IFN-γ Induces IL-15 Trans-Presentation by Epithelial Cells via IRF1

Abstract IL-15 exhibits pleiotropic effects on NK and CD8+ T cells and contributes to host protection or immunopathology during infection. Although both type I IFNs and IFN-γ upregulate IL-15 expression, their effects on IL-15 upregulation and underlying mechanisms have not been compared comprehensively. In addition, little is known about trans-presentation of IL-15 by epithelial cells to lymphocytes. In this study, we analyzed the expression of IL-15 and IL-15Rα in the human hepatocyte-derived Huh-7 cell line after stimulation with IFN-α, IFN-β, or IFN-γ using RT-PCR, flow cytometry, and confocal microscopy. We also performed knockdown experiments to investigate the signaling pathway involved in IL-15 upregulation. IFN-γ more potently upregulated IL-15 expression in Huh-7 cells than IFN-α and IFN-β. Knockdown experiments revealed that IFN-γ– and IFN-β–induced IL-15 expression relied on IFN regulatory factor 1 (IRF1), which is upregulated by STAT1 and IFN-stimulated gene factor 3, respectively. Inhibitor of κB kinase α/β was also involved in IFN-γ–induced upregulation of IL-15. Furthermore, human NK cells were activated by coculture with IFN-γ–treated Huh-7 cells, which was abrogated by knocking down IL-15Rα in IFN-γ–treated Huh-7 cells, indicating that IFN-γ–induced IL-15 on Huh-7 cells activates NK cells via trans-presentation. In summary, our data demonstrate that IFN-γ potently elicits IL-15 trans-presentation by epithelial cells via IRF1. These data also suggest that the IFN-γ–IRF1–IL-15 axis may be a regulatory target for the treatment of diseases with IL-15 dysregulation.