Ascites-resident innate-like CD8⁺T cells contribute to inflammation and disease pathogenesis in patients with liver cirrhosis

 

Introduction Patients 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.

Aims In this study we aim to analyze the role of CD8⁺T cells in the ascites immune compartment using high-dimensional flow cytometry.

Methods Matched peripheral blood and ascites fluid were collected from 49 patients with decompensated liver 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.

Results High-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 ascites-specific (CXCR6⁺CD69⁺) clusters of late effector-memory CD8⁺T cells that were rarely found in blood and correlated with clinical parameters of disease severity (p=0.01 for bilirubin, p=0.004 for International Normalized Ratio). Moreover, this CD8⁺T cell population was hyperresponsive to innate cytokines and exhibited cytokine-mediated bystander activation. Interestingly, the JAK inhibitor tofacitinib was able to effectively block bystander-activated CXCR6⁺CD69⁺CD8⁺T cells and significantly suppress effector molecule production.

Conclusions These results indicate that CD8⁺bystander T cells in ascites contribute to inflammation and disease pathogenesis in patients with decompensated liver cirrhosis, and JAK inhibitors could be a conceivable therapeutic option to inhibit hyperinflammation and ACLF.

Publication History

Article published online:
28 August 2023

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