MicroRNAs control developmental pathways and effector functions in immune cells. Previous studies have studied the role of microRNAs in natural killer (NK) cells. However, the mouse models of microRNA depletion used were nonNK-specific and only partially depleting, hampering the interpretation of the data obtained. To clarify the role of microRNAs in murine NK cells, we deleted the RNase III enzyme Dicer1 in NKp46-expressing cells. We observed a drastic decrease in several microRNAs specifically in NK cells. Furthermore, the overall size of the "NK-cell" pool was severely decreased, a phenotype associated with compromised survival. Moreover, performing a broad flow cytometry profiling, we show that Dicer1-deficient NK cells failed to complete their differentiation program. In particular, several integrins were inappropriately expressed in mature NK cells. These defects coincided with decreased response to IL-15, a cytokine responsible for "NK-cell" maturation and survival. In addition, Dicer1 deletion impaired key "NK-cell" functions: target cell killing and production of IFN-γ, leading to defective control of metastasis. Dicer1 deletion thus affects "NK-cell" biology in a cell intrinsic manner at several distinct stages.
Keywords: Cytotoxicity Dicer1 IFN-γ MicroRNA NK cellsAdditional supporting information may be found in the online version of this article at the publisher's web-site
IntroductionNatural killer (NK) cells are group 1 innate lymphoid cells (ILC1) differentiating in the bone marrow (BM) under the influence of Interleukin (IL)-15 [1]. Following commitment to the "NK-cell" lineage, sequential developmental intermediates, from immature to mature, can be defined on the basis of surface expression of Correspondence: Dr. Antoine Marçais e-mail: antoine.marcais@inserm.fr the tumor necrosis factor (TNF) superfamily member CD27 and the integrin CD11b: CD11b lo CD27 hi NK cells (hereafter referred to as "CD11b lo "), CD11b hi CD27 hi (double positive or "DP"), and CD11b hi CD27 lo ("CD27 lo ") [2,3]. In addition, NK cells lose their capacity to proliferate upon maturation, acquire "NK-cell" receptors as well as cytotoxic arsenal, and modify their trafficking machinery to reach peripheral organs where they exert their role of innate sentinels [4]. They have indeed the capacity to kill cells recognized as targets and to produce IFN-γ upon activation, two functions responsible for their role in the defense against intracellular pathogens and in the immunosurveillance of cancer [5]. This C 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2016. 46: 1902-1911 capacity is potentiated by preexposure to IL-15, a process involving the mTOR pathway and granzyme B synthesis [6,7]. Similarly, cytokine stimulation, in particular IL-12/18, triggers secretion of IFN-γ, a property essential to fight intracellular pathogens [1]. Several of these processes might be posttranscriptionally controlled. MicroRNAs are small, noncoding RNAs regulating posttranscriptional gene expression. They are ...