Elsevier

Journal of Hepatology

Volume 48, Issue 6, June 2008, Pages 903-913
Journal of Hepatology

Peripheral virus-specific T-cell interleukin-10 responses develop early in acute hepatitis C infection and become dominant in chronic hepatitis

https://doi.org/10.1016/j.jhep.2008.01.030Get rights and content

Background /Aims

Interleukin-10 (IL-10) has been ascribed pro-viral but anti-fibrotic properties in chronic hepatitis C virus (HCV) infection. In this study, we examined the role of HCV-specific T-cell IL-10 response in patients with acute and chronic HCV infection.

Methods

Peripheral HCV-specific T-cell IL-10 and IFNγ responses were measured in cytokine Elispot assay using overlapping HCV-derived peptides in patients with chronic (n = 61), resolved (n = 15) and acute (n = 8) hepatitis C, looking for their onset, quantity, breadth and durability relative to clinical and virological outcomes. The source and effect of HCV-specific IL-10 response were determined in depletion and IL-10 neutralization experiments.

Results

Both HCV-specific IL-10 and IFNγ responses were detected early within 1–2 months of acute clinical hepatitis C. However, only HCV-specific IL-10 response correlated with elevated liver enzymes, increased viremia and suppressed HCV-specific CD4+ T-cell proliferation in acute infection. While these associations were lost in established chronic infection, HCV-specific IL-10 responses were increased in patients without cirrhosis while IL-10 blockade enhanced antiviral effector IFNγ responses.

Conclusions

HCV-specific IL-10 Tr1 responses may play a dual role in HCV infection, dampening effector T-cells to promote viral persistence in acute infection but also protecting against progressive fibrosis in chronic infection.

Introduction

T-cells play a critical role in natural hepatitis C virus (HCV) clearance. While HCV is spontaneously cleared with a vigorous and broad virus-specific effector T-cell response, such responses are impaired in persistent infections [1], [2], [3], [4], [5]. While most studies have focused on the antiviral effector cytokine IFNγ, a role for the immune regulatory cytokine interleukin-10 (IL-10) has been suggested by enhanced HCV titers and reduced hepatic fibrosis during exogenous IL-10 therapy in HCV-infected patients [6] as well as associations between IL-10 promoter polymorphisms and clinical outcomes [7], [8]. IL-10 is an important immune regulatory cytokine with pleiotropic effects [9], [10]. T-cells that predominantly secrete IL-10 (but not IFNγ, IL-4 or IL-5) with immune regulatory properties have been termed ‘Tr1’ cells, defining a subset of antigen-specific regulatory T-cells (Tregs) [11] distinct from thymic-derived, naturally occurring CD25+Foxp3+ Tregs [12]. Relevant for HCV pathogenesis, circulating CD4+ T-cells with HCV-specific IL-10 production have been described in patients with chronic HCV infection [5], [13], [14]. Furthermore, HCV-specific IL-10+ CD8+ Tr1 cells have been detected in the liver of HCV-infected patients with IL-10-dependent effector T-cell suppression [15], [16].

In this study, we report that a broadly specific HCV-specific Tr1 response is induced early during acute hepatitis C associated with reduced HCV-specific CD4+ T-cell proliferation and increased HCV viremia. Both CD4+ and CD8+ T-cells (but not CD25+ Tregs) contributed to HCV-specific Tr1 response that was also associated with reduced fibrosis in established chronic HCV infection. Collectively, these results suggest that HCV-specific Tr1 response may suppresses antiviral effector response, promoting chronic evolution in acute infection while limiting progressive liver damage in established chronic infection [17].

Section snippets

Patients

Subjects were recruited from the Gastroenterology Clinics at the Philadelphia Veterans Affairs Medical Center and the Clinical Translational Research Center at the University of Pennsylvania following informed consent according to the protocols approved by the respective institutional review boards. All patients were assessed for baseline demographic, clinical and virological parameters, including serum HCV RNA by Roche COBAS qualitative, quantitative COBAS, or TaqMan reverse-transcriptase

Results

HCV-specific Tr1 response is associated with increased viremia and liver inflammation but reduced HCV-specific CD4+ proliferative T-cell response in acute hepatitis C. We began by determining the kinetics of HCV-specific IL-10+ Tr1 and IFNγ+ Th1 responses during acute hepatitis C relative to HCV-specific CD4+ T-cell proliferation, serum alanine aminotransferase (sALT) activity and HCV RNA titer as well as virological outcome. As shown in Fig. 1A, HCV-specific IL-10+ Tr1 response was detected

Discussion

IL-10+ Tr1 cells represent a subset of Tregs, distinct from CD4+CD25+ regulatory T-cells and with suppressive or regulatory properties [25], [26], [27]. IL-10 is produced by many cell types including dendritic cells [28], [29], macrophages, monocytes, NK [30], [31] and NKT-cells [32] with pleiotropic effects. For example, IL-10 can downregulate antigen processing by transporter-associated with antigen processing, MHC expression and IL-12 production by antigen-presenting cells (APC) [9], [10],

Acknowledgements

This material is based upon work supported in part by the Office of Research and Development, Department of Veterans Affairs and with the resources and the use of facilities at the Philadelphia VA Medical Center. This study was also supported by NIH Grants R01-AI-47519 and R01-AA-12849; the Philadelphia VA Medical Research; NIH/NIDDK Center of Molecular Studies in Digestive and Liver Diseases P30DK50306 and its Molecular Biology and Cell Culture Core Facilities; the NIH Public Health Service

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    The authors who have taken part in the research of this paper declared that they do not have a relationship with the manufacturers of the materials involved either in the past or present and they did not receive funding from the manufacturers to carry out their research. NIH funded study (Grants R01-AI-47519, R01-AA-12849, P30DK50306, M01-RR00040, NIH T32 DK 07066, NIH K12-RR-017625).

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