Abstract
During chronic hepatitis C virus (HCV) infection, both CD4+ and CD8+ T-cells become functionally exhausted, which is reflected by increased expression of programmed cell death-1 (PD-1) and T-cell immunoglobulin and mucin domain-containing protein 3 (Tim-3), and elevated anti-inflammatory interleukin 10 (IL-10) plasma levels. We studied 76 DAA-treated HCV-positive patients and 18 non-infected controls. Flow cytometry measured pretreatment frequencies of CD4+PD-1+, CD4+PD-1+Tim-3+ and CD8+PD-1+Tim-3+ T-cells and IL-10 levels measured by ELISA were significantly higher and CD4+PD-1−Tim-3− and CD8+PD-1−Tim-3− T-cells were significantly lower in patients than in controls. Treatment resulted in significant decrease of CD4+Tim-3+, CD8+Tim-3+, CD4+PD-1+Tim-3+ and CD8+PD-1+Tim-3+ T-cell frequencies as well as IL-10 levels and increase in CD4+PD-1−Tim-3− and CD8+PD-1−Tim-3− T-cells. There were no significant changes in the frequencies of CD4+PD-1+ T-cells, while CD8+PD-1+ T-cells increased. Patients with advanced liver fibrosis had higher PD-1 and lower Tim-3 expression on CD4+T-cells and treatment had little or no effect on the exhaustion markers. HCV-specific CD8+T-cells frequency has declined significantly after treatment, but their PD-1 and Tim-3 expression did not change. Successful treatment of chronic hepatitis C with DAA is associated with reversal of immune exhaustion phenotype, but this effect is absent in patients with advanced liver fibrosis.
Highlights
During chronic hepatitis C virus (HCV) infection, both CD4+ and CD8+ T-cells become functionally exhausted, which is reflected by increased expression of programmed cell death-1 (PD-1) and T-cell immunoglobulin and mucin domain-containing protein 3 (Tim-3), and elevated anti-inflammatory interleukin 10 (IL-10) plasma levels
Tim-3 is mainly present on Th1 and Tc1 subsets, but it is expressed on innate immune cells such as dendritic cells (DCs), natural killer (NK) cells, and m onocytes[25]
We found that an effective antiviral therapy of chronic HCV infection decreases the frequencies of T-cells expressing exhaustion markers and lowers plasma concentrations of IL-10, but these effects are absent in patients with advanced liver fibrosis
Summary
During chronic hepatitis C virus (HCV) infection, both CD4+ and CD8+ T-cells become functionally exhausted, which is reflected by increased expression of programmed cell death-1 (PD-1) and T-cell immunoglobulin and mucin domain-containing protein 3 (Tim-3), and elevated anti-inflammatory interleukin 10 (IL-10) plasma levels. As the HCV infection progresses, there is a gradual decrease of the effector functions of T-cells including diminished proliferative potential and cytotoxicity, and lowered IL-2, tumor necrosis factor α (TNF-α), and interferon γ (IFNγ) production. This progressive impairment of the host immune function is referred to as immune e xhaustion[6]. These findings are congruent with the concept of hierarchical model of functional T-cell exhaustion in which restoration of proliferation capacity is followed by restoration of effector cytokines production and only by the restoration of cytotoxicity
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