Abstract
BACKGROUND & AIMS: Patients with advanced cirrhosis often develop hepatic decompensation, which is accompanied by systemic inflammation and may eventually lead to acute-on-chronic liver failure. One important cause of systemic hyperinflammation is a dysregulated overshooting immune response in ascites in the abdominal cavity. In this study, we analyzed the role of CD8(+) T cells in the ascites immune compartment. METHODS: Peripheral blood and ascites fluid were collected from 50 patients with decompensated cirrhosis. Phenotype and functional responses of CD8(+) T cells were analyzed, and obtained data were compared with each other as well as with healthy controls and patients with compensated cirrhosis. RESULTS: High-dimensional flow cytometry revealed that CD8(+) T cells are abundant in the ascites of patients with cirrhosis and exhibit a chronically activated bystander phenotype with innate-like functions. Indeed, we identified distinct CXCR6(+)CD69(+) clusters of late effector memory CD8(+) T cells that were rarely found in blood and correlated with clinical parameters of disease severity. Moreover, this CD8(+) T-cell population was hyperresponsive to innate cytokines and exhibited cytokine-mediated bystander activation. Interestingly, the Janus kinase (JAK) inhibitor tofacitinib was able to effectively block bystander-activated CXCR6(+)CD69(+) CD8(+) T cells and significantly suppress effector molecule production. CONCLUSIONS: The results indicate that CXCR6(+)CD69(+) CD8(+) T cells in ascites are associated with disease severity and may contribute to inflammation in patients with decompensated cirrhosis, suggesting that targeted inhibition of this immune cell subset may be a viable therapeutic option. IMPACT AND IMPLICATIONS: Patients with advanced cirrhosis often develop hepatic decompensation, which is accompanied by systemic inflammation and eventually leads to acute-on-chronic liver failure. One important cause of systemic hyperinflammation is a dysregulated overshooting immune response in ascites in the abdominal cavity. In this study, we demonstrate that CXCR6(+)CD69(+) CD8(+) T cells are abundant in the ascites of patients with cirrhosis, exhibit a chronically activated bystander phenotype, and correlate with clinical parameters of disease severity. Moreover, we show that the Janus kinase (JAK) inhibitor tofacitinib can effectively block these bystander-activated CXCR6(+)CD69(+) CD8(+) T cells, suggesting that targeted inhibition of this immune cell subset may be a potential therapeutic strategy. CLINICAL TRIAL NUMBER: Prospective registry: INFEKTA (DRKS00010664).