Abstract
Immune dysfunction in liver disease contributes to significant morbidities, depending on liver damage severity and aetiology. We previously reported long-lasting generalized CD8 T cell hyperfunction in chronic HCV infection with advanced fibrosis, yet its separation from viral and fibrosis-driven effects, as well as clinical outcomes of advanced fibrosis, remains unclear. In a murine model of carbon tetrachloride-induced progressive liver fibrosis, advanced fibrosis was observed by 12 weeks, with pathologies similar to those of human chronic HCV infection. Blood-circulating CD8 T cells showed IFN-γ and granzyme B (GrB) hyperfunction in response to anti-CD3/28 stimulation, as well as impaired responses to ectopic tumour challenge and anti-PD-1/CTLA-4 immunotherapy. Hyperfunction and impaired tumour responses were retained despite liver insult cessation. In a 45% HFD model, which induced steatosis and minimal fibrosis, IFN-γ and GrB hyperfunction was also observed in blood-circulating CD8 T cells. This study highlights a prolonged systemic CD8 T cell dysfunction acquired during progressive liver disease, associated with impaired antitumour and immunotherapy responses. These mirror the bulk CD8 T cell dysfunction observed in advanced liver diseases in humans, suggesting that these models could be valuable for future mechanistic studies aimed at identifying targets to help improve clinical outcomes in chronic liver disease.