Recent findings underline the role of NK cell subsets in regulating adaptive immunity. To define characteristics of NK cell subpopulations, purified CD56(dim) and CD56(bright) NK cells were analyzed by using gene chip arrays covering more than 39,000 transcripts. Gene profiling revealed resting NK cells to differ in respect to 473 transcripts with 176 exclusively expressed in CD56(dim) and 130 solely in CD56(bright) NK cells. Results were compared with array analyses using mRNA obtained from activated CD56(dim) and CD56(bright) NK cells. In this approach, NK cell receptors, cytolytic molecules, adhesion structures, and chemokine ligands showed differential expression patterns in the two subpopulations. These data were validated using FACS, RT-qPCR, or cytokine bead array (CBA) techniques. Cytokines produced by CD56(dim) and CD56(bright) NK cells were determined using a protein array covering 79 different bioactive mediators. GDNF, IGFBP-1, EGF, and TIMP-2 were detected in both subsets. In contrast, IGFBP-3 and IGF-1 were mainly produced by CD56(dim), while GM-CSF, TARC, and TGFbeta3 were expressed by CD56(bright) NK cells. In summary, we report new characteristic features of CD56(dim) and CD56(bright) NK cells, further underscoring that they represent independent populations with functionally diverse capabilities. The information on NK cells generated in this study will help to define corresponding NK cell populations in other species that lack CD56 expression on NK cells, such as mice. This will subsequently lead to the establishment of suitable animal models for detailed analysis of NK cell populations in vivo.
Summary Interleukin‐21 (IL‐21) is a cytokine with pleiotropic effects on various cell types including dendritic cells, B cells, T cells and natural killer (NK) cells. To evaluate if IL‐21 affects human NK cell subpopulations in a similar fashion, functional studies were performed on CD56dim and CD56bright NK cells, both bearing IL‐21 receptors at identical densities. Stimulation with IL‐21 strongly induced proliferation of CD56bright NK cells and cytotoxicity against K562 target cells was preferentially augmented in CD56dim NK cells. In contrast, stimulation with IL‐2 and IL‐21 alone or in combination failed to induce interferon‐γ and tumour necrosis factor‐α production in the two NK cell subsets. Intracellular analysis of signal transducer and activator of transcription (STAT) proteins revealed that IL‐21 by itself induces phosphorylation of STAT1 and STAT3 in CD56dim NK cells, and to an even higher degree in CD56bright NK cells. In this CD56bright NK cell population alone, IL‐2 weakly phosphorylated STAT1 and STAT3, which was further increased when cells were treated with the combination of both cytokines. In contrast, STAT5 was strongly phosphorylated only in CD56bright NK cells by low‐dose IL‐2, while IL‐21 did not affect STAT5 at all. In summary, we present data indicating that the NK‐cell‐directed cytokines IL‐2 and IL‐21 not only affect functions in NK cell subpopulations differently but can also act additively.
HIV patients either on highly active antiviral therapy (HAART) or therapy naive were analyzed for their CD56 phenotype and cytokine production in comparison to healthy controls (HC). Both NK cell populations (CD56(dim) and CD56(bright)) are found to be present in all groups with selectively decreased CD56(dim) NK cells in HAART naive patients. Patients on HAART exhibited significantly diminished numbers of CD161+CD56(dim) NK cells. CD56(dim) were equally potent in producing IFNgamma in all three groups. The number of TNFalpha+CD56(bright) NK cells from patients on HAART and TNFalpha+CD56(dim) NK cells from HAART naive patients was significantly reduced as compared to healthy controls. In summary our data revealed that functional capacities and coexpression patterns of lectin-like receptors on lymphocytes are differentially affected in HIV patients depending on the state of therapy (under HAART or HAART naive) or the cell type (NK or T cells), respectively.
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