Interleukin 21 Reinvigorates the Antiviral Activity of Hepatitis B Virus (HBV)-Specific CD8+ T Cells in Chronic HBV Infection

Background Strategies that target functional recovery of exhausted hepatitis B virus (HBV)-specific CD8(+) T cells are beneficial for viral control, but the potential for interleukin 21 (IL-21) to rescue CD8(+) T-cell function is not well understood. Methods We investigated the effect of IL-21 on CD8(+) T-cell responses by phenotypic and functional analysis of samples from patients with chronic HBV infection and a mouse model with HBV expression. Results IL-21 promoted the proliferative capacity of HBV-specific CD8(+) T cells and down-regulated expression of the inhibitory receptors programmed death 1 and T-cell immunoglobulin domain and mucin domain 3. Additionally, IL-21 boosted the production of interferon-, granzyme B, and CD107a in HBV-specific CD8(+) T cells and enhanced the cytolytic activity of CD8(+) T cells against HepG2.2.15 cells. Notably, an HBV mouse model established from IL-21 receptor knockout mice showed significantly decreased frequency of HBV-specific CD8(+) T cells and increased levels of serum hepatitis B surface antigen (HBsAg). Meanwhile, administration of recombinant mouse IL-21 in an HBV mouse model established from wild-type mice resulted in enhanced functionality of HBV-specific CD8(+) T cells and accelerated HBsAg clearance. Conclusions IL-21 enhances the antiviral effect of HBV-specific CD8(+) T cells, suggesting that it may contribute to viral clearance in chronic HBV infection. Interleukin-21 is highly expressed in chronic hepatitis B patients with favorable treatment response, and it can reinvigorate antiviral activity of hepatitis B virus (HBV)-specific CD8(+) T cells by down-regulating expression of inhibitory receptors and boosting production of antiviral cytokines.