subfamily A; D018121:Receptors, Cytokine