PLoS Pathogens (Mar 2013)

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

  • Anna Schurich,
  • Laura J Pallett,
  • Marcin Lubowiecki,
  • Harsimran D Singh,
  • Upkar S Gill,
  • Patrick T Kennedy,
  • Eleni Nastouli,
  • Sudeep Tanwar,
  • William Rosenberg,
  • Mala K Maini

DOI
https://doi.org/10.1371/journal.ppat.1003208
Journal volume & issue
Vol. 9, no. 3
p. e1003208

Abstract

Read online

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.