Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria of Parma, Parma, Italy.
Biochemistry and Molecular Biology Unit, Laboratory of Functional Genomics and Protein Engineering, Department of Life Sciences, University of Parma, Parma, Italy.
Nat Med. 2017 Mar;23(3):327-336. doi: 10.1038/nm.4275. Epub 2017 Feb 6.
Hepatitis 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.
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耗竭，通过抑制途径的调节只能部分纠正这种状态，这表明 T 细胞耗竭的背后存在更复杂的分子相互作用。为了更全面地了解这一过程并确定恢复 T 细胞功能的其他靶点，我们比较了急性和慢性乙型肝炎患者的 HBV 特异性 CD8 T 细胞与能够自发清除 HBV 感染的 HBV 特异性 CD8 T 细胞以及健康参与者的流感 (FLU) 特异性 CD8 T 细胞的转录组谱。结果表明，耗竭的 HBV 特异性 CD8 T 细胞在多个水平上受到明显损害，并表现出各种细胞过程的大量下调，这些过程集中在广泛的线粒体改变上。靶向线粒体的抗氧化剂可显著改善线粒体和抗病毒 CD8 功能，这表明活性氧 (ROS) 在 T 细胞耗竭中起核心作用。因此，线粒体是治疗慢性乙型肝炎感染的新型重建治疗的有前途的靶点。
