CXCR6+CD69+ CD8+ T cells in ascites are associated with disease severity in patients with cirrhosis

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).