MicroRNA-155 Tunes Both the Threshold and Extent of NK Cell Activation via Targeting of Multiple Signaling Pathways
| Autor: | Ryan P. Sullivan, Anthony R. French, To-Ha Thai, Stephanie E. Schneider, Jeffrey W. Leong, Veronika Sexl, Leslie A. Fogel, Rachel O.L. Wong, Rizwan Romee, Scot J. Matkovich, Todd A. Fehniger, Gerald W. Dorn |
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| Rok vydání: | 2013 |
| Předmět: |
Recombinant Fusion Proteins
Genetic Vectors Immunology Biology Lymphocyte Activation Article CD49b Interferon-gamma Mice Phosphatidylinositol 3-Kinases Interleukin 21 Genes Reporter Transduction Genetic medicine Animals Humans Immunology and Allergy Interferon gamma Cells Cultured PI3K/AKT/mTOR pathway Mice Knockout Lymphokine-activated killer cell Sequence Analysis RNA Calcineurin Interleukins Janus kinase 3 Lentivirus Models Immunological NF-kappa B NFKB1 Specific Pathogen-Free Organisms Up-Regulation Cell biology Killer Cells Natural Mice Inbred C57BL MicroRNAs Gene Expression Regulation Cytomegalovirus Infections Interleukin 12 RNA Interference Signal Transduction medicine.drug |
| Zdroj: | The Journal of Immunology. 191:5904-5913 |
| ISSN: | 1550-6606 0022-1767 |
| DOI: | 10.4049/jimmunol.1301950 |
| Popis: | NK cells are innate lymphocytes important for host defense against viral infections and malignancy. However, the molecular programs orchestrating NK cell activation are incompletely understood. MicroRNA-155 (miR-155) is markedly upregulated following cytokine activation of human and mouse NK cells. Surprisingly, mature human and mouse NK cells transduced to overexpress miR-155, NK cells from mice with NK cell–specific miR-155 overexpression, and miR-155−/− NK cells all secreted more IFN-γ compared with controls. Investigating further, we found that activated NK cells with miR-155 overexpression had increased per-cell IFN-γ with normal IFN-γ+ percentages, whereas greater percentages of miR-155−/− NK cells were IFN-γ+. In vivo murine CMV–induced IFN-γ expression by NK cells in these miR-155 models recapitulated the in vitro phenotypes. We performed unbiased RNA-induced silencing complex sequencing on wild-type and miR-155−/− NK cells and found that mRNAs targeted by miR-155 were enriched in NK cell activation signaling pathways. Using specific inhibitors, we confirmed these pathways were mechanistically involved in regulating IFN-γ production by miR-155−/− NK cells. These data indicate that miR-155 regulation of NK cell activation is complex and that miR-155 functions as a dynamic tuner for NK cell activation via both setting the activation threshold as well as controlling the extent of activation in mature NK cells. In summary, miR-155−/− NK cells are more easily activated, through increased expression of proteins in the PI3K, NF-κB, and calcineurin pathways, and miR-155−/− and 155-overexpressing NK cells exhibit increased IFN-γ production through distinct cellular mechanisms. |
| Databáze: | OpenAIRE |
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