Weak and functionally impaired hepatitis C virus (HCV)-specific T cell responses are a characteristic feature of HCV infection. Whereas spontaneously recovered patients maintain strong and broad HCV-specific T cell responses for decades, patients with persistent infection either never mount detectable responses or they become rapidly impaired. To identify mechanisms that contribute to these insufficient immune responses, investigators have focused on dendritic cells (DCs). ? DCs are antigen presenting cells that operate at the interface between innate and adaptive immune responses. DCs express pathogen recognition receptors and display a remarkable capacity to capture antigens in peripheral tissues, process them and present them to CD4 and CD8 T cell in regional lymph nodes, thereby initiating priming and differentiation of virus-specific T cells. Recently, human DCs have been categorized into two major subsets, myeloid DC (mDC) and plasmacytoid DC (pDC). Whereas mDC express high levels of CD11c, pDC lack CD11c and express CD123 (IL-3Ra). pDC are especially important in viral infections due to their capacity to produce high levels of type I interferon. ? ? DC function in HCV infection has been controversially discussed. Most studies used monocyte-derived DC (MoDC) and described reduced CD86 expression or impaired allostimulatory capacity of DC from patients with hepatitis C as compared to those of healthy subjects and patients who cleared HCV after treatment. Other studies demonstrated that MoDC from HCV-infected chimpanzees did not differ from those of uninfected chimpanzees as regards to LPS-induced maturation, cytokine and chemokine production, peptide presentation and T cell stimulation. Normal maturation in response to TNF-alpha normal induction of T cell proliferation and normal responses to influenza A virus have also been reported for MoDC from HCV-infected patient. ? ? When ex vivo isolation techniques became available, the frequency of peripheral blood mDC and pDC was reported to be lower in the blood of HCV-infected patients compared to treatment-recovered patients. However, the function of these ex vivo studied DCs still remains controversial. Whereas some studies describe that pDC of HCV-infected patients produce normal levels of IFN-alpha or TNF-alpha when compared to pDCs of healthy controls, others describe reduced levels. Multiple factors may contribute to these discrepant results. For example, the specific cytokine milieu in a chronic inflammatory situation may affect the function of DC isolated from the blood of patients with chronic hepatitis C. Moreover, altered activation and migration patterns of dendritic cells may contribute to redistribution of specific DC population between blood, lymph nodes and infected liver. Finally, pegylated interferon-a and ribavirin, the standard treatment regimen for chronic HCV infection, are known to affect both number and function of pDC.? ? The recently developed HCV culture system enabled us to test the effect of HCV on DC subpopulations under controlled in vitro conditions. Specifically, we asked whether exposure to HCV affected cytokine production and maturation of ex vivo isolated pDCs and mDCs and in vitro generated MoDCs who had never been exposed to HCV. PBMC and DC subpopulations were exposed to HCVcc in an acute setting, i.e. for up to 42h, and at HCV RNA and core protein concentrations similar to those observed in the blood of acute HCV infection. The study also provided the opportunity to assess the effect of HCV structural proteins in the context of their configuration in infectious viral particles rather than as recombinant proteins as in previous studies. ? ? HCV inhibited TLR9 (CpG and herpes simples virus)-mediated IFN-a production by PBMC and pDC. This inhibitory effect was also observed in response to UV-inactivated, non-infectious HCV, and it was not abrogated by neutralizing antibodies, thus did not appear to require DC infection. Influenza A virus restored maturation and TLR9-mediated IFN-_a production, consistent with the clinical finding that the influenza A virus-specific immune response of HCV-infected patients is not impaired. ? ? In contrast to its effect on pDCs, HCV did not inhibit TLR3- and TLR4-mediated maturation (CD80, CD83 and DR expression) and IL-12, IL-6, IL-10, IFN-g and TNF-a production by mDCs and MoDC, even at the higher concentration. HCV RNA and HCVcore concentrations in these experiments (5x10e7 RNA copies/ml and 30,000 fmol HCVcore/L, respectively) were comparable to those in the sera of HCV-infected patients and to those used in in vitro experiments with recombinant HCVcore (4,500 fmol/L to 22,500 fmol/L), in which an inhibitory effect was observed.? ? In conclusion, HCV inhibited TLR9-induced maturation and IFN-production of pDCs, but not mDCs and MoDCs via a direct interaction that did not require infection.
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