New miRNA Signature Heralds Human NK Cell Subsets at Different Maturation Steps: Involvement of miR-146a-5p in the Regulation of KIR Expression

Abstract

Natural killer cells are cytotoxic innate lymphoid cells that play an important role for early host defenses against infectious pathogens and surveillance against tumor. In humans, NK cells may be divided in various subsets on the basis of the relative CD56 expression and of the low-affinity FcγRIIIA CD16. In particular, the two main NK cell subsets are represented by the CD56bright/CD16−/dim and the CD56dim/CD16bright NK cells. Experimental evidences indicate that CD56bright and CD56dim NK cells represent different maturative stages of the NK cell developmental pathway. We identified multiple miRNAs differentially expressed in CD56bright/CD16− and CD56dim/CD16bright NK cells using both univariate and multivariate analyses. Among these, we found a few miRNAs with a consistent differential expression in the two NK cell subsets, and with an intermediate expression in the CD56bright/CD16dim NK cell subset, representing a transitional step of maturation of NK cells. These analyses allowed us to establish the existence of a miRNA signature able to efficiently discriminate the two main NK cell subsets regardless of their surface phenotype. In addition, by analyzing the putative targets of representative miRNAs we show that hsa-miR-146a-5p, may be involved in the regulation of killer Ig-like receptor (KIR) expression. These results contribute to a better understanding of the physiologic significance of miRNAs in the regulation of the development/function of human NK cells. Moreover, our results suggest that hsa-miR-146a-5p targeting, resulting in KIR down-regulation, may be exploited to generate/increment the effect of NK KIR-mismatching against HLA-class I+ tumor cells and thus improve the NK-mediated anti-tumor activity.

miRNAs in NK Cell-Based Immune Responses and Cancer Immunotherapy

“…In a recent study we proved that the miR-146a-5p is able to downregulate both KIR2DL1 and KIR2DL2, two HLA-specific inhibitory receptors belonging to KIR family (Pesce et al, 2018) (Figure 1A). Furthermore, in silico functional characterization of miR-146a-5p gene targets, identified CD94, HLA-C, HLA-E, Prf1, and several other KIRs genes as additional targets.…”

“…Furthermore, Ni et al (2015) identified the miRNA profiles of human NK cells from different compartments (peripheral blood, cord blood, and uterine decidua). Very recently, our group, by analyzing peripheral blood NK cells from 10 different human healthy donors, identified a 108 miRNA signature able to discriminate CD56 bright from CD56 dim NK cell subsets independently from their surface phenotype (Pesce et al, 2018). Interestingly, we found some miRNAs (miR-146a-5p, miR-92a-3p, miR-223-3p, miR-873-5p, miR-31a-5p, hsa-miR-130a-5p, miR-181a-2-3p) with consistent differential expression in the two NK cell subsets, and with an intermediate expression in the CD56 bright /CD16 dim NK cell subset, which represents a transition phase in the NK cell maturation process of NK cells.…”

Natural killer cells in patients with hematologic malignancies, solid tumors and in recipients of hematopoietic stem cell transplantation

“…The micro-RNA, has-miRNA-146a-5p, may be involved in the regulation of KIR expression. Targeting has-miRNA-146a-5p downregulates KIR and may improve NK-mediated antitumor activity [60]. Vitamins: A, B, C, D, and E as well as natural compounds such as: genistein, curcumin, ginseng extract, garlic extract, resveratrol, ashwagandha extract, ingenol mebutate, kumquat pericarp extract, prostratin, lectins, and polysaccharides affect NK cell function by: increasing cytotoxicity, enhancing proliferation, and stimulating cytokine production [61].…”

Report from the Eleventh Killer Immunoglobulin‐like Receptor (KIR) Workshop: Novel insights on KIR polymorphism, ligand recognition, expression and function

“…He showed that it is possible to establish the existence of a miRNA signature able to discriminate these two main NK cell subsets using both univariate and multivariate analyses. Interestingly, through the analysis of the putative targets of representative miRNAs, he reported that miR‐146a‐5p might be involved in the regulation of KIR expression, suggesting that KIR down‐regulation by miR‐146a‐5p targeting could be exploited to improve the NK‐mediated anti‐tumor activity . In a model for homeostatic NK cell proliferation in response to IL‐15 stimulation, Aline Pfefferle described an intricate interplay between proliferation and functionality.…”