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HCV immune evasion and regulatory T cell activation: cause or consequence?

Cellular & Molecular Immunology volume 15, pages 536–538 (2018)Cite this article

Hepatitis C virus (HCV) infection remains a major public health problem given that an estimated 71 million people are currently infected and 1.75 million are newly infected every year. Up to 85% of HCV infections become persistent and may eventually lead to chronic liver diseases, including cirrhosis and hepatocellular carcinoma.1 Immune responses play a crucial role in virus control and liver injury; however, the underlying mechanism is not completely understood. Patients chronically infected with HCV generally exhibit a weak peripheral blood T cell response against HCV, which could explain viral persistence. As cells that play a key role in dominant immune tolerance, regulatory T (T-reg) cells suppress inflammatory responses and prevent the development of autoimmune diseases. CD4+CD25+Foxp3+ T-reg cells, which are divided into natural T-reg (nT-reg) cells or thymus-derived T-reg cells and induced T-reg (iT-reg) cells or peripherally derived T-reg cells, also suppress antiviral T cell responses and protect the liver from immune-mediated damage in chronic HCV infection.2 T-reg cells control HCV-specific T cells not only in persistent infection but also after recovery, where they may regulate memory T cell responses by controlling their activation and preventing apoptosis.3 In this commentary, we discuss whether activated T-reg cells and non-functional effector cells are the causes or consequences of chronic HCV infection.

The picture our paper paints is that activated CD4+ T-reg cells co-exist with viremia and functionally impaired effector CD4+ T cells in chronic HCV-infected patients,5 and the work of others have demonstrated that CD8+ T cells are functionally impaired. The issue arises regarding the extent to which the CD4+ and CD8+ T-cell dysfunction is a result of viremia given that HCVc drives it via T-reg cells.5 In addition, the extent to which T-cell dysfunction is the cause of the viremia also remains a question given that Grakoui et al. 10 demonstrated that viral containment depends on functional T cells. The emergence of viruses with mutations in class I MHC-restricted epitopes is the direct result of inadequate virus-specific CD4+ T cells in persistent HCV infection. In the minority of patients who achieve spontaneous clearance of HCV infection, functional effector T cells are present, and T-reg cells are not strongly activated.11 A previous study indicated that patients with acute HCV infection who develop chronicity versus spontaneous resolution exhibit temporal changes in T-reg cell function; the resolution of disease was associated with a relative loss of functional suppression.12 It is possible that repetitive viral antigenic stimulation alters the function of T-reg cells over time. However, the primary genetic determinant of the virological outcome in HCV infection is not linked to T-cell immunity but to innate immunity. Polymorphisms in the gene encoding IL-28B powerfully predict the probability of self-cure in HCV infection. Chronic HCV-infected patients with the TT-IL28B rs12979860 genotype (unfavorable genotype) exhibit significantly increased frequencies of the T-reg cell population compared with the CT and CC genotypes.13 One possible explanation is that in chronically HCV-infected individuals, the primary defect is the lack of a favorable IL-28B genotype, resulting in sustained viremia, the presence of HCVc, and the activation of T-reg cells. In the majority of chronic HCV-infected patients, high numbers of CD4+CD25+FoxP3+ T-reg cells accumulated in the HCV-infected liver display a highly activated and differentiated effector/memory phenotype and may be involved in limiting HCV-induced fibrogenesis.14 Liver pathology is relatively mild and progresses slowly, which may be a benefit of these T-reg cells. As a consequence, the trade-off is that effective immune control is not achieved, resulting in the maintenance of chronic HCV infection. We conclude that the effect of HCVc on T-reg cells indicates that the activated T-reg cells and non-functional effector cells are consequences rather than causes of chronic infection. The dysfunctional effector CD4+ T cells and T-reg cells could, therefore, constitute a biomarker of viremia.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (#81373143, #81571535, to ZT).

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  1. Institute of Translational Medicine, the First Hospital, Jilin University, Changchun, China

    Haijun Li, Tianyang Li & Zhengkun Tu

  2. Department of Pathology, University of Washington, Seattle, Washington, USA

    Ian Nicholas Crispe

  3. Institute of Liver diseases, the First Hospital, Jilin University, Changchun, China

    Zhengkun Tu

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Correspondence to Zhengkun Tu.

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Li, H., Li, T., Crispe, I.N. et al. HCV immune evasion and regulatory T cell activation: cause or consequence?. Cell Mol Immunol 15, 536–538 (2018). https://doi.org/10.1038/cmi.2017.131

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