Functional exhaustion of virus specific CD8+ T-cell immunity in fibrotic liver leads to viral persistence

The impact of liver fibrosis or cirrhosis on hepatic immune regulation is unkown. Here we addressed the impact of fibrotic liver diseases on virus-specific immune response. Liver fibrosis and cirrhosis was induced in mice by CCl₄ treatment prior to infection with the lymphocytic choriomeningitis virus (LCMV). On day 8, 10 and 14 post infection viral load and effector functions of virus specific immune cells were determined. While control mice were able to clear the infection after day 8, LCMV persisted in liver and spleen of cirrhotic and fibrotic mice until day 30 post infection. Impaired viral clearance in the cirrhotic mice was accompanied by an impaired effector function of the virus-specific CD8⁺ T cells despite normal cellular expression levels of granzyme B and perforin. In contrast to control mice, virus specific CD8⁺ T-cells from cirrhotic mice show enhanced expression of PD-1, TGF-β and sustained responsiveness to this cytokine through the upregulation of TGFBR-II. Level of IL-10 as well as the number of IL-10⁺ macrophages, were significantly higher in the liver of cirrhotic mice than the control group during LCM virus infection. Interestingly, two days after infection, hepatic NKT cells were completely depleted in cirrhotic and mock-treated mice, but recolonization of the liver by NKT cells was only observed in the control but not the cirrhotic mice, suggesting that NKT cell contributed to anti-viral immunity. Apart from the impaired anti-viral immune response in the acute phase of the infection, cirrhotic mice were not able to mount an efficient memory response as 50% of them succumbed the re-challenge with LCMV. Taken together, these data propose that fibrotic liver diseases alter the microenvironment and the cellular composition of the liver, which lead to functional exhaustion of the virus specific CD8⁺ T -cells during chronic viral infections.

Fig.1

T cell exhaustion - fibrosis - persistent viral infection