| Hepatitis B virus (HBV) is known as a hepatotropic, noncytopathic DNA virus, infecting more than300million people worldwide and readily establishing chronicity. In patients chronically infected with HBV, specific antiviral T-cell response is weak or undetected, resulting in persistence of infection and development of severe liver diseases. Although the mechanisms responsible for T cell hyporesponsiveness or tolerance to HBV antigens are not fully elucidated, substantial studies suggest both CD4+and CD8+T cells of regulatory property would play an important role in inhibiting HBV-specific T-cell responses.CD3+CD8loW T cells are recognized as a subset of CD8+T cells with down-regulated CD8expression, whose increase is observed in chronic and persistent antigen exposure, e.g. patients infected with HIV, patients underwent transplantation and mouse chronically infected with parasite. The CD8low T cells are reported to be type-2polarized and poorly cytolytic, and even exhibit suppressive function via IL-10 or membrane-bound TGF-β1(mTGF-β1). Given that chronic HBV infection is also a persistent antigen exposure, in this study, we explored the role of CD8low T cells in the impaired CD8+T cell response in patients with chronic HBV infection.1. Frequency of CD8low T cells is increased in peripheral blood of chronic HBV patients19healthy individuals and47chronic HBV patients were selected. PBMC were isolated and flow cytometry was performed to determine the circulating CD8low T-cell frequency. There was a significantly higher frequency of circulating CD8low T cells in chronic HBV patients than that in healthy controls (the CD8low cells in CD8+T cell:15.20%±1.04%vs.5.66%±0.57%[mean±SEM]; p<0.001). we also found the patients with the disease course longer than5years (n=21) showed a markedly higher frequency of CD8low T cells compared to those shorter than5years (n=10)(the CD8low cells in CD8+T cell:18.64%±1.70%vs.10.37%±1.84%[mean±SEM]; p<0.01).2. Soluble HLA class I plasma levels show a positive relationship with frequency of CD8low T cells in chronic HBV patientsThe concentrations of plasma HLA class I molecules from47chronic HBV patients and19healthy donors were measured. In comparison to healthy donors, soluble HLA class I plasma levels were significantly higher in chronic HBV patients (ng/mL,850.1±79.77vs.263.1±29.67[mean±SEM];p<0.001). There was a positive correlation between soluble HLA class I plasma levels and the percentage of CD8low cells in CD8+T cells (R2=0.2155;p=0.001). In contrast, no correlation was found in healthy donors.3. Phenotype of CD8low T cells in chronic HBV patientsThe CD8low T cells in chronic HBV patients and healthy donors were typed for the commonly used effector and suppressive markers. We found CD8low T cells in the patients, compared to that in healthy donors, seemed phenotypically to be type-2polarized (more IL-4and less IFN-y expression) and of regulatory/suppressive properties (elevated expression of suppressive markers, especially mTGF-β1).4. CD8low T-cell frequency is negatively correlated with HBci8-27-specific CD8+T-cell responses in chronic HBV patientsCD8+T-cell responses to the HBC18-27peptide were evaluated with HLA-A2+ve samples by IFN-y Elispot assay. The CD8+T cells of chronic HBV patients showed significantly lower IFN-γ production in response to the HBc peptide (15.39±1.59vs.36.78±10.01[mean±SEM];p<0.01). Notably, a significantly negative correlation was observed between frequency of CD8low T cells and HBc-speciflc CD8+T-cell responses in chronic HBV patients (r2=0.376, p=0.003). In contrast, no correlation was found in healthy donors (r2=0.195,r2=0.234).5. ConclusionCD8low T-cell subpopulation is significantly increased in chronic HBV patients, which is type-2polarized and expresses elevated levels of suppressive markers. The prevalence of CD8low T cells in patients with chronic HBV infection may be one of the factors that resulting in impaired CD8+T-cell response. |
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