Genome wide transcriptional analysis of resting and IL2 activated human natural killer cells: gene expression signatures indicative of novel molecular signaling pathways

• Main Authors: Schmitz Alexander, Xiao Li, Geng Huimin, Zhou Guimei, Iqbal Javeed, Dybkaer Karen, d'Amore Francesco, Chan Wing C
• Format: Article
• Language: English
• Published: BMC 2007-07-01
• Series: BMC Genomics
• Online Access: http://www.biomedcentral.com/1471-2164/8/230

<p>Abstract</p> <p>Background</p> <p>Human natural killer (NK) cells are the key contributors of innate immune response and the effector functions of these cells are enhanced by cytokines such as interleukine 2 (IL2). We utilized genome-wide transcriptional profiling to identify gene expression signatures and pathways in resting and IL2 activated NK cell isolated from peripheral blood of healthy donors.</p> <p>Results</p> <p>Gene expression profiling of resting NK cells showed high expression of a number of cytotoxic factors, cytokines, chemokines and inhibitory and activating surface NK receptors. Resting NK cells expressed many genes associated with cellular quiescence and also appeared to have an active TGFβ (TGFB1) signaling pathway. IL2 stimulation induced rapid downregulation of quiescence associated genes and upregulation of genes associated with cell cycle progression and proliferation. Numerous genes that may enhance immune function and responsiveness including activating receptors (<it>DNAM1, KLRC1 </it>and <it>KLRC3</it>), death receptor ligand (<it>TNFSF6 (FASL</it>) and <it>TRAIL</it>), chemokine receptors (<it>CX3CR1, CCR5 </it>and <it>CCR7</it>), interleukin receptors (<it>IL2RG, IL18RAB </it>and <it>IL27RA</it>) and members of secretory pathways (<it>DEGS1, FKBP11, SSR3, SEC61G </it>and <it>SLC3A2</it>) were upregulated. The expression profile suggested PI3K/AKT activation and NF-κB activation through multiple pathways (TLR/IL1R, TNF receptor induced and TCR-like possibly involving BCL10). Activation of NFAT signaling was supported by increased expression of many pathway members and downstream target genes. The transcription factor <it>GATA3 </it>was expressed in resting cells while <it>T-BET </it>was upregulated on activation concurrent with the change in cytokine expression profile. The importance of NK cells in innate immune response was also reflected by late increased expression of inflammatory chemotactic factors and receptors and molecules involved in adhesion and lymphocyte trafficking or migration.</p> <p>Conclusion</p> <p>This analysis allowed us to identify genes implicated in cellular quiescence and the cytokines and cytotoxic factors ready for immediate immune response. It also allowed us to observe the sequential immunostimulatory effects of IL2 on NK cells improving our understanding of the biology and molecular mediators behind NK cell activation.</p>