Libo Tang1, Chengcong Chen1, Xueping Gao1,2, Wanyue Zhang1, Xin Yan1,3, Yang Zhou1, Ling Guo1, Xinchun Zheng1, Weibin Wang1, Fuqiang Yang4, Guangze Liu4, Jian Sun1, Jinlin Hou1, Yongyin Li1. 1. State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China. 2. Department of Hepatology, Huizhou Municipal Central Hospital, Guangzhou, China. 3. Department of Infectious Diseases and Hepatology Unit, Huadu District People's Hospital of Guangzhou, Guangzhou, China. 4. Liver Disease Research Center, 458th Hospital of the Chinese People's Liberation Army, Guangzhou, China.
Abstract
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-γ, 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.
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-γ, 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 HBVmouse 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 mouseIL-21 in an HBVmouse 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.