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. 2016 Jan 25:13:14.
doi: 10.1186/s12985-016-0473-y.

T-bet expression in CD8+ T cells associated with chronic hepatitis B virus infection

Rongshan Fan  1 , Yinghua Lan  2 , Jiwang Chen  3 , Yanxin Huang  4 , Qin Yan  5 , Lisheng Jiang  6 , Shupeng Song  7 , Yongguo Li  8
Affiliations

T-bet expression in CD8+ T cells associated with chronic hepatitis B virus infection

Rongshan Fan et al. Virol J. .

Abstract

Background: The mechanisms leading to virus-specific CD8+ T cell dysfuction in chronic hepatitis B virus (HBV) infection remain to be elucidated. Our study focused on the role of transcription factor T-bet in HBV infection because it is a crucial regulator of T cell immunity.

Methods: We assessed the expression of T-bet along with PD-1, IFN-γ and perforin, in HBV-specific CD8+ T cells from resolved acute hepatitis B (rAHB) patients, chronic hepatitis B (CHB) patients, as well as asymptomatic HBV carriers (ASCs). We observed dynamic changes of T-bet, PD-1, IFN-γ and perforin in acute stage and recovery stage of acute hepatitis B (AHB).

Results: Comparing with other cohorts, HBV-specific CD8+ T cells from rAHB demonstrated a superior ability in T-bet, IFN-γ and perforin expression, but an inferior ability in PD-1 expression. In the CHB group, the level of T-bet has a linear relationship with the level of PD-1, IFN-γ and HBV DNA, respectively. A lower expression of T-bet and PD-1 was observed in ASCs when compared with CHB. A higher expression of T-bet, PD-1, IFN-r and perforin was observed in acute stage when compared with the recovery stage of AHB.

Conclusions: Our results suggest that expression of T-bet may influence the function of HBV-specific CD8+ T cells and thus can be an attractive target for modulation to improve HBV-specific immunity in CHB.

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Figures

Fig. 1
Fig. 1
Percentage of pentamer + CD8+ T cells in the total CD8 + T cells after in vitro induction. After induced amplification, peripheral blood mononuclear cells (PBMCs) from patients with resolved acute hepatitis B (rAHB), chronic hepatitis B (CHB) and asymptomatic hepatitis B virus carriers (ASCs) were used to detect the percentage of pentamer + CD8+ T cells in total CD8 + T cells. Each dot represents an individual data point and the horizontal lines represent the mean percentage of pentamer + CD8 T cells in the total CD8+ T cells determined by flow cytometry. **represent P < 0.01,***represent P < 0.001, by Mann Whitney test
Fig. 2
Fig. 2
T-bet expression in HBV-specific CD8+ T cells. a Percentage of T-bet + cells in the total CD8+ T cell population (CD8 + T-bet+/CD8+) determined by flow cytometry. Data are shown as median (IQR). IQR = interquartile range. P > 0.05, by Kruskal-Wallis H test. b Percentage of T-bet + cells in HBV-specific CD8+ T cells (pentamer + CD8 + T-bet+/pentamer + CD8+) determined by flow cytometry. Data are shown as median (IQR). IQR = interquartile range. **represent P < 0.01,***represent P < 0.001, by Mann Whitney test. c Representative flow cytometry data of T-bet expression
Fig. 3
Fig. 3
PD-1 expression in the HBV-specific CD8+ T cells. a Percentage of PD-1+ cells in total CD8+ T cells (CD8 + PD-1+/CD8+) determined by flow cytometry. Data are shown as median (IQR). IQR = interquartile range. P > 0.05, by Kruskal-Wallis H test. b Percentage of PD-1+ cells in the HBV-specific CD8+ T cell population (pentamer + CD8 + PD-1+/pentamer + CD8+) determined by flow cytometry. Data are shown as median (IQR). IQR = interquartile range. ns represent no significant, **represent P < 0.01, ***represent P < 0.001, by Mann Whitney test. c Representative flow cytometry data of PD-1 expression
Fig. 4
Fig. 4
IFN-γ and perforin levels in the HBV-specific CD8+ T cell population. a Mean level of IFN-γ produced by HBV-specific T cells. Error bars indicate SEM. b Mean level of Perforin levels produced by HBV-specific T cells. Error bars indicate SEM. *represents P < 0.05, **represents P < 0.01, ***represents P < 0.001, ns means no significant, by unpaired t test
Fig. 5
Fig. 5
Correlation between percentage of T-bet + or PD-1+ HBV-specific CD8+ T cells and HBV DNA content or IFN-γ level in PBMC from CHB patients. a The percentage of T-bet + cells was negatively related to the percentage of PD-1+ cells (r = −0.8638, p < 0.0001); b The percentage of T-bet + cells was negatively related to HBV DNA (r = −0.8741, p < 0.0001); c The percentage of PD-1+ cells was positively related to HBV DNA (r = 0.8864, p < 0.0001); d The percentage of T-bet + cells was positively related to IFN-γ level (r = 0.7193, p = 0.0008); e The percentage of PD-1+ cells was negatively related to IFN-γ level (r = −0.7027, p = 0.0011), Spearman rank correlation test was used for data analysis
Fig. 6
Fig. 6
Changes of HBV-specific CD8+ T cells, T-bet, PD-1, IFN-γand perforin in AHB. a Percentage of HBV-specific CD8+ T cells existed in the acute and recovery stages (p = 0.0343, by Wilcoxon signed rank test); b Level of T-bet in HBV-specific CD8+ T cells in the acute and recovery stages (p = 0.0156, by Wilcoxon signed rank test); c Level of PD-1 in HBV-specific CD8+ T cells in the acute and recovery stages (P = 0.0313, by Wilcoxon signed rank test); d Level of IFN-γ in HBV-specific CD8+ T cells in the acute and recovery stages (P = 0.0006, by paired t test); e Level of perforin in HBV-specific CD8+ T cells in the acute and recovery stages (P = 0.0062, by paired t test); f Representative flow cytometry data of T-bet and PD-1 expression in acute stage and recovery stage of AHB
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