T lymphocytes from chronic HCV-infected patients are primed for activation-induced apoptosis and express unique pro-apoptotic gene signature

PLoS One. 2013 Oct 10;8(10):e77008. doi: 10.1371/journal.pone.0077008. eCollection 2013.

Abstract

Although extensive studies have demonstrated the functional impairment of antigen-specific CD4(+) and CD8(+) T-cells during chronic hepatitis C virus (HCV) infection, the functional status of global CD4(+) and CD8(+) T-cells remains unclear. In this report, we recruited 42 long-term (~20 years) treatment-naïve chronic HCV (CHC) patients and 15 healthy donors (HDs) to investigate differences in global CD4(+) and CD8(+) T-cells function. We show that CD4(+) and CD8(+) T-cells from CHC patients underwent increased apoptosis after TCR stimulation. Furthermore, IFN-γ, IL-9 and IP-10 were elevated in CHC patients' plasma and promoted activation-induced T-cells death. Global CD4(+) and CD8(+) T-cells also showed unique transcriptional profiles in the expression of apoptosis-related genes. We identified BCL2, PMAIP1, and CASP1 in CD4(+) T-cells and IER3 and BCL2A1 in CD8(+) T-cells from CHC patients as HCV-specific gene signatures. Importantly, the gene expression patterns of CD4(+) and CD8(+) T-cells from CHC patients differ from those in CD4(+) and CD8(+) T-cells from human immunodeficiency virus type 1 (HIV-1) or hepatitis B virus (HBV) infected individuals. Our results indicate that chronic HCV infection causes a systemic change in cytokine levels that primes T-cells for activation-induced apoptosis. Furthermore, HCV infection programs unique apoptosis-related gene expression profiles in CD4(+) and CD8(+) T-cells, leading to their enhanced activation-induced apoptosis. These results provide novel insights to the pathogenesis of chronic HCV infection.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Apoptosis / immunology*
  • Cytokines / blood
  • Female
  • Gene Expression Regulation / immunology*
  • Hepatitis C, Chronic / blood
  • Hepatitis C, Chronic / immunology*
  • Humans
  • Lymphocyte Activation / genetics*
  • Male
  • Middle Aged
  • T-Lymphocytes / cytology
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism*

Substances

  • Cytokines

Grant support

This study is supported by the National Grand Program on Key Infectious Diseases (No. 2012ZX10002-006, No.2013ZX10004-601, No.2013ZX10002002-006; No.2012ZX10002004-006) from the Ministry of Health of China, the Capital Health Development Research Project (No.2011-2018-04) from Beijing Municipal Bureau of Health and the Institute of Pathogen Biology (No.2009IPB108), Chinese Academy of Medical Science & Peking Union Medical College. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.