Restoration of HBV-specific CD8+ T cell function by PD-1 blockade in inactive carrier patients is linked to T cell differentiation

J Hepatol. 2014 Dec;61(6):1212-9. doi: 10.1016/j.jhep.2014.07.005. Epub 2014 Jul 10.


Background & aims: The upregulation of several inhibitory signalling pathways by exhausted HBV-specific CD8+ T cells in chronic infection is thought to contribute to viral persistence. Blockade of inhibitory receptors to reinvigorate exhausted T cell function is a promising novel therapeutic approach. However, little information is available regarding the relative contribution of individual inhibitory pathways to HBV-specific CD8+ T cell failure and the impact of inhibitory receptor blockade on restoration of T cell function in chronic HBV.

Methods: 98 HLA-A2+ chronically infected patients were analysed ex vivo for HBV-specific CD8+ T cell responses, the expression of multiple inhibitory receptors and T cell differentiation markers. The effects of inhibitory receptor blockade targeting PD-1, 2B4, Tim-3, CTLA-4, and BTLA were assessed in vitro.

Results: In our cohort, ex vivo HBV-specific CD8+ T cell responses were identified preferentially in HBeAg patients with low ALT and low viral load (inactive carriers). We observed a clear hierarchy of inhibitory receptor expression dominated by PD-1. The response to inhibitory receptor blockade was heterogeneous. Compared to the blockade of other inhibitory receptors, blockade of the PD-1 pathway resulted in the strongest increase in function. Of note, a positive effect of PD-1 blockade was linked to intermediate T cell differentiation.

Conclusions: Despite the expression of multiple inhibitory receptors by HBV-specific CD8+ T cells, expression and response to blockade was dominated by PD-1. However, PD-1 expression did not predict response to blockade. Rather, response to blockade was associated with intermediate T cell differentiation. These findings have important implications for our understanding of inhibitory receptor blockade as a novel therapeutic strategy.

Keywords: HBV; Inactive carrier; Inhibitory receptors; PD-1; T cell differentiation; T cell exhaustion; Virus-specific CD8+ T cells.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Alanine Transaminase / metabolism
  • Antibodies / pharmacology
  • CD8-Positive T-Lymphocytes / drug effects
  • CD8-Positive T-Lymphocytes / physiology*
  • Cell Differentiation / physiology*
  • Cells, Cultured
  • Female
  • Hepatitis B / metabolism
  • Hepatitis B / pathology
  • Hepatitis B / physiopathology*
  • Hepatitis B e Antigens / blood
  • Hepatitis B virus / physiology*
  • Humans
  • Male
  • Middle Aged
  • Programmed Cell Death 1 Receptor / antagonists & inhibitors*
  • Programmed Cell Death 1 Receptor / drug effects
  • Programmed Cell Death 1 Receptor / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Viral Load / physiology


  • Antibodies
  • Hepatitis B e Antigens
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor
  • Alanine Transaminase