Abstract
Chronic hepatitis C virus (HCV) infection causes generalized CD8+ T cell impairment, not limited to HCV-specific CD8+ T-cells. Liver-infiltrating monocyte-derived macrophages (MDMs) contribute to the local micro-environment and can interact with and influence cells routinely trafficking through the liver, including CD8+ T-cells. MDMs can be polarized into M1 (classically activated) and M2a, M2b, and M2c (alternatively activated) phenotypes that perform pro- and anti-inflammatory functions, respectively. The impact of chronic HCV infection on MDM subset functions is not known. Our results show that M1 cells generated from chronic HCV patients acquire M2 characteristics, such as increased CD86 expression and IL-10 secretion, compared to uninfected controls. In contrast, M2 subsets from HCV-infected individuals acquired M1-like features by secreting more IL-12 and IFN-γ. The severity of liver disease was also associated with altered macrophage subset differentiation. In co-cultures with autologous CD8+ T-cells from controls, M1 macrophages alone significantly increased CD8+ T cell IFN-γ expression in a cytokine-independent and cell-contact-dependent manner. However, M1 macrophages from HCV-infected individuals significantly decreased IFN-γ expression in CD8+ T-cells. Therefore, altered M1 macrophage differentiation in chronic HCV infection may contribute to observed CD8+ T-cell dysfunction. Understanding the immunological perturbations in chronic HCV infection will lead to the identification of therapeutic targets to restore immune function in HCV+ individuals, and aid in the mitigation of associated negative clinical outcomes.
Highlights
Infection with hepatitis C virus (HCV) affects nearly 200 million people worldwide, establishing in most infected individuals chronicity that can lead to cirrhosis and liver cancer and has been a leading indication for liver transplantation
We demonstrate impaired monocyte-derived macrophages (MDMs) subset differentiation in chronic HCV infection and our results suggest that macrophage dysfunction can contribute to observed CD8+ T-cell dysfunction
We have previously shown that this culture system polarizes human macrophages into various subsets, on the basis of an extensive assessment of cell surface receptors (CD14, CD80, CD86, CD163, CD200, and TLR4) and cytokine expression
Summary
Infection with hepatitis C virus (HCV) affects nearly 200 million people worldwide, establishing in most infected individuals chronicity that can lead to cirrhosis and liver cancer and has been a leading indication for liver transplantation. Chronic HCV infection has a significant impact on cells of the innate and adaptive immune system, including the shift of monocytes from anti- to pro-inflammatory states, caused in part by circulating HCV core protein [2,3,4,5,6]. The effects of impaired monocyte/macrophage function in chronic HCV infection on macrophage differentiation and subsequent influence on adaptive immune responses are not known. Macrophages respond to their immediate environment by differentiating into pro- or anti-inflammatory cell subsets, described as M1-like or classically activated and M2-like or alternatively activated macrophages, respectively [7]. The M2c subset is formed in response to IL-10, TGF-β, and glucocorticoids [8]
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call