Targeting mitochondrial dysfunction can restore antiviral activity of exhausted HBV-specific CD8 T cells in chronic hepatitis B
- 6 February 2017
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Medicine
- Vol. 23 (3), 327-336
- https://doi.org/10.1038/nm.4275
Abstract
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.Keywords
This publication has 62 references indexed in Scilit:
- The Hallmarks of AgingCell, 2013
- A travel guide to Cytoscape pluginsNature Methods, 2012
- Mitochondrial Respiratory Capacity Is a Critical Regulator of CD8+ T Cell Memory DevelopmentImmunity, 2012
- Aging and Immune Function: Molecular Mechanisms to InterventionsAntioxidants and Redox Signaling, 2011
- Reduced histone biosynthesis and chromatin changes arising from a damage signal at telomeresNature Structural & Molecular Biology, 2010
- The immunoregulatory role of CD244 in chronic hepatitis B infection and its inhibitory potential on virus-specific CD8+ T-cell functionJournal of Hepatology, 2010
- Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene listsNucleic Acids Research, 2008
- Convergence of multiple signaling pathways is required to coordinately up-regulate mtDNA and mitochondrial biogenesis during T cell activationMitochondrion, 2007
- Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profilesProceedings of the National Academy of Sciences of the United States of America, 2005
- Immunology of hepatitis B virus and hepatitis C virus infectionNature Reviews Immunology, 2005