microRNA management of NK-cell developmental and functional programs

Abstract

NK cells are innate lymphoid cells that are critical for host defense against infection, and mediate anti-tumor responses. MicroRNAs (miRNAs) are a large family of small noncoding RNAs that target the 3' untranslated region (UTR) of mRNAs, thereby attenuating protein translation. The expression of miRNAs within human peripheral blood and mouse splenic NK cells has been cataloged, with the majority of the miRNA sequence pool represented in the top 60 most abundantly expressed miRNAs. Global miRNA deficiency within NK cells has confirmed their critical role in NK-cell biology, including defects in NK-cell development and altered functionality. Studies using gain- and loss-of-function of individual miRNAs in NK cells have demonstrated the role of specific miRNAs in regulating NK-cell development, maturation, and activation. miRNAs also regulate fundamental NK-cell processes including cytokine production, cytotoxicity, and proliferation. This review provides an update on the intrinsic miRNA regulation of NK cells, including miRNA expression profiles, as well as their impact on NK-cell biology. Additional profiling is needed to better understand miRNA expression within NK-cell developmental intermediates, subsets, tissues, and in the setting of disease. Furthermore, key open questions in the field as well as technical challenges in the study of miRNAs in NK cells are highlighted.

Keywords: Activation; Development; Lymphocyte; NK cell; microRNA.

Figure 1. An abundance of resting splenic mouse NK cell miRNAs defined by small RNA sequencing

The relative expression of the top 60 expressed miRNAs from Fehniger et. al. [27], are shown with the 20 most abundant featured in the circle chart (left) and the remaining 40 rank ordered in the table (right). Relative expression was determined by enumerating the number of unique sequence reads that corresponded to a miRNA mature sequence, as a percentage of all mature miRNA sequences identified.

Figure 2. Schematic summary of how miRNAs regulate NK cell development and function

The green arrows represent a positive influence of the miRNA on the indicated developmental stage or NK cell function, while red bars indicate inhibition. This summary integrates findings within both mouse and human NK cells. miR-155 (denoted by an *) has unclear roles in maturation, displaying either no effect on maturation or a repression.