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- Title
The Third Signal Cytokine IL-12 Rescues the Anti-Viral Function of Exhausted HBV-Specific CD8 T Cells.
- Authors
Schurich, Anna; Pallett, Laura J.; Lubowiecki, Marcin; Singh, Harsimran D.; Gill, Upkar S.; Kennedy, Patrick T.; Nastouli, Eleni; Tanwar, Sudeep; Rosenberg, William; Maini, Mala K.
- Abstract
Optimal immune activation of naïve CD8 T cells requires signal 1 mediated by the T cell receptor, signal 2 mediated by costimulation 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 downregulation 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 proapoptotic 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.
- Subjects
CYTOKINES; T cell receptors; CYTOMEGALOVIRUSES; HEPATITIS B virus; ANTIGENS; ANTIBODY-dependent cell cytotoxicity; VIRUS diseases; PATIENTS
- Publication
PLoS Pathogens, 2013, Vol 9, Issue 3, p1
- ISSN
1553-7366
- Publication type
Article
- DOI
10.1371/journal.ppat.1003208