Hepatitis C Virus Induces MDSCs-Like Monocytes through TLR2/PI3K/AKT/STAT3 Signaling

BACKGROUND AND AIMS: Recent 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. METHODS: Purified 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. RESULTS: Both 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. CONCLUSIONS: 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. It will be of interest to test whether antagonizing suppressive functions of MDSCs could enhance immune responses and virus control in chronic HCV infection.