title: Distinct requirements of microRNAs in NK cell activation, survival, and function.
abstract: MicroRNAs (miRNAs) are small noncoding RNAs that have recently emerged as critical regulators of gene expression within the immune system. In this study, we used mice with conditional deletion of Dicer and DiGeorge syndrome critical region 8 (Dgcr8) to dissect the roles of miRNAs in NK cell activation, survival, and function during viral infection. We developed a system for deletion of either Dicer or Dgcr8 in peripheral NK cells via drug-induced Cre activity. We found that Dicer- and Dgcr8-deficient NK cells were significantly impaired in survival and turnover, and had impaired function of the ITAM-containing activating NK cell receptors. We further demonstrated that both Dicer- and Dgcr8-dependent pathways were indispensable for the expansion of Ly49H(+) NK cells during mouse cytomegalovirus infection. Our data indicate similar phenotypes for Dicer- and Dgcr8-deficient NK cells, which strongly suggest that these processes are regulated by miRNAs. Thus, our findings indicate a critical role for miRNAs in controlling NK cell homeostasis and effector function, with implications for miRNAs regulating diverse aspects of NK cell biology.
authors.affiliation: Department of Microbiology and Immunology, Cancer Research Institute, University of California San Francisco, San Francisco, CA 94143, USA.
authors.forename: Natalie A
authors.initials: NA
authors.lastname: Bezman
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Cedars
authors.forename: David F
authors.initials: DF
authors.lastname: Steiner
authors.forename: Robert
authors.initials: R
authors.lastname: Blelloch
authors.forename: David G T
authors.initials: DG
authors.lastname: Hesslein
authors.forename: Lewis L
authors.initials: LL
authors.lastname: Lanier
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D002469:Cell Separation; D002470:Cell Survival; D053487:DEAD-box RNA Helicases / Q000235:genetics; D004722:Endoribonucleases / Q000235:genetics; D005434:Flow Cytometry; D015870:Gene Expression; D020869:Gene Expression Profiling; D055786:Gene Knockout Techniques; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000235:genetics* / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D011506:Proteins / Q000235:genetics; D016601:RNA-Binding Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction; D043244:Ribonuclease III
chemical_list: C474044:Dgcr8 protein, mouse; D035683:MicroRNAs; D011506:Proteins; D016601:RNA-Binding Proteins; D004722:Endoribonucleases; C509781:Dicer1 protein, mouse; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases
references.citation: Curr Top Microbiol Immunol. 2008;320:77-97
references.pmid: 18268840
references.citation: Nat Rev Immunol. 2003 Oct;3(10):781-90
references.pmid: 14523385
references.citation: J Exp Med. 2005 Jul 18;202(2):261-9
references.pmid: 16009718
references.citation: Circ Res. 2009 Sep 11;105(6):585-94
references.pmid: 19679836
references.citation: Cell Stem Cell. 2007 Jun 7;1(1):113-26
references.pmid: 18371340
references.citation: Cell. 2007 Jun 29;129(7):1401-14
references.pmid: 17604727
references.citation: Curr Biol. 2010 Feb 9;20(3):271-7
references.pmid: 20116247
references.citation: Blood. 2009 May 28;113(22):5488-96
references.pmid: 19234143
references.citation: Cell. 2004 Jan 23;116(2):281-97
references.pmid: 14744438
references.citation: Nature. 2008 May 22;453(7194):539-43
references.pmid: 18404146
references.citation: Nat Immunol. 2008 May;9(5):495-502
references.pmid: 18425106
references.citation: Cell. 2008 Mar 7;132(5):860-74
references.pmid: 18329371
references.citation: J Immunol. 2009 Aug 15;183(4):2506-12
references.pmid: 19625646
references.citation: Cell. 2007 Oct 5;131(1):146-59
references.pmid: 17923094
references.citation: Immunol Rev. 2010 Jul;236:83-94
references.pmid: 20636810
references.citation: Nat Genet. 2007 Mar;39(3):380-5
references.pmid: 17259983
references.citation: Biochem Biophys Res Commun. 1997 Aug 28;237(3):752-7
references.pmid: 9299439
references.citation: Nat Immunol. 2008 Sep;9(9):1065-73
references.pmid: 18677316
references.citation: J Immunol. 2004 Jan 15;172(2):864-70
references.pmid: 14707057
references.citation: J Exp Med. 2008 Sep 1;205(9):1993-2004
references.pmid: 18725526
references.citation: Proc Natl Acad Sci U S A. 2007 Apr 24;104(17):7080-5
references.pmid: 17438277
references.citation: Immunity. 2004 Jul;21(1):107-19
references.pmid: 15345224
references.citation: Proc Natl Acad Sci U S A. 2002 Jun 25;99(13):8826-31
references.pmid: 12060703
references.citation: J Exp Med. 2008 Sep 1;205(9):2005-17
references.pmid: 18725527
references.citation: J Immunol. 2001 Nov 1;167(9):5286-93
references.pmid: 11673544
references.citation: J Exp Med. 2006 Oct 30;203(11):2519-27
references.pmid: 17060477
references.citation: Nat Immunol. 2006 May;7(5):507-16
references.pmid: 16617337
references.citation: Proc Natl Acad Sci U S A. 2009 Jun 23;106(25):10266-71
references.pmid: 19509335
references.citation: Cell. 2006 Jun 2;125(5):887-901
references.pmid: 16751099
references.citation: J Exp Med. 2001 Jul 2;194(1):29-44
references.pmid: 11435470
references.citation: PLoS One. 2007 Oct 10;2(10):e1020
references.pmid: 17925868
references.citation: Immunol Rev. 2010 May;235(1):267-85
references.pmid: 20536569
references.citation: J Exp Med. 2003 Apr 21;197(8):967-76
references.pmid: 12695488
references.citation: Annu Rev Immunol. 2005;23:225-74
references.pmid: 15771571
references.citation: Blood. 2010 Mar 18;115(11):2186-95
references.pmid: 20029045
references.citation: Proc Natl Acad Sci U S A. 2005 Aug 2;102(31):10898-903
references.pmid: 16040801
references.citation: Nat Cell Biol. 2010 Jan;12(1):94-9; sup pp 1-6
references.pmid: 20010811
references.citation: Nat Rev Immunol. 2008 Apr;8(4):259-68
references.pmid: 18340344
references.citation: Nature. 2005 Aug 25;436(7054):1186-90
references.pmid: 15995699
references.citation: Nature. 2008 May 22;453(7194):534-8
references.pmid: 18404147
references.citation: J Exp Med. 2008 Sep 1;205(9):1983-91
references.pmid: 18725525
references.citation: J Cell Biol. 2008 Jul 28;182(2):233-9
references.pmid: 18644891
references.citation: J Immunol. 2009 Jan 1;182(1):39-43
references.pmid: 19109132
references.citation: Cell. 2007 Apr 6;129(1):147-61
references.pmid: 17382377
references.citation: Nature. 2003 Sep 25;425(6956):415-9
references.pmid: 14508493
references.citation: Nature. 2005 Aug 4;436(7051):740-4
references.pmid: 15973356
references.citation: BMC Dev Biol. 2001;1:4
references.pmid: 11299042
references.citation: Nat Immunol. 2008 Oct;9(10):1091-4
references.pmid: 18800157
references.citation: Nature. 2009 Jan 29;457(7229):557-61
references.pmid: 19136945
references.citation: Nat Cell Biol. 2004 Aug;6(8):784-91
references.pmid: 15247924
references.citation: Science. 2002 May 17;296(5571):1323-6
references.pmid: 11950999
references.citation: Nat Genet. 2003 Nov;35(3):215-7
references.pmid: 14528307
references.citation: J Immunol. 2006 Feb 1;176(3):1517-24
references.pmid: 16424180
references.citation: Blood. 2009 Oct 8;114(15):3265-75
references.pmid: 19641183
references.citation: Genes Dev. 2008 Oct 15;22(20):2773-85
references.pmid: 18923076
references.citation: Annu Rev Immunol. 2006;24:257-86
references.pmid: 16551250