Key Points
IFN-γ induces IL-15 upregulation in epithelial cells more potently than type I IFNs.
IFN-γ induces IL-15 expression in epithelial cells via the STAT1/IRF1 pathway.
IFN-γ–induced IL-15 on epithelial cells activates NK cells via trans-presentation.
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.
Footnotes
T.-S.K. and E.-C.S. designed the study. T.-S.K. and M.-S.R. performed the experiments. T.-S.K., M.-S.R., and E.-C.S. analyzed the data and wrote the manuscript.
This work was supported by the Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education (NRF-2018R1A6A3A01010977) and by the Samsung Science and Technology Foundation under Project SSTF-BA1402-51.
The online version of this article contains supplemental material.
- Received January 20, 2021.
- Accepted November 8, 2021.
- Copyright © 2021 by The American Association of Immunologists, Inc.
Pay Per Article - You may access this article (from the computer you are currently using) for 1 day for US$37.50
Regain Access - You can regain access to a recent Pay per Article purchase if your access period has not yet expired.