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

Tae-Shin Kim, Min-Seok Rha and Eui-Cheol Shin
J Immunol January 15, 2022, 208 (2) 338-346; DOI: https://doi.org/10.4049/jimmunol.2100057
Tae-Shin Kim
*Laboratory of Immunology and Infectious Diseases, Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea;
†Department of Laboratory Medicine, Seoul National University Hospital, Seoul, Republic of Korea;
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Min-Seok Rha
*Laboratory of Immunology and Infectious Diseases, Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea;
‡Department of Otorhinolaryngology, Yonsei University College of Medicine, Seoul, Republic of Korea; and
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Eui-Cheol Shin
*Laboratory of Immunology and Infectious Diseases, Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea;
§The Center for Epidemic Preparedness, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea
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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.

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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.

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Footnotes

  • 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.

  • 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.

  • The online version of this article contains supplemental material.

  • Abbreviations used in this article

    COVID-19
    coronavirus disease 2019
    DC
    dendritic cell
    HPRT
    hypoxanthine phosphoribosyltransferase
    hTERT-HME1
    human telomerase reverse transcriptase human mammary epithelial
    IKK, inhibitor of κB kinase; IL-2/15Rβ
    IL-2/IL-15 receptor β-chain
    IL-15Rα
    IL-15 receptor α
    IKK
    inhibitor of κB kinase
    IRF1
    IFN regulatory factor 1
    ISGF3
    IFN-stimulated gene factor 3
    qPCR
    quantitative PCR
    siRNA
    small interfering RNA
    WT
    wild type

  • Received January 20, 2021.
  • Accepted November 8, 2021.
  • Copyright © 2022 by The American Association of Immunologists, Inc.
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The Journal of Immunology: 208 (2)
The Journal of Immunology
Vol. 208, Issue 2
15 Jan 2022
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IFN-γ Induces IL-15 Trans-Presentation by Epithelial Cells via IRF1
Tae-Shin Kim, Min-Seok Rha, Eui-Cheol Shin
The Journal of Immunology January 15, 2022, 208 (2) 338-346; DOI: 10.4049/jimmunol.2100057

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IFN-γ Induces IL-15 Trans-Presentation by Epithelial Cells via IRF1
Tae-Shin Kim, Min-Seok Rha, Eui-Cheol Shin
The Journal of Immunology January 15, 2022, 208 (2) 338-346; DOI: 10.4049/jimmunol.2100057
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