Dendritic cells: The warriors upfront-turned defunct in chronic hepatitis C infection

Abstract

Hepatitis C virus (HCV) infection causes tremendous morbidity and mortality with over 170 million people infected worldwide. HCV gives rise to a sustained, chronic disease in the majority of infected individuals owing to a failure of the host immune system to clear the virus. In general, an adequate immune response is elicited by an efficient antigen presentation by dendritic cells (DCs), the cells that connect innate and adaptive immune system to generate a specific immune response against a pathogen. However, HCV seems to dysregulate the activity of DCs, making them less proficient antigen presenting cells for the optimal stimulation of virus-specific T cells, hence interfering with an optimal anti-viral immune response. There are discordant reports on the functional status of DCs in chronic HCV infection (CHC), from no phenotypic or functional defects to abnormal functions of DCs. Furthermore, the molecular mechanisms behind the impairment of DC function are even so not completely elucidated during CHC. Understanding the mechanisms of immune dysfunction would help in devising strategies for better management of the disease at the immunological level and help to predict the prognosis of the disease in the patients receiving antiviral therapy. In this review, we have discussed the outcomes of the interaction of DCs with HCV and the mechanisms of DC impairment during HCV infection with its adverse effects on the immune response in the infected host.

Keywords: Dendritic cells; Hepatitis C; Mechanism of functional impairment.

Figure 1

Proposed mechanism of dendritic cell impairment during chronic hepatitis infection and its relationship with antiviral therapy. Exposure of mo-DCs to HCV proteins ex vivo upregulated the expression of SOCS 3, IDO and PD-L1 that may be responsible for the observed maturation and activation defects in DCs including decreased secretion of IL-12 and IFNγ on LPS stimulation leading to the differentiation of Th2 cells. Such DCs also produced increased levels of IL-10 that promote the differentiation of regulatory T cells. Antiviral therapy along with some immunomodulation targeting these inhibitory molecules would help in the reconstitution of DC function in the antiviral therapy non-responders and would help to achieve SVR. SVR: Sustained virological response; NR: Non-responders to therapy; IL: Interleukin; IFN: Interferon; Th: T helper; SOCS: Suppressor of cytokine signalling; IDO: Indoleamine 2,3-dioxygenase; PD-L1: Programmed death ligand 1; LPS: Lipopolysaccharide; CHC: Chronic hepatitis C; DC: Dendritic cells; HCV: Hepatitis C virus; mo-DC: Monocyte-derived DCs; Treg: Regulatory T cells.