Abstract
Natural killer (NK) cells are innate immune effector cells that protect against cancer and some viral infections. Until recently, most studies have investigated the molecular signatures of human or mouse NK cells to identify genes that are specifically expressed during NK cell development. However, the mechanism regulating NK cell development remains unclear. Here, we report a regulatory network of potential interactions during in vitro differentiation of human NK cells, identified using genome-wide mRNA and miRNA databases through hierarchical clustering analysis, gene ontology analysis and a miRNA target prediction program. The microRNA (miR)-583, which demonstrated the largest ratio change in mature NK cells, was highly correlated with IL2 receptor gamma (IL2Rγ) expression. The overexpression of miR-583 had an inhibitory effect on NK cell differentiation. In a reporter assay, the suppressive effect of miR-583 was ablated by mutating the putative miR-583 binding site of the IL2Rγ 3′ UTR. Therefore, we show that miR-583 acts as a negative regulator of NK cell differentiation by silencing IL2Rγ. Additionally, we provide a comprehensive database of genome-wide mRNA and miRNA expression during human NK cell differentiation, offering a better understanding of basic human NK cell biology for the application of human NK cells in immunotherapy.
Highlights
Natural killer (NK) cells are lymphocytes that can eliminate cancer and some viral infections without prior sensitization by targeting major histocompatibility complex (MHC) antigens on target cells through their effector functions, such as cytotoxicity and cytokine secretion [1]
We noted from previous work that the NK cell marker CD56 was detectable approximately 7 days (7d) after IL-15 supplementation during NK cell differentiation in vitro (Fig. 1a) [31]
To identify differentially expressed genes during human NK cell development, we performed mRNA arrays using total RNA isolated from 1, 7- or 14-d cultured cells that had been grown in media supplemented with IL15 to induce their differentiation into NK cells
Summary
Natural killer (NK) cells are lymphocytes that can eliminate cancer and some viral infections without prior sensitization by targeting major histocompatibility complex (MHC) antigens on target cells through their effector functions, such as cytotoxicity and cytokine secretion [1]. Human NK cells, granular CD56+CD32 lymphocytes, are derived from CD34+ hematopoietic stem cells (HSCs) in the bone marrow (BM) and are subsequently differentiate into fully functional mature NK cells (mNK) in peripheral tissue microenvironments, such as the fetal thymus [1,2]. During NK cell development process, these cells acquire optimal cytolytic and effector abilities depending on the balance between activating and inhibitory receptors. The determination of intermediates in the development of NK cells is primarily dependent on NK cell surface markers, including CD56 and killer inhibitory receptors (KIRs) in humans and NK1.1, DX5, and Ly49 in mice [1]. Freud et al suggested that NK cells differentiate through four discrete intermediate stages in secondary lymphoid tissue: stage 1, CD34+CD1172CD942, stage 2, CD34+CD117+CD942, stage 3, CD342CD117+CD942, and stage, CD342CD117+/2CD94+ [4]
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