The Third Signal Cytokine Interleukin 12 Rather Than Immune Checkpoint Inhibitors Contributes to the Functional Restoration of Hepatitis D Virus-Specific T Cells

J Infect Dis. 2017 Jan 1;215(1):139-149. doi: 10.1093/infdis/jiw514. Epub 2016 Oct 31.


Background: Hepatitis D virus (HDV) infection affects 15-20 million individuals worldwide and causes severely progressive hepatitis. It is unknown to what extent cellular immune responses contribute to liver disease and control of viral replication in HDV infection.

Methods: Immune cell frequencies and phenotypes were determined in 49 HDV-infected patients, 25 individuals with hepatitis B virus monoinfection and 18 healthy controls. T-cell proliferative and cytokine-producing capacities were analyzed by stimulation with overlapping peptides spanning the large HDV antigen. To restore T-cell responses, blocking antibodies (anti-cytotoxic T-lymphocyte antigen 4, anti-programmed death ligand 1) or proinflammatory cytokines (interleukin [IL] 12) were used.

Results: Immune cell frequencies and phenotypes did not vary between the groups. Exclusively, the senescence marker CD57 was significantly up-regulated in CD8+ T cells from patients with hepatitis delta. HDV-specific T-cell proliferation and cytokine production were weak and could only partly be rescued by blockade of the programmed death 1 pathway. However, a more robust and consistent increase in HDV-specific CD4+ and CD8+ T-cell responses was evident when the third signal cytokine IL-12 was added, which also affected cytomegalovirus- and Epstein-Barr virus-specific T cells.

Conclusions: This investigation of virus-specific T-cell immunity in patients with HDV infection, the largest to date, revealed premature aging of immune cells and impaired T-cell functionality. This could be restored by blocking inhibitory pathways and, in particular, by supplementing with IL-12.

Keywords: CD4 T cells; CD57; CD8 T cells; CTLA-4; IL-12; PD-1.

MeSH terms

  • Adult
  • Aged
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / metabolism
  • CD4-Positive T-Lymphocytes / virology
  • CD57 Antigens / immunology
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / metabolism
  • CD8-Positive T-Lymphocytes / virology
  • CTLA-4 Antigen / immunology
  • Cytokines / biosynthesis
  • Cytomegalovirus / immunology
  • Female
  • Hepatitis D, Chronic / immunology*
  • Hepatitis D, Chronic / virology
  • Hepatitis Delta Virus / chemistry
  • Hepatitis Delta Virus / immunology*
  • Herpesvirus 4, Human / immunology
  • Humans
  • Interleukin-12 / administration & dosage*
  • Interleukin-12 / immunology*
  • Lymphocyte Activation*
  • Male
  • Middle Aged
  • Programmed Cell Death 1 Receptor / immunology
  • T-Box Domain Proteins / metabolism
  • Virus Replication


  • CD57 Antigens
  • CTLA-4 Antigen
  • CTLA4 protein, human
  • Cytokines
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor
  • T-Box Domain Proteins
  • T-box transcription factor TBX21
  • Interleukin-12