靶向线粒体功能障碍可以恢复慢性乙型肝炎患者HBV特异性CD8 T

StephenW

Nat Med. 2017 Feb 6. doi: 10.1038/nm.4275. [Epub ahead of print]
Targeting mitochondrial dysfunction can restore antiviral activity of exhausted HBV-specific CD8 T cells in chronic hepatitis B.Fisicaro P1, Barili V1, Montanini B2, Acerbi G1, Ferracin M3, Guerrieri F4, Salerno D4, Boni C1, Massari M5, Cavallo MC1, Grossi G6, Giuberti T1, Lampertico P6, Missale G1, Levrero M4,7,8, Ottonello S2,9, Ferrari C1,10.
Author information

• 1Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria of Parma, Parma, Italy.
• 2Biochemistry and Molecular Biology Unit, Laboratory of Functional Genomics and Protein Engineering, Department of Life Sciences, University of Parma, Parma, Italy.
• 3Department of Experimental, Diagnostic and Specialty Medicine-DIMES, University of Bologna, Bologna, Italy.
• 4Center for Life Nanoscience Laboratory IIT-CNLS, Sapienza University Rome, Italy.
• 5Unit of Infectious Diseases, IRCCS-Azienda Ospedaliera S. Maria Nuova, Reggio Emilia, Italy.
• 61st Division of Gastroenterology, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy.
• 7Department of Internal Medicine (DMISM), Sapienza University, Rome, Italy.
• 8Cancer Research Center of Lyon (CRCL)-INSERM U1052, Lyon, France.
• 9Biopharmanet-Tec Laboratory, University of Parma, Parma, Italy.
• 10Department of Medicine and Surgery, University of Parma, Parma, Italy.
  

AbstractHepatitis B virus (HBV)-specific CD8 T cells are functionally exhausted in chronic hepatitis B infection, and this condition can be corrected only partially through the modulation of inhibitory pathways, which suggests that a more complex molecular interplay underlies T cell exhaustion. To gain broader insight into this process and identify additional targets for the restoration of T cell function, we compared the transcriptome profiles of HBV-specific CD8 T cells from patients with acute and chronic disease with those of HBV-specific CD8 T cells from patients able to resolve HBV infection spontaneously and influenza (FLU)-specific CD8 T cells from healthy participants. The results indicate that exhausted HBV-specific CD8 T cells are markedly impaired at multiple levels and show substantial downregulation of various cellular processes centered on extensive mitochondrial alterations. A notable improvement of mitochondrial and antiviral CD8 functions was elicited by mitochondrion-targeted antioxidants, which suggests a central role for reactive oxygen species (ROS) in T cell exhaustion. Thus, mitochondria represent promising targets for novel reconstitution therapies to treat chronic hepatitis B infection.


PMID:28165481DOI:10.1038/nm.4275

StephenW

Nat Med。 2017年2月6.doi：10.1038 / nm.4275。 [打印前的电子版]
靶向线粒体功能障碍可以恢复慢性乙型肝炎患者HBV特异性CD8 T细胞的抗病毒活性
Fisicaro P1，Barili V1，Montanini B2，Acerbi G1，Ferracin M3，Guerrieri F4，Salerno D4，Boni C1，Massari M5，Cavallo MC1，Grossi G6，Giuberti T1，Lampertico P6，Missale G1，Levrero M4,7,8，Ottonello 9，法拉利C1,10。
作者信息

1病毒免疫病理学实验室，传染病和肝病学单位，帕尔马，意大利帕尔马Azienda Ospedaliero大学。
2Biochemistry and Molecular Biology Unit，Laboratory of Functional Genomics and Protein Engineering，Department of Life Sciences，Parma，Parma，Italy。
意大利博洛尼亚大学，实验，诊断和特殊医学的DIMES。
4生命中心纳米科学实验室IIT-CNLS，Sapienza大学罗马，意大利。
5Unit of Infectious Diseases，IRCCS-Azienda Ospedaliera S.Maria Nuova，Reggio Emilia，Italy。
61st Division of Gastroenterology，Fondazione IRCCS Ca'Granda，Ospedale Maggiore Policlinico，Universitàdegli Studi di Milano，Milan，Italy。
7内科学部（DMISM），Sapienza大学，罗马，意大利。
里昂法国研究中心（CRCL）-INSERM U1052，里昂，法国。
Biopharmanet-Tec Laboratory，Parma大学，帕尔马，意大利。
10意大利帕尔马帕尔马大学医学与外科系。

抽象

乙型肝炎病毒（HBV）特异性CD8 T细胞在慢性乙型肝炎感染中功能性耗尽，并且该病症可以通过抑制性途径的调节仅部分校正，这表明更复杂的分子相互作用是T细胞衰竭的基础。为了获得更多的洞察这个过程和确定额外的目标恢复T细胞功能，我们比较HBV特异性CD8 T细胞从急性和慢性疾病患者的转录组配置文件的HBV特异性CD8 T细胞从患者能结果表明，耗尽的HBV特异性CD8 T细胞在多个水平上显着受损并且显示出以广泛的线粒体改变为中心的各种细胞过程的显着下调。值得注意的线粒体和抗病毒CD8功能是由线粒体靶向抗氧化剂，这表明活性氧（ROS）在T细胞耗竭的中心作用。因此，线粒体代表新的重建治疗慢性乙型肝炎感染的有希望的目标。

PMID：
28165481
DOI：
10.1038 / nm.4275