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

Abstract

Background & AimsPatients with advanced liver cirrhosis often develop hepatic decompensation, which is accompanied by systemic inflammation and may eventually lead to acute-on-chronic liver failure (ACLF). 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.MethodsPeripheral 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 to each other as well as to healthy controls and compensated cirrhosis patients.ResultsHigh-dimensional flow cytometry revealed that CD8+ T cells are abundant in the ascites of patients with liver 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.ConclusionsThese results indicate that CXCR6+CD69+ CD8+ T cells in ascites are associated with disease severity and may contribute to inflammation in patients with decompensated liver cirrhosis, suggesting that targeted inhibition of this immune cell subset may be a viable therapeutic option.Impact and implicationsPatients with advanced liver cirrhosis often develop hepatic decompensation, which is accompanied by systemic inflammation and eventually lead to acute-on-chronic liver failure (ACLF). One important cause of systemic hyperinflammation is a dysregulated overshooting immune response in ascites in the abdominal cavity. Here, we demonstrate that CXCR6+CD69+ CD8+ T cells are abundant in the ascites of patients with liver 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 is able to 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 numberProspective registry: INFEKTA (DRKS00010664)