Abstract
Background and AimsRecent studies reveal the accumulation of myeloid derived suppressor cells (MDSCs) in human peripheral blood mononuclear cells (PBMCs) following HCV infection, which may facilitate and maintain HCV persistent infection. The mechanisms by which HCV induces MDSCs are poorly understood. In the present study, we investigated the mechanisms by which HCV induces MDSCs that lead to suppression of T cell proliferation and expansion of CD4+Foxp3+ regulatory T cells.MethodsPurified monocytes from healthy donors were cultured with HCV core protein (HCVc) or cell culture-derived HCV virions (HCVcc), and characterized the phenotype and function of these monocytes by flow cytometry, quantitative PCR, ELISA and western blot assays. In addition, peripheral blood from healthy donors and chronic HCV infected patients was collected, and MDSCs and CD4+CD25+CD127- regulatory T cells were analyzed by flow cytometry.ResultsBoth HCVc and HCVcc induced expression of IDO1, PD-L1 and IL-10, and significantly down-regulated HLA-DR expression in human monocytes. HCVc-treated monocytes triggered CD4+Foxp3+ Tregs expansion, and inhibited autologous CD4+ T cell activation in an IDO1-dependent fashion. Our results showed that HCV virions or HCV core proteins induced MDSC-like suppressive monocytes via the TLR2/PI3K/AKT/STAT3 signaling pathway. Monocytes derived from patients with chronic HCV infection displayed MDSCs characteristics. Moreover, the percentages of CD14+ MDSCs and CD4+CD25+CD127- Tregs in chronic HCV infected patients were significantly higher than healthy individuals, and the frequency of MDSCs correlated with CD4+CD25+CD127- Tregs.ConclusionsHCV induced MDSC-like suppressive monocytes through TLR2/PI3K/AKT/STAT3 signaling pathway to induce CD4+Foxp3+ regulatory T cells and inhibit autologous CD4+ T cell activation. It will be of interest to test whether antagonizing suppressive functions of MDSCs could enhance immune responses and virus control in chronic HCV infection.
Highlights
Hepatitis C virus (HCV) infection is a major public health problem
Our results showed that HCV virions or HCV core proteins induced myeloid derived suppressor cells (MDSCs)-like suppressive monocytes via the TLR2/PI3K/AKT/STAT3 signaling pathway
HCV induced MDSC-like suppressive monocytes through TLR2/PI3K/AKT/STAT3 signaling pathway to induce CD4+Foxp3+ regulatory T cells and inhibit autologous CD4+ T cell activation
Summary
Up to 85% of HCV infection become persistent, and may eventually lead to chronic liver diseases, including cirrhosis and hepatocellular carcinoma [1]. Many studies have demonstrated that the adaptive T cell immune response plays a major role both in controlling HCV infection and in contributing to hepatocellular damage [3]. The control of HCV infection requires a complex and coordinated interaction between innate and adaptive immune responses. The immune response to HCV is significantly impaired in patients with chronic infection. A better understanding of the host immune response to HCV infection will be critical for HCV vaccine development. We investigated the mechanisms by which HCV induces MDSCs that lead to suppression of T cell proliferation and expansion of CD4+Foxp3+ regulatory T cells
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