肝内引发的CD8 + T细胞中I型干扰素信号传导的恢复促进功能分

StephenW

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 , Yasuhito Tanaka  6
Affiliations
Affiliations

    1
    Department of Virology & Liver unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
    2
    Department of Immunology, National Institute of Infectious Diseases, Tokyo, Japan.
    3
    Department of Virology & Liver unit, Nagoya City University Graduate School of Medical Science, Nagoya, Japan.
    4
    Department of Gastroenterology and Hepatology, Yokohama City University School of Medicine, Yokohama, Japan.
    5
    Institute for Frontier Life and Medical Science, Kyoto University, Kyoto, Japan.
    6
    Department of Gastroenterology and Hepatology, Kumamoto University, Kumamoto, Japan.

    PMID: 33400688 DOI: 10.1172/jci.insight.145761

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.

Keywords: Cellular immune response; Hepatitis; Immunology; Infectious disease; T cells.

StephenW

肝内引发的CD8 + T细胞中I型干扰素信号传导的恢复促进功能分化
川岛圭吾1，矶川正德2，大西雅史3，伊甸宝帝1，斋藤悟4，中岛淳4，藤田隆5，田中康人6
隶属关系
隶属关系

    1个
    名古屋市立大学医学研究科病毒与肝病学系，日本名古屋。
    2
    日本东京国立传染病研究所免疫学系。
    3
    名古屋市立大学医学研究科病毒与肝病学系，日本名古屋。
    4
    横滨市立大学医学院胃肠病学和肝病学系，日本横滨。
    5
    日本京都大学前沿生命与医学研究所。
    6
    熊本大学胃肠病学和肝病学系，日本熊本。

    PMID：33400688 DOI：10.1172 / jci.insight.145761

抽象

乙肝病毒（HBV）特异的CD8 + T细胞在肝脏中引发后无法获得效应子功能，但对该功能障碍的分子基础了解甚少。通过比较肝内启动的，功能失调的HBV特异性CD8 + T细胞与系统启动的，功能性效应子对应物的基因表达谱，我们发现干扰素刺激基因（ISG）的表达在功能失调的CD8 + T细胞中被选择性抑制。 ISG抑制与对IFNα治疗的STAT1磷酸化受损有关。重要的是，在肝脏中强烈诱导类型干扰素（IFN-Is）有助于肝内启动的HBV特异性CD8 + T细胞的功能分化，以及T细胞中ISGs表达的恢复。这些结果表明，肝内启动抑制了CD8 + T细胞中的IFN-I信号传导，这可能导致功能障碍。数据还表明，强烈诱导肝内IFN-Is对于慢性HBV感染的治疗价值。

关键词：细胞免疫反应；肝炎;免疫学传染病; T细胞。

StephenW

https://df6sxcketz7bb.cloudfront ... sight.145761.v1.pdf