title: Stage-specific regulation of natural killer cell homeostasis and response against viral infection by microRNA-155.
abstract: Natural killer (NK) cells function in the recognition and destruction of host cells infected with pathogens. Many regulatory mechanisms govern the potent responses of NK cells, both at the cellular and molecular level. Ablation of microRNA (miRNA) processing enzymes demonstrated that miRNAs play critical roles in NK cell differentiation and function; however, the role of individual miRNAs requires further investigation. Using mice containing a targeted deletion of microRNA-155 (miR-155), we observed defects in NK cell maintenance and maturation at steady state, as well as in homeostatic proliferation in lymphopenic mice. In addition, we discovered that miR-155 is up-regulated in activated NK cells during mouse cytomegalovirus (MCMV) infection in response to signals from the proinflammatory cytokines IL-12 and IL-18 and through signal transducer and activator of transcription 4 (STAT4) signaling. Although miR-155 was found to be dispensable for cytotoxicity and cytokine production when triggered through activating receptors, NK cells lacking miR-155 exhibited severely impaired effector and memory cell numbers in both lymphoid and nonlymphoid tissues after MCMV infection. We demonstrate that miR-155 differentially targets Noxa and suppressor of cytokine signaling 1 (SOCS1) in NK cells at distinct stages of homeostasis and activation. NK cells constitutively expressing Noxa and SOCS1 exhibit profound defects in expansion during the response to MCMV infection, suggesting that their regulation by miR-155 promotes antiviral immunity.
authors.affiliation: Immunology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Carolyn L
authors.initials: CL
authors.lastname: Zawislak
authors.forename: Aimee M
authors.initials: AM
authors.lastname: Beaulieu
authors.forename: Gabriel B
authors.initials: GB
authors.lastname: Loeb
authors.forename: Jenny
authors.initials: J
authors.lastname: Karo
authors.forename: David
authors.initials: D
authors.lastname: Canner
authors.forename: Natalie A
authors.initials: NA
authors.lastname: Bezman
authors.forename: Lewis L
authors.initials: LL
authors.lastname: Lanier
authors.forename: Alexander Y
authors.initials: AY
authors.lastname: Rudensky
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Sun
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D047369:Chromatin Immunoprecipitation; D017353:Gene Deletion; D005786:Gene Expression Regulation / Q000276:immunology*; D006566:Herpesviridae Infections / Q000276:immunology*; D006706:Homeostasis / Q000276:immunology*; D018664:Interleukin-12 / Q000378:metabolism; D020382:Interleukin-18 / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology*; D008156:Luciferases; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D018146:Muromegalovirus / Q000276:immunology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D050797:STAT4 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism
chemical_list: D020382:Interleukin-18; D035683:MicroRNAs; C532623:Mirn155 microRNA, mouse; C408009:Pmaip1 protein, mouse; D019253:Proto-Oncogene Proteins c-bcl-2; D050797:STAT4 Transcription Factor; C491590:Socs1 protein, mouse; C494091:Stat4 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D018664:Interleukin-12; D008156:Luciferases