Immunomodulatory signaling by HCV core protein through the complement receptor,gC1qR, on antigen-presenting cells

Innate immunity is activated very rapidly following microbial insult and is critical to the development of adaptive immune responses. Dendritic cells (DCs) in particular are crucial for the activation of pathogen-specific T lymphocytes. Specifically, TLR ligand-induced production of IL-12 by DCs is important for T cell-mediated IFN-gamma production and antiviral activity.; The central role of IL-12 in both the resolution of infection and the induction of autoimmune disease implies that microbe- and host-mediated mechanisms must exist to regulate production of IL-12. In fact, the putative C1q receptor, gC1qR, has been implicated in the specific suppression of TLR-induced IL-12 production by DCs. This receptor interacts with a number of bacterially- and virally-encoded proteins, including hepatitis C virus (HCV) core. Given the high rate of persistent infection with HCV, due in part to defects in T cell-mediated IFN-gamma production, the association of core protein with gC1gR is likely to play a role in dysregulation of host immunity and establishment of chronic infection.; To examine the impact of HCV core/gC1qR interaction-induced signaling on DC activation and T cell stimulatory capacity, we first generated monoclonal antibodies specific for gC1gR. Ligation of gC1gR on human monocytes and DCs results in a potent, albeit specific, suppression of TLR-stimulated production of IL-12. Of interest, TLR-induced expression of co-stimulatory receptors and additional cytokines was completely normal. Importantly, suppression of IL-12 secretion by anti-gC1gR antibody was mediated through activation of the P13K pathway. Following treatment with anti-gC1qR antibody or HCV core protein, DCs displayed a reduced ability to induce IFN-gamma production and TH1 differentiation of CD4+ T cells. Moreover, the phenotype of these T cells was skewed in favor of increased TH2 cytokine secretion (e.g. IL-4). The inhibition of TH1 cytokine induction by anti-gC1gR antibody- or core-treated DCs was completely abrogated following restoration of IL-12 levels in the DC/T cell co-culture. These results indicate that gC1gR plays a potentially crucial role in the negative regulation of IL-12 production and subsequent differentiation of TH1 immune responses. Therefore, gC1qR-dependent immune regulation may be subverted during the establishment and maintenance of chronic HCV infection.