The third signal cytokine IL-12 rescues the anti-viral function of exhausted HBV-specific CD8 T cells

PLoS Pathog. 2013 Mar;9(3):e1003208. doi: 10.1371/journal.ppat.1003208. Epub 2013 Mar 14.


Optimal immune activation of naïve CD8 T cells requires signal 1 mediated by the T cell receptor, signal 2 mediated by co-stimulation and signal 3 provided by pro-inflammatory cytokines. However, the potential for signal 3 cytokines to rescue anti-viral responses in functionally exhausted T cells has not been defined. We investigated the effect of using third signal cytokines IL-12 or IFN-α to rescue the exhausted CD8 T cell response characteristic of patients persistently infected with hepatitis B virus (HBV). We found that IL-12, but not IFN-α, potently augmented the capacity of HBV-specific CD8 T cells to produce effector cytokines upon stimulation by cognate antigen. Functional recovery mediated by IL-12 was accompanied by down-modulation of the hallmark inhibitory receptor PD-1 and an increase in the transcription factor T-bet. PD-1 down-regulation was observed in HBV but not CMV-specific T cells, in line with our finding that the highly functional CMV response was not further enhanced by IL-12. IL-12 enhanced a number of characteristics of HBV-specific T cells important for viral control: cytotoxicity, polyfunctionality and multispecificity. Furthermore, IL-12 significantly decreased the pro-apoptotic molecule Bim, which is capable of mediating premature attrition of HBV-specific CD8 T cells. Combining IL-12 with blockade of the PD-1 pathway further increased CD8 functionality in the majority of patients. These data provide new insights into the distinct signalling requirements of exhausted T cells and the potential to recover responses optimised to control persistent viral infections.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antiviral Agents / immunology
  • Antiviral Agents / metabolism
  • Apoptosis Regulatory Proteins / metabolism
  • Bcl-2-Like Protein 11
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / metabolism
  • Cytokines / immunology
  • Cytokines / metabolism
  • Cytomegalovirus / immunology
  • Cytomegalovirus Infections / immunology
  • Cytomegalovirus Infections / metabolism
  • Cytomegalovirus Infections / virology
  • Down-Regulation
  • Gene Expression Regulation, Viral
  • Hepatitis B virus / immunology*
  • Hepatitis B, Chronic / immunology*
  • Hepatitis B, Chronic / metabolism
  • Hepatitis B, Chronic / virology
  • Humans
  • Interferon-alpha / immunology
  • Interferon-alpha / metabolism
  • Interleukin-12 / immunology*
  • Interleukin-12 / metabolism
  • Lymphocyte Activation
  • Membrane Proteins / metabolism
  • Programmed Cell Death 1 Receptor / metabolism
  • Proto-Oncogene Proteins / metabolism
  • Signal Transduction / immunology*
  • Species Specificity


  • Antiviral Agents
  • Apoptosis Regulatory Proteins
  • BCL2L11 protein, human
  • Bcl-2-Like Protein 11
  • Cytokines
  • Interferon-alpha
  • Membrane Proteins
  • Programmed Cell Death 1 Receptor
  • Proto-Oncogene Proteins
  • Interleukin-12