摘要
CD4＋CD25＋FoxP3 ＋ regulatory T ceils （Tregs） are increased in patients with chronic hepatitis C, which may contribute to the sustained suppression of hepatitis C virus （HCV）-specific T-cell responses and viral persistence in HCV-infected individuals. We postulated that HCV core protein （HCVc） directly contributes to the expansion of Tregs in HCV-infected patients, and we provide evidence to support this hypothesis in the report. Peripheral blood mononuclear cells （PBMCs） and sera were collected from 87 treatment-naive chronic HCV-infected patients, CD4＋CD25＋ Tregs were measured by flow cytometry, and HCV RNA and HCVc levels were detected using qPCR and enzyme-linked immunosorbent assay （ELISA）, respectively. CD4＋, CD8＋, CD4＋CD25＋ and CD4＋CD25- T cells were purified from healthy donors and cultured with recombinant HCVc and Toll-like receptor （TLR） ligands. Flow cytometry was used to analyze cell proliferation, and ELISA was performed to measure cytokine production. In the 87 chronic HCV-infected patients, HCVc showed a significant correlation with HCV RNA and CD4＋CD25＋Tregs. Mechanistic studies showed that HCVc, together with anti-CD3 antibody, augmented CD4＋CD25＋ Treg proliferation, but inhibited CD4＋CD25- T-cell proliferation and IFN-γ production, in a dose-dependent and Treg-dependent manner. Moreover, unlike the TLR3 ligand （poly hC） and the TLR4 ligand （lipopolysaccharide, LPS）, the TLR2 ligand （lipoteichoic acid, LTA） and HCVc both inhibited TCR-induced CD4＋ T-cell proliferation and IFN-γ secretion in a Treg-dependent manner. These data indicate that HCVc, like other TLR2 ligands, triggers CD4＋CD25＋ Treg activation and expansion to inhibit host immune responses, which may play a critical role in viral persistence in HCV-infected patients.
CD4＋CD25＋FoxP3 ＋ regulatory T ceils （Tregs） are increased in patients with chronic hepatitis C, which may contribute to the sustained suppression of hepatitis C virus （HCV）-specific T-cell responses and viral persistence in HCV-infected individuals. We postulated that HCV core protein （HCVc） directly contributes to the expansion of Tregs in HCV-infected patients, and we provide evidence to support this hypothesis in the report. Peripheral blood mononuclear cells （PBMCs） and sera were collected from 87 treatment-naive chronic HCV-infected patients, CD4＋CD25＋ Tregs were measured by flow cytometry, and HCV RNA and HCVc levels were detected using qPCR and enzyme-linked immunosorbent assay （ELISA）, respectively. CD4＋, CD8＋, CD4＋CD25＋ and CD4＋CD25- T cells were purified from healthy donors and cultured with recombinant HCVc and Toll-like receptor （TLR） ligands. Flow cytometry was used to analyze cell proliferation, and ELISA was performed to measure cytokine production. In the 87 chronic HCV-infected patients, HCVc showed a significant correlation with HCV RNA and CD4＋CD25＋Tregs. Mechanistic studies showed that HCVc, together with anti-CD3 antibody, augmented CD4＋CD25＋ Treg proliferation, but inhibited CD4＋CD25- T-cell proliferation and IFN-γ production, in a dose-dependent and Treg-dependent manner. Moreover, unlike the TLR3 ligand （poly hC） and the TLR4 ligand （lipopolysaccharide, LPS）, the TLR2 ligand （lipoteichoic acid, LTA） and HCVc both inhibited TCR-induced CD4＋ T-cell proliferation and IFN-γ secretion in a Treg-dependent manner. These data indicate that HCVc, like other TLR2 ligands, triggers CD4＋CD25＋ Treg activation and expansion to inhibit host immune responses, which may play a critical role in viral persistence in HCV-infected patients.
基金
This work was supported by the Natural Science Foundation of China （81373143, to ZT） and by NIH （AI095097, to LS）. The funders had no role in the study design, data collection and analysis, decision to publish or preparation of the paper.
