Innate-like bystander-activated CD38+HLA-DR+CD8+T cells play a pathogenic role in patients with chronic hepatitis C

Chien Hao Huang, Jian He Fan, Wen Juei Jeng, Shu Ting Chang, Chan Keng Yang, Wei Teng, Tsung Han Wu, Yi Chung Hsieh, Wei Ting Chen, Yi Cheng Chen, I. Shyan Sheen, Yung Chang Lin*, Chun Yen Lin*

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

10 Scopus citations

Abstract

Background and Aims: HCV-specific T cells are few and exhausted in patients with chronic hepatitis C (CHC). Whether these T cells are responsible for the liver damage and fibrosis is still debated. However, cluster of differentiation 38–positive (CD38+) human leukocyte antigen DR–positive (HLA-DR+) CD8+ T cells are regarded as bystander CD8+ T cells that cause liver injury in acute hepatitis. We propose that these innate CD8+ T cells play a pathogenic role in CHC. Methods: Lymphocytes from peripheral blood were obtained from 108 patients with CHC and 43 healthy subjects. Immunophenotyping, functional assays, T-cell receptor (TCR) repertoire, and cytotoxic assay of CD38+HLA-DR+CD8+ T cells were studied. Results: The percentage of CD38+HLA-DR+CD8+ T cells increased significantly in patients with CHC. These cells expressed higher levels of effector memory and proinflammatory chemokine molecules and showed higher interferon-γ production than CD38HLA-DR CD8 T cells. They were largely composed of non-HCV-specific CD8+ T cells as assessed by HLA-A2-restricted pentamers and next-generation sequencing analysis of the TCR repertoire. In addition, these CD38+HLA-DR+CD8+ T cells had strong cytotoxicity, which could be inhibited by anti–DNAX accessory molecule 1, anti–NKG2 family member D, and anti–natural killer NKp30 antibodies. Lastly, the percentage of CD38+HLA-DR+CD8+ T cells was significantly associated with liver injury and fibrosis and decreased significantly along with serum alanine aminotransferase normalization after successful direct-acting antiviral treatment. Conclusions: The TCR-independent, cytokine-responsive bystander CD38+HLA-DR+CD8+ T cells are strongly cytotoxic and play a pathogenic role in patients with CHC.

Original languageEnglish
Pages (from-to)803-818
Number of pages16
JournalHepatology
Volume76
Issue number3
DOIs
StatePublished - 09 2022

Bibliographical note

Publisher Copyright:
© 2022 American Association for the Study of Liver Diseases.

Fingerprint

Dive into the research topics of 'Innate-like bystander-activated CD38+HLA-DR+CD8+T cells play a pathogenic role in patients with chronic hepatitis C'. Together they form a unique fingerprint.

Cite this