Distinct requirements of microRNAs in NK cell activation, survival, and function.
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.
Bezman
Natalie A
NA
Department of Microbiology and Immunology, Cancer Research Institute, University of California San Francisco, San Francisco, CA 94143, USA.
Cedars
Elizabeth
E
Steiner
David F
DF
Blelloch
Robert
R
Hesslein
David G T
DG
Lanier
Lewis L
LL
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
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
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