Novel Insights on Human NK Cells’ Immunological Modalities Revealed by Gene Expression Profiling

Abstract

As part of the innate immune system, human NK cells play a critical role early in the systemic host defense against pathogens and tumor cells. Recent studies suggest a more complex view of NK cell behavior, as different functions and tissue localizing capabilities seem to be preferentially assigned to distinct subpopulations of NK cells, CD56dimCD16+ or CD56brightCD16−. In this study, we used oligonucleotide microarrays to compare the expression profile of ∼20,000 genes in three NK cell subpopulations: peripheral blood-derived CD56dimCD16+, CD56brightCD16−, and in vitro-activated CD16+ NK cells. The differential expression of selected genes was verified by flow cytometry and functional assays. When comparing CD56dimCD16+ and CD56brightCD16− subsets, a new heterogeneous molecular basis for the functional and developmental differences between these two subsets was revealed. Furthermore, systematic analysis of transcriptional changes in activated CD16+ NK cells provided us with a better understanding of NK function in inflamed tissues. We highlight a number of genes that were overexpressed upon activation (e.g., OX40 ligand, CD86, Tim3, galectins, etc.), that enable these cells to directly cross-talk with other innate and adaptive immune effectors. The overexpressed genes assign novel intriguing immunomodulatory functions to activated NK cells, in addition to their potent cytotoxic abilities.

The CD16−CD56bright NK Cell Subset Is Resistant to Reactive Oxygen Species Produced by Activated Granulocytes and Has Higher Antioxidative Capacity Than the CD16+CD56dim Subset

“…In addition, the measurement of antioxidant ability of cellular lysates from CD56 dim and CD56 bright NK cells lends further support to the notion that differences in antioxidative function could explain the difference in sensitivity to H 2 O 2 between these two NK subsets. Recently, expression of genes in CD56 dim CD16 ϩ and CD56 bright CD16 Ϫ NK cell subsets was analyzed using a gene array approach (44). Several genes found to be differentially expressed between CD56 dim and CD56 bright NK cells may be candidate antioxidants, as inferred from this study.…”

Herpes Simplex Virus Antigens Directly Activate NK Cells via TLR2, Thus Facilitating Their Presentation to CD4 T Lymphocytes

“…Both MHC II molecules were significantly upregulated on NK cells, and HLA-DR expression was upregulated to the greatest extent on the CD56 bright CD16 2 NK cell subset (data not shown). Expression of MHC II molecules on human NK cells as mRNA and protein was reported (67,68) but not previously shown to be upregulated by lipopeptide or a viral pathogen, although similar lipopeptides induce maturation and upregulate MHC II on DCs (71).…”

“…NK cells can mature DCs and induce the Th1 transcription factor T-bet in CD4 T lymphocytes through IFN-g production (65,66), both of which promote Th1 responses. Hanna et al (28) reported that NK cells (especially the CD56 bright CD16 2 subset) activated by PHA and IL-2 can present Ag, and they defined distinct proteomic and genomic profiles of the two NK cell subsets (67,68).…”

Transcript origin analysis identifies antigen-presenting cells as primary targets of socially regulated gene expression in leukocytes

“…CD16 + /CD56 + NK cells were cultured in medium alone or stimulated with IL-2 + IL-15 before transcriptional profiling by Amersham CodeLink Human 20K I spotted cDNA arrays (GEO accession no. GSE1511) (52). CD3 + T lymphocytes activated with antibodies to CD3 + CD28 were exposed to norepinephrine or vehicle before transcriptional profiling by Affymetrix HuGene FL high-density oligonucleotide arrays (53).…”