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T lymphocytes from chronic HCV-infected patients are primed for activation-induced apoptosis and express unique pro-apoptotic gene signature.

Zhao BB, Zheng SJ, Gong LL, Wang Y, Chen CF, Jin WJ, Zhang D, Yuan XH, Guo J, Duan ZP, He YW - PLoS ONE (2013)

Bottom Line: Global CD4(+) and CD8(+) T-cells also showed unique transcriptional profiles in the expression of apoptosis-related genes.We identified BCL2, PMAIP1, and CASP1 in CD4(+) T-cells and IER3 and BCL2A1 in CD8(+) T-cells from CHC patients as HCV-specific gene signatures.These results provide novel insights to the pathogenesis of chronic HCV infection.

View Article: PubMed Central - PubMed

Affiliation: Key Laboratory of Systems Biology of Pathogens, Ministry of Health, Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, R. P. China.

ABSTRACT
Although extensive studies have demonstrated the functional impairment of antigen-specific CD4(+) and CD8(+) T-cells during chronic hepatitis C virus (HCV) infection, the functional status of global CD4(+) and CD8(+) T-cells remains unclear. In this report, we recruited 42 long-term (~20 years) treatment-naïve chronic HCV (CHC) patients and 15 healthy donors (HDs) to investigate differences in global CD4(+) and CD8(+) T-cells function. We show that CD4(+) and CD8(+) T-cells from CHC patients underwent increased apoptosis after TCR stimulation. Furthermore, IFN-γ, IL-9 and IP-10 were elevated in CHC patients' plasma and promoted activation-induced T-cells death. Global CD4(+) and CD8(+) T-cells also showed unique transcriptional profiles in the expression of apoptosis-related genes. We identified BCL2, PMAIP1, and CASP1 in CD4(+) T-cells and IER3 and BCL2A1 in CD8(+) T-cells from CHC patients as HCV-specific gene signatures. Importantly, the gene expression patterns of CD4(+) and CD8(+) T-cells from CHC patients differ from those in CD4(+) and CD8(+) T-cells from human immunodeficiency virus type 1 (HIV-1) or hepatitis B virus (HBV) infected individuals. Our results indicate that chronic HCV infection causes a systemic change in cytokine levels that primes T-cells for activation-induced apoptosis. Furthermore, HCV infection programs unique apoptosis-related gene expression profiles in CD4(+) and CD8(+) T-cells, leading to their enhanced activation-induced apoptosis. These results provide novel insights to the pathogenesis of chronic HCV infection.

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Elevated cytokine levels in the plasma of CHC patients and their roles in sensitizing T-cells to activation-induced apoptosis.(A), Cytokine levels, including IFN-γ, IL-1β, IL-9, and IP-10, in the plasma of CHC patients and HDs as measured by Luminex assay. (B), Effect of pre-incubation of PBMCs with the indicated cytokines on T-cells proliferation as measured by CFSE dilution and T-cells apoptosis as measured by Annexin-V staining. PBMCs from HDs were pre-incubated with or without (NC) the indicated cytokines for 48 hrs and then stimulated with anti-CD3/CD28 for 3 days before the measurement of proliferation and apoptosis. Data were from 5 independent HDs. (C), Representative FACS profiles of CD4+ and CD8+ T-cells apoptosis after pre-incubation with cytokines followed by stimulation. *, p<0.05; **, p<0.01.
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pone-0077008-g004: Elevated cytokine levels in the plasma of CHC patients and their roles in sensitizing T-cells to activation-induced apoptosis.(A), Cytokine levels, including IFN-γ, IL-1β, IL-9, and IP-10, in the plasma of CHC patients and HDs as measured by Luminex assay. (B), Effect of pre-incubation of PBMCs with the indicated cytokines on T-cells proliferation as measured by CFSE dilution and T-cells apoptosis as measured by Annexin-V staining. PBMCs from HDs were pre-incubated with or without (NC) the indicated cytokines for 48 hrs and then stimulated with anti-CD3/CD28 for 3 days before the measurement of proliferation and apoptosis. Data were from 5 independent HDs. (C), Representative FACS profiles of CD4+ and CD8+ T-cells apoptosis after pre-incubation with cytokines followed by stimulation. *, p<0.05; **, p<0.01.

Mentions: Cytokines play important roles in regulating T-cells survival. We hypothesized that dysregulated cytokine expression in the CHC patients might sensitize CD4+ and CD8+ T-cells to activation-induced apoptosis. Plasma levels of IFN-γ, IL-1β, IL-9, and IP-10 were elevated in the CHC patients (Figure 4A). Interestingly, the levels of IFN-γ and IL-9 were highest in the HCV-h group, whereas the levels of IL-1β and IP-10 were highest in the HCV-l group (Figure 4A). The levels of other primary inflammatory cytokines, such as TNF-α, were similar in CHC patients and HDs (data not shown).


T lymphocytes from chronic HCV-infected patients are primed for activation-induced apoptosis and express unique pro-apoptotic gene signature.

Zhao BB, Zheng SJ, Gong LL, Wang Y, Chen CF, Jin WJ, Zhang D, Yuan XH, Guo J, Duan ZP, He YW - PLoS ONE (2013)

Elevated cytokine levels in the plasma of CHC patients and their roles in sensitizing T-cells to activation-induced apoptosis.(A), Cytokine levels, including IFN-γ, IL-1β, IL-9, and IP-10, in the plasma of CHC patients and HDs as measured by Luminex assay. (B), Effect of pre-incubation of PBMCs with the indicated cytokines on T-cells proliferation as measured by CFSE dilution and T-cells apoptosis as measured by Annexin-V staining. PBMCs from HDs were pre-incubated with or without (NC) the indicated cytokines for 48 hrs and then stimulated with anti-CD3/CD28 for 3 days before the measurement of proliferation and apoptosis. Data were from 5 independent HDs. (C), Representative FACS profiles of CD4+ and CD8+ T-cells apoptosis after pre-incubation with cytokines followed by stimulation. *, p<0.05; **, p<0.01.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3794995&req=5

pone-0077008-g004: Elevated cytokine levels in the plasma of CHC patients and their roles in sensitizing T-cells to activation-induced apoptosis.(A), Cytokine levels, including IFN-γ, IL-1β, IL-9, and IP-10, in the plasma of CHC patients and HDs as measured by Luminex assay. (B), Effect of pre-incubation of PBMCs with the indicated cytokines on T-cells proliferation as measured by CFSE dilution and T-cells apoptosis as measured by Annexin-V staining. PBMCs from HDs were pre-incubated with or without (NC) the indicated cytokines for 48 hrs and then stimulated with anti-CD3/CD28 for 3 days before the measurement of proliferation and apoptosis. Data were from 5 independent HDs. (C), Representative FACS profiles of CD4+ and CD8+ T-cells apoptosis after pre-incubation with cytokines followed by stimulation. *, p<0.05; **, p<0.01.
Mentions: Cytokines play important roles in regulating T-cells survival. We hypothesized that dysregulated cytokine expression in the CHC patients might sensitize CD4+ and CD8+ T-cells to activation-induced apoptosis. Plasma levels of IFN-γ, IL-1β, IL-9, and IP-10 were elevated in the CHC patients (Figure 4A). Interestingly, the levels of IFN-γ and IL-9 were highest in the HCV-h group, whereas the levels of IL-1β and IP-10 were highest in the HCV-l group (Figure 4A). The levels of other primary inflammatory cytokines, such as TNF-α, were similar in CHC patients and HDs (data not shown).

Bottom Line: Global CD4(+) and CD8(+) T-cells also showed unique transcriptional profiles in the expression of apoptosis-related genes.We identified BCL2, PMAIP1, and CASP1 in CD4(+) T-cells and IER3 and BCL2A1 in CD8(+) T-cells from CHC patients as HCV-specific gene signatures.These results provide novel insights to the pathogenesis of chronic HCV infection.

View Article: PubMed Central - PubMed

Affiliation: Key Laboratory of Systems Biology of Pathogens, Ministry of Health, Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, R. P. China.

ABSTRACT
Although extensive studies have demonstrated the functional impairment of antigen-specific CD4(+) and CD8(+) T-cells during chronic hepatitis C virus (HCV) infection, the functional status of global CD4(+) and CD8(+) T-cells remains unclear. In this report, we recruited 42 long-term (~20 years) treatment-naïve chronic HCV (CHC) patients and 15 healthy donors (HDs) to investigate differences in global CD4(+) and CD8(+) T-cells function. We show that CD4(+) and CD8(+) T-cells from CHC patients underwent increased apoptosis after TCR stimulation. Furthermore, IFN-γ, IL-9 and IP-10 were elevated in CHC patients' plasma and promoted activation-induced T-cells death. Global CD4(+) and CD8(+) T-cells also showed unique transcriptional profiles in the expression of apoptosis-related genes. We identified BCL2, PMAIP1, and CASP1 in CD4(+) T-cells and IER3 and BCL2A1 in CD8(+) T-cells from CHC patients as HCV-specific gene signatures. Importantly, the gene expression patterns of CD4(+) and CD8(+) T-cells from CHC patients differ from those in CD4(+) and CD8(+) T-cells from human immunodeficiency virus type 1 (HIV-1) or hepatitis B virus (HBV) infected individuals. Our results indicate that chronic HCV infection causes a systemic change in cytokine levels that primes T-cells for activation-induced apoptosis. Furthermore, HCV infection programs unique apoptosis-related gene expression profiles in CD4(+) and CD8(+) T-cells, leading to their enhanced activation-induced apoptosis. These results provide novel insights to the pathogenesis of chronic HCV infection.

Show MeSH
Related in: MedlinePlus