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ResearchIn-Press PreviewImmunologyInfectious disease Open Access | 10.1172/jci.insight.145761

Restoration of type I interferon signaling in intrahepatically primed CD8+ T cells promotes functional differentiation

Keigo Kawashima,1 Masanori Isogawa,2 Masaya Onishi,3 Ian Baudi,1 Satoru Saito,4 Atsushi Nakajima,4 Takashi Fujita,5 and Yasuhito Tanaka6

1Department of Virology & Liver unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan

2Department of Immunology, National Institute of Infectious Diseases, Tokyo, Japan

3Department of Virology & Liver unit, Nagoya City University Graduate School of Medical Science, Nagoya, Japan

4Department of Gastroenterology and Hepatology, Yokohama City University School of Medicine, Yokohama, Japan

5Institute for Frontier Life and Medical Science, Kyoto University, Kyoto, Japan

6Department of Gastroenterology and Hepatology, Kumamoto University, Kumamoto, Japan

Find articles by Kawashima, K. in: JCI | PubMed | Google Scholar |

1Department of Virology & Liver unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan

2Department of Immunology, National Institute of Infectious Diseases, Tokyo, Japan

3Department of Virology & Liver unit, Nagoya City University Graduate School of Medical Science, Nagoya, Japan

4Department of Gastroenterology and Hepatology, Yokohama City University School of Medicine, Yokohama, Japan

5Institute for Frontier Life and Medical Science, Kyoto University, Kyoto, Japan

6Department of Gastroenterology and Hepatology, Kumamoto University, Kumamoto, Japan

Find articles by Isogawa, M. in: JCI | PubMed | Google Scholar |

1Department of Virology & Liver unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan

2Department of Immunology, National Institute of Infectious Diseases, Tokyo, Japan

3Department of Virology & Liver unit, Nagoya City University Graduate School of Medical Science, Nagoya, Japan

4Department of Gastroenterology and Hepatology, Yokohama City University School of Medicine, Yokohama, Japan

5Institute for Frontier Life and Medical Science, Kyoto University, Kyoto, Japan

6Department of Gastroenterology and Hepatology, Kumamoto University, Kumamoto, Japan

Find articles by Onishi, M. in: JCI | PubMed | Google Scholar

1Department of Virology & Liver unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan

2Department of Immunology, National Institute of Infectious Diseases, Tokyo, Japan

3Department of Virology & Liver unit, Nagoya City University Graduate School of Medical Science, Nagoya, Japan

4Department of Gastroenterology and Hepatology, Yokohama City University School of Medicine, Yokohama, Japan

5Institute for Frontier Life and Medical Science, Kyoto University, Kyoto, Japan

6Department of Gastroenterology and Hepatology, Kumamoto University, Kumamoto, Japan

Find articles by Baudi, I. in: JCI | PubMed | Google Scholar |

1Department of Virology & Liver unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan

2Department of Immunology, National Institute of Infectious Diseases, Tokyo, Japan

3Department of Virology & Liver unit, Nagoya City University Graduate School of Medical Science, Nagoya, Japan

4Department of Gastroenterology and Hepatology, Yokohama City University School of Medicine, Yokohama, Japan

5Institute for Frontier Life and Medical Science, Kyoto University, Kyoto, Japan

6Department of Gastroenterology and Hepatology, Kumamoto University, Kumamoto, Japan

Find articles by Saito, S. in: JCI | PubMed | Google Scholar

1Department of Virology & Liver unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan

2Department of Immunology, National Institute of Infectious Diseases, Tokyo, Japan

3Department of Virology & Liver unit, Nagoya City University Graduate School of Medical Science, Nagoya, Japan

4Department of Gastroenterology and Hepatology, Yokohama City University School of Medicine, Yokohama, Japan

5Institute for Frontier Life and Medical Science, Kyoto University, Kyoto, Japan

6Department of Gastroenterology and Hepatology, Kumamoto University, Kumamoto, Japan

Find articles by Nakajima, A. in: JCI | PubMed | Google Scholar |

1Department of Virology & Liver unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan

2Department of Immunology, National Institute of Infectious Diseases, Tokyo, Japan

3Department of Virology & Liver unit, Nagoya City University Graduate School of Medical Science, Nagoya, Japan

4Department of Gastroenterology and Hepatology, Yokohama City University School of Medicine, Yokohama, Japan

5Institute for Frontier Life and Medical Science, Kyoto University, Kyoto, Japan

6Department of Gastroenterology and Hepatology, Kumamoto University, Kumamoto, Japan

Find articles by Fujita, T. in: JCI | PubMed | Google Scholar |

1Department of Virology & Liver unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan

2Department of Immunology, National Institute of Infectious Diseases, Tokyo, Japan

3Department of Virology & Liver unit, Nagoya City University Graduate School of Medical Science, Nagoya, Japan

4Department of Gastroenterology and Hepatology, Yokohama City University School of Medicine, Yokohama, Japan

5Institute for Frontier Life and Medical Science, Kyoto University, Kyoto, Japan

6Department of Gastroenterology and Hepatology, Kumamoto University, Kumamoto, Japan

Find articles by Tanaka, Y. in: JCI | PubMed | Google Scholar |

Published January 5, 2021 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.145761.
Copyright © 2021, Kawashima et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published January 5, 2021 - Version history
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Abstract

Hepatitis B virus (HBV)-specific CD8+ T cells fail to acquire effector functions after priming in the liver, but the molecular basis for the dysfunctionality is poorly understood. By comparing the gene expression profile of intrahepatically primed, dysfunctional HBV-specific CD8+ T cells with that of systemically primed, functional effector counterparts, we found that the expression of interferon-stimulated genes (ISGs) is selectively suppressed in the dysfunctional CD8+ T cells. The ISG suppression was associated with impaired phosphorylation of STAT1 in response to IFNα treatment. Importantly, a strong induction of type interferons (IFN-Is) in the liver facilitated the functional differentiation of intrahepatically primed HBV-specific CD8+ T cells in association with the restoration of ISGs expression in the T cells. These results suggest that intrahepatic priming suppresses IFN-I signaling in CD8+ T cells, which may contribute to the dysfunctionality. The data also suggest a therapeutic value of the robust induction of intrahepatic IFN-Is for the treatment of chronic HBV infection.

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