NKp46-mediated Dicer1 inactivation results in defective NK-cell differentiation and effector functions in mice

Abstract

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.