Article Text

Download PDFPDF
Original research
Impaired antibacterial response of liver sinusoidal Vγ9+Vδ2+ T cells in patients with chronic liver disease
  1. Min-Seok Rha1,
  2. Ji Won Han1,2,
  3. June-Young Koh1,
  4. Ha Seok Lee1,
  5. Jong Hoon Kim1,3,
  6. Kyungjoo Cho4,
  7. Soon Il Kim5,
  8. Myoung Soo Kim5,
  9. Jae Geun Lee5,
  10. Su-Hyung Park1,
  11. Dong Jin Joo5,6,
  12. Jun Yong Park7,
  13. Eui-Cheol Shin1
  1. 1Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea
  2. 2Division of Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul St. Mary’s Hospital, Seoul, Republic of Korea
  3. 3Department of Dermatology and Cutaneous Biology Research Institute, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
  4. 4Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea
  5. 5Department of Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
  6. 6The Research Institute for Transplantation, Yonsei University College of Medicine, Seoul, Republic of Korea
  7. 7Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
  1. Correspondence to Professor Eui-Cheol Shin, Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea; ecshin{at}kaist.ac.kr; Professor Jun Yong Park, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea; DRPJY{at}yuhs.ac

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 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

Statistics from Altmetric.com

Footnotes

  • 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.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.