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.
Highlights
Natural killer (NK) cells are crucial effectors in the immune response against pathogen infection, in tumor surveillance and in regulating immune homeostasis [1]
NK cells were negatively isolated from fresh peripheral blood mononuclear cells (PBMC) derived from 10 different healthy donors and the most immature CD56bright/CD16− and the mature CD56dim/CD16bright NK cell subsets were sorted by the expression of CD56 and CD16 and analyzed by flow cytometry for different markers in order to control their purity and phenotypic features (Figures 1A–C)
MiRNA expression profiles of human CD56bright and CD56dim NK cells subsets were investigated with the human miRNA microarray kit v19.0, which allows for the detection of a total of 2006 different human miRNA sequences
Summary
Natural killer (NK) cells are crucial effectors in the immune response against pathogen infection, in tumor surveillance and in regulating immune homeostasis [1]. The distribution/intensity of the surface markers CD56 and CD16 (FcγRIIIA) defines two NK lymphocytes subsets: the CD56bright/CD16−/dim population that makes up about 10% of peripheral blood NK cells and the CD56dim/CD16bright subset that represents about 90% of circulating NK cells [2]. Additional NK cell populations exist but are a minority in healthy individuals. These include the CD56dim/CD16− (whose function is largely unknown) [5] and the functional CD56−/CD16bright NK cell subsets. This last subset is often expanded during certain viral infections, but it is usually hyporesponsive under these conditions [6,7,8,9]
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