Abstract

The liver possesses distinct tolerogenic properties because of its role in the apoptosis and removal of activated CD8⁺ T-cells and also because of its ability to successfully maintain allogenic liver transplants without immunosuppression. The central immune mediators required for the generation of effective immune responses in the liver environment have not been fully elucidated. In my thesis work, we report that the site of initial T-cell activation determines the balance between T-cell tolerance and immunity in the liver. Our work demonstrates that the liver can indeed support effector CD8 ⁺ T-cells during adenovirus infection when the T-cells are primed in secondary lymphoid tissues. In contrast, when viral antigen is delivered predominantly to the liver during intravenous (IV) adenovirus infection intrahepatic CD8⁺ T-cells are significantly impaired in their ability to produce inflammatory cytokines and lyse target T-cells. Additionally, CD8 ⁺ T-cells generated in the liver during IV adenovirus infection express elevated levels of PD-1, downregulate TCR, and undergo enhanced apoptosis as compared to that in subcutaneous (SubQ) adenovirus infection. Notably, lower doses of adenovirus infection does not rescue the impaired effector function of intrahepatic CD8⁺ T-cell responses, suggesting that the defective antiviral CD8⁺ T-cell responses observed during IV adenovirus infection are not due to overwhelming levels of viral antigen in the liver. Instead, intrahepatic antigen recognition limits the generation of potent anti-viral responses at both priming and effector stages of the T-cell response and accounts for the dysfunctional CD8⁺ T-cell response that is observed during IV adenovirus infection. Furthermore, the expression of HCV core protein in the livers of transgenic mice during adenovirus infection enhances the impairment of intrahepatic CD8⁺ T-cells responses and leads to antigen persistence. The expression of PD-1 by antigen-specific CD8⁺ T-cells and B7-H1 by intrahepatic DCs is elevated in core expressing mice during IV adenovirus infection. Importantly, blockade of the PD-1/B7-H1 inhibitory pathway significantly improves effector CD8⁺ T-cell responses in the liver and enhances adenovirus clearance. Collectively, these results show that the PD-1/B7-H1 inhibitory pathway plays a central role in core-mediated impairment of intrahepatic anti-viral responses.