The Third Signal Cytokine IL-12 Rescues the Anti-Viral Function of Exhausted HBV-Specific CD8 T Cells

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. © 2013 schurich et al.