title: MicroRNA-deficient NK cells exhibit decreased survival but enhanced function.
abstract: NK cells are innate immune lymphocytes important for early host defense against infectious pathogens and malignant transformation. MicroRNAs (miRNAs) are small RNA molecules that regulate a wide variety of cellular processes, typically by specific complementary targeting of the 3'UTR of mRNAs. The Dicer1 gene encodes a conserved enzyme essential for miRNA processing, and Dicer1 deficiency leads to a global defect in miRNA biogenesis. In this study, we report a mouse model of lymphocyte-restricted Dicer1 disruption to evaluate the role of Dicer1-dependent miRNAs in the development and function of NK cells. As expected, Dicer1-deficient NK cells had decreased total miRNA content. Furthermore, miRNA-deficient NK cells exhibited reduced survival and impaired maturation defined by cell surface phenotypic markers. However, Dicer1-deficient NK cells exhibited enhanced degranulation and IFN-γ production in vitro in response to cytokines, tumor target cells, and activating NK cell receptor ligation. Moreover, a similar phenotype of increased IFN-γ was evident during acute MCMV infection in vivo. miRs-15a/15b/16 were identified as abundant miRNAs in NK cells that directly target the murine IFN-γ 3'UTR, thereby providing a potential mechanism for enhanced IFN-γ production. These data suggest that the function of miRNAs in NK cell biology is complex, with an important role in NK cell development, survival, or homeostasis, while tempering peripheral NK cell activation. Further study of individual miRNAs in an NK cell specific fashion will provide insight into these complex miRNA regulatory effects in NK cell biology.
authors.affiliation: Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Ryan P
authors.initials: RP
authors.lastname: Sullivan
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Leong
authors.forename: Stephanie E
authors.initials: SE
authors.lastname: Schneider
authors.forename: Catherine R
authors.initials: CR
authors.lastname: Keppel
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Germino
authors.forename: Anthony R
authors.initials: AR
authors.lastname: French
authors.forename: Todd A
authors.initials: TA
authors.lastname: Fehniger
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D015550:Cell Degranulation; D002470:Cell Survival; D016207:Cytokines / Q000378:metabolism; D003602:Cytotoxicity, Immunologic; D053487:DEAD-box RNA Helicases / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D006566:Herpesviridae Infections / Q000276:immunology; D007113:Immunity, Innate; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D019409:Interleukin-15 / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000276:immunology*; D008221:Lymphoid Tissue / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000096:biosynthesis / Q000502:physiology*; D018146:Muromegalovirus; D009928:Organ Specificity; D043244:Ribonuclease III / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D013047:Specific Pathogen-Free Organisms
chemical_list: D020413:3' Untranslated Regions; D016207:Cytokines; D019409:Interleukin-15; D035683:MicroRNAs; D007371:Interferon-gamma; C509781:Dicer1 protein, mouse; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases