Impaired antibacterial response of liver sinusoidal V gamma 9(+)V delta 2(+) T cells in patients with chronic liver disease

Abstract

Objective The liver acts as a frontline barrier against diverse gut-derived pathogens, and the sinusoid is the primary site of liver immune surveillance. However, little is known about liver sinusoidal immune cells in the context of chronic liver disease (CLD). Here, we investigated the antibacterial capacity of liver sinusoidal gamma delta T cells in patients with various CLDs. Design We analysed the frequency, phenotype and functions of human liver sinusoidal gamma delta T cells from healthy donors and recipients with CLD, including HBV-related CLD (liver cirrhosis (LC) and/or hepatocellular carcinoma (HCC)), alcoholic LC and LC or HCC of other aetiologies, by flow cytometry and RNA-sequencing using liver perfusates obtained during living donor liver transplantation. We also measured the plasma levels of D-lactate and bacterial endotoxin to evaluate bacterial translocation. Results The frequency of liver sinusoidal V gamma 9(+)V delta 2(+) T cells was reduced in patients with CLD. Immunophenotypic and transcriptomic analyses revealed that liver sinusoidal V gamma 9(+)V delta 2(+) T cells from patients with CLD were persistently activated and pro-apoptotic. In addition, liver sinusoidal V gamma 9(+)V delta 2(+) T cells from patients with CLD showed significantly decreased interferon (IFN)-gamma production following stimulation with bacterial metabolites and Escherichia coli. The antibacterial IFN-gamma response of liver sinusoidal V gamma 9(+)V delta 2(+) T cells significantly correlated with liver function, and inversely correlated with the plasma level of D-lactate in patients with CLD. Repetitive in vitro stimulation with E. coli induced activation, apoptosis and functional impairment of liver sinusoidal V gamma 9(+)V delta 2(+) T cells. Conclusion Liver sinusoidal V gamma 9(+)V delta 2(+) T cells are functionally impaired in patients with CLD. Bacterial translocation and decreasing liver functions are associated with functional impairment of liver sinusoidal V gamma 9(+)V delta 2(+) T cells.