The Role of microRNAs in NK Cell Development and Function.

Arash Nanbakhsh,Subramaniam Malarkannan

doi:10.3390/cells10082020

Arash Nanbakhsh, Subramaniam Malarkannan

Open Access

https://doi.org/10.3390/cells10082020

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Abstract

The clinical use of natural killer (NK) cells is at the forefront of cellular therapy. NK cells possess exceptional antitumor cytotoxic potentials and can generate significant levels of proinflammatory cytokines. Multiple genetic manipulations are being tested to augment the anti-tumor functions of NK cells. One such method involves identifying and altering microRNAs (miRNAs) that play essential roles in the development and effector functions of NK cells. Unique miRNAs can bind and inactivate mRNAs that code for cytotoxic proteins. MicroRNAs, such as the members of the Mirc11 cistron, downmodulate ubiquitin ligases that are central to the activation of the obligatory transcription factors responsible for the production of inflammatory cytokines. These studies reveal potential opportunities to post-translationally enhance the effector functions of human NK cells while reducing unwanted outcomes. Here, we summarize the recent advances made on miRNAs in murine and human NK cells and their relevance to NK cell development and functions.

Highlights

In humans, peripheral blood natural killer (NK) cells represent 10–15% of the circulating lymphocytes [1].NK cells do not express clonotypic receptors
Non-coding RNAs can be subgrouped into small nucleolar RNAs, small nuclear RNAs, short interfering RNAs, and microRNAs [9]
These findings set the stage for future studies to utilize naturally occurring miRNAs that can help in in vitro generation of custom-made human NK cells for clinical utilization

Summary

Introduction

Peripheral blood NK cells represent 10–15% of the circulating lymphocytes [1]. NK cells are defined by the expression of CD56 (NCAM or Leu-19), and a subset of mature NK cells express the activating Fc receptor CD16 [2,3]. Recent studies have elucidated many physiological functions of non-coding RNAs in multiple cell types [7,8]. Based on their functions, non-coding RNAs can be subgrouped into small nucleolar RNAs (snoRNAs), small nuclear RNAs (snRNAs), short interfering RNAs (siRNAs), and microRNAs (miRNAs) [9]. The expression of miRNAs is cell-specific, and each cell type expresses a distinct set of miRNAs at various stages of maturation, differentiation, or activation [14]. Several of them play essential roles in NK cell development and maturation [25]

MicroRNA-Mediated Commitment to the NK Cell Lineage

MicroRNA-Mediated Control of NK Cell Maturation

Additional Mechanisms Employed by miRNA during NK Cell Development

MicroRNA and NK Cell Effector Functions

Findings

Mirc11 Cistron Has Only a Minimal Influence on NK Cell-Mediated Cytotoxicity