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DENDRITIC CELLS CAN KILL T CELLS DURING CHRONIC HCV INFECTION
L Zhao, L TyrrellDepartment of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta
Aims: The function of dendritic cells (DCs) has been well-established as the most potent antigen-presenting cells that initiate and maintain specific immune responses. However, there have been few reports about whether human DCs may induce immune tolerance. The aim of this study was to determine if human DCs induce immune tolerance during HCV infection.
Methods: DCs from chronic HCV-infected patients and healthy controls were co-cultured with CD4+ T cells. The apoptosis rate was determined by terminal deoxynucleotidyl transferase biotin-dUTP nick-end labeling (TUNEL) staining and flow cytometry analysis.
Results: DCs from chonic HCV-infected patients induced T cell apoptosis. Furthermore, DCs from chonic HCV-infected patients expressed up-regulated levels of inhibitory ligands, Fas ligand (FasL) and ligand 2 of PD-1 (PD-L2), compared to DCs from healthy controls.
To determine if the killing effect of DCs on T cells was mediated by the interactions between FasL/Fas and PD-L2/PD-1,antibodies against these inhibitory ligands and their corresponding receptors were applied to the co-culture system. Antibodies against FasL, PD-L2 and PD-1 all partially blocked the killing effect, while isotype control antibodies did not. Interestingly, antibody against T cell receptor also partially blocked the killing. When DCs from patients were co-cultured with T cells while they were separated by polycarbonate membrane, the killing effect was almost completely blocked. These results demonstrated that killing effect of DCs on T cells required cell-cell contact and it was primarily mediated by the interactions between FasL/Fas and PD-L2/PD-1.
A well-established NF-kappaB inhibitor, caffeic acid phenethyl ester (CAPE), was used to determine if there is a correlation of NF-kappaB activity with the killing effects of DCs. Upon CAPE dministration, DCs from healthy controls demonstrated up-regulated killing effect. These attributes of healthy DCs treated with CAPE are similar to the DCs from chronic HCV-infected patients, which prove that HCV inhibits the NF-kappaB activity of DCs and switch their role from an immunogenic function to a tolerogenic function.
Conclusions: This study demonstrates a novel mechanism of HCV immune evasion. HCV induces DCs to switch to a tolerogenic function and leads to T cell apoptosis. The killing effect of patient DCs is mediated by their increased expression of inhibitory ligands, FasL and PD-L2. Furthermore, the switch of DCs from an immunogenic function to a tolerogenic function is manipulated by inhibiting their NF-kappaB activity. This study further demonstrates the function of DCs in immune response, which can be immunogenic or tolerogenic. By demonstrating HCV affects DCs to evade human immune response, this study provides clues to devise new strategies to recover the immunogenic function of DCs and to clear HCV infection.