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 γδ T cells in patients with various CLDs.
Design We analysed the frequency, phenotype and functions of human liver sinusoidal γδ 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 Vγ9+Vδ2+ T cells was reduced in patients with CLD. Immunophenotypic and transcriptomic analyses revealed that liver sinusoidal Vγ9+Vδ2+ T cells from patients with CLD were persistently activated and pro-apoptotic. In addition, liver sinusoidal Vγ9+Vδ2+ T cells from patients with CLD showed significantly decreased interferon (IFN)-γ production following stimulation with bacterial metabolites and Escherichia coli. The antibacterial IFN-γ response of liver sinusoidal Vγ9+Vδ2+ 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 Vγ9+Vδ2+ T cells.
Conclusion Liver sinusoidal Vγ9+Vδ2+ T cells are functionally impaired in patients with CLD. Bacterial translocation and decreasing liver functions are associated with functional impairment of liver sinusoidal Vγ9+Vδ2+ T cells.
- bacterial translocation
- chronic liver disease
- gamma-delta cells
- liver immunology
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JYP and E-CS are joint senior authors.
Contributors M-SR, JYP and E-CS designed the study. M-SR, JWH, JYK, HSL, JHK, KC, SK, MSK, JGL, DJJ, JYP and E-CS were involved in data acquisition. M-SR, S-HP, JYP and E-CS were involved in data analysis and interpretation. M-SR, JYP and E-CS wrote the manuscript.
Funding This work was supported by Samsung Science and Technology Foundation under Project Number SSTF-BA1402-51.
Competing interests None declared.
Patient consent for publication Not required.
Ethics approval This study was reviewed and approved by the institutional review board of Severance Hospital (Seoul, Republic of Korea; 4-2014-0261 and 4-2018-0777) and conducted according to the principles of the Declaration of Helsinki. Informed consent was obtained from all donors and patients.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement RNA sequencing data are deposited in the Gene Expression Omnibus database under accession number GSE164266. All other data relevant to the study are included in the article or uploaded as online supplementary information.
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