Regulation of dendritic cell function and cell-based therapy in chronic hepatitis C virus infection

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Sequential activation of innate and adaptive immune response is crucial for virus elimination. Dendritic cells (DCs) sense virus infection via toll-like receptors (TLR) or retinoic acid inducible gene-I (RIG-I), resulting in the secretion of type-I interferons (IFN) and inflammatory cytokines. Blood DC consist of two subsets; myeloid DC (MDC) and plasmacytoid DC (PDC). In chronic hepatitis C patients, both of these DC subsets decreased compared to healthy subjects. Furthermore, MDC and PDC are functionally impaired in HCV-infected patients in the ability to stimulate T cell proliferation as well as cytokine secretion. In MDC from HCV-infected patients, regardless of higher expression of TLR2, TLR4 and RIG-I compared to the controls, the levels of TLR/RIG-I-mediated IFN-β, TNF-α or IL-12p70 induction are lower than those in uninfected donors. These results suggest that the signal transduction in the downstream of TLR/RIG-I in DC is profoundly impaired in HCV infection. In order to searc … More h for the mechanisms of above-mentioned DC malfunction in HCV infection, we inoculated pseudo-HCV particles, covered by chimeric HCV E1/E2 protein, to MDC or PDC recovered from healthy donors. Pseudo-HCV enters only MDC but not PDC, suggesting that HCV aims to infect myeloid subsets. However, unanswered question still remains for the mechanisms of HCV-induced PDC dysfunction. Cumulative reports have been published for pervasive impairment in adaptive immune system in HCV infection, such as virus-specific CD4^+ or CD8^+ T cells. Naturally occurring regulatory T cells (Tregs) are specialized T cell subsets that are capable of suppressing auto-reactive T cells. In order to clarify the roles of Treg in chronic HCV infection, we compared the frequency and function of Tregs between the patients and uninfected donors. Peripheral Tregs in chronic HCV infection is greater in frequency and in suppressive ability than those in healthy counterparts, much more in patients with persistently normal ALT levels compared to those with active hepatitis. These results imply that the abundance of Treg is beneficial for the maintenance of low-grade liver inflammation, possibly by suppressing inflammatory Th1 cells. In conclusion, active and reciprocal interactions among innate and adaptive immune cells, which are orchestrated by DC, are critical in shaping immuno-pathogenesis of HCV infection. Less