Hepatitis B Virus--Specific and Global T-Cell Dysfunction in Chronic Hepatitis B

Gastroenterology. 2016 Mar;150(3):684-695.e5. doi: 10.1053/j.gastro.2015.11.050. Epub 2015 Dec 10.

Abstract

Background & aims: T cells play a critical role in viral infection. We examined whether T-cell effector and regulatory responses can define clinical stages of chronic hepatitis B (CHB).

Methods: We enrolled 200 adults with CHB who participated in the National Institutes of Health-supported Hepatitis B Research Network from 2011 through 2013 and 20 uninfected individuals (controls). Peripheral blood lymphocytes from these subjects were analyzed for T-cell responses (proliferation and production of interferon gamma and interleukin 10) to overlapping hepatitis B virus (HBV) peptides (preS, S, preC, core, and reverse transcriptase), influenza matrix peptides, and lipopolysaccharide. T-cell expression of regulatory markers FOXP3, programmed death-1, and cytotoxic T lymphocyte-associated antigen-4 was examined by flow cytometry. Immune measures were compared with clinical parameters, including physician-defined immune-active, immune-tolerant, or inactive CHB phenotypes, in a blinded fashion.

Results: Compared with controls, patients with CHB had weak T-cell proliferative, interferon gamma, and interleukin 10 responses to HBV, with increased frequency of circulating FOXP3(+)CD127(-) regulatory T cells and CD4(+) T-cell expression of programmed death-1 and cytotoxic T lymphocyte-associated antigen-4. T-cell measures did not clearly distinguish between clinical CHB phenotypes, although the HBV core-specific T-cell response was weaker in hepatitis B e antigen (HBeAg)(+) than HBeAg(-) patients (percent responders: 3% vs 23%; P = .00008). Although in vitro blockade of programmed death-1 or cytotoxic T lymphocyte-associated antigen-4 increased T-cell responses to HBV, the effect was weaker in HBeAg(+) than HBeAg(-) patients. Furthermore, T-cell responses to influenza and lipopolysaccharide were weaker in CHB patients than controls.

Conclusions: HBV persists with virus-specific and global T-cell dysfunction mediated by multiple regulatory mechanisms, including circulating HBeAg, but without distinct T-cell-based immune signatures for clinical phenotypes. These findings suggest additional T-cell-independent or regulatory mechanisms of CHB pathogenesis that warrant further investigation.

Keywords: HBRN; IFN; IL10; LPS.

Publication types

  • Multicenter Study
  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adult
  • Case-Control Studies
  • Cell Proliferation
  • Cells, Cultured
  • Female
  • Hepatitis B e Antigens / blood
  • Hepatitis B virus / immunology
  • Hepatitis B virus / pathogenicity*
  • Hepatitis B, Chronic / blood
  • Hepatitis B, Chronic / immunology
  • Hepatitis B, Chronic / virology*
  • Host-Pathogen Interactions
  • Humans
  • Interferon-gamma / immunology
  • Interferon-gamma / metabolism
  • Interleukin-10 / immunology
  • Interleukin-10 / metabolism
  • Lipopolysaccharides / pharmacology
  • Lymphocyte Activation* / drug effects
  • Male
  • Orthomyxoviridae / immunology
  • Phenotype
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism
  • T-Lymphocytes / virology*
  • T-Lymphocytes, Regulatory / immunology
  • T-Lymphocytes, Regulatory / virology
  • United States

Substances

  • Hepatitis B e Antigens
  • IFNG protein, human
  • IL10 protein, human
  • Lipopolysaccharides
  • Interleukin-10
  • Interferon-gamma

Grant support