Abstract
T-cell immunoglobulin domain and mucin domain-containing molecule-3 (Tim-3) was up-regulated on viral specific T cells and contributed to T cells exhaustion during chronic hepatitis B virus (HBV) infection. However, modulation of Tim-3 expression was still not fully elucidated. To evaluate the potential viral and inflammatory factors involved in the inductor of Tim-3 expression on T cells, 76 patients with chronic HBV infection (including 40 chronic hepatitis B [CHB] and 36 asymptomatic HBV carriers [AsC]) and 40 of normal controls (NCs) were enrolled in this study. Tim-3 expressions on CD4+ and CD8+ T cells were assessed in response to HBV-encoding antigens, HBV peptide pools, and common γ-chain (γc) cytokines stimulation by flow cytometry. HBV peptides and anti-CD3/CD28 directly induced Tim-3 expression on T cells. γc cytokines also drive Tim-3 up-regulations on both CD4+ and CD8+ T cells in patients with chronic HBV infection. However, γc cytokines did not enhance the Tim-3 inductions by either anti-CD3/CD28 or HBV peptides stimulation. Furthermore, γc cytokines-mediated Tim-3 induction could not be abrogated by γc cytokine receptor-neutralizing antibodies. The current results suggested that elevation of Tim-3 expression on T cells could be regulated by both antigen-dependent and -independent manner in patients with chronic HBV infection. The role of γc cytokines in modulation of inhibitory pathway might be evaluated as immunotherapies in humans.
Highlights
Hepatitis B virus (HBV) leads to a chronic infection in 10% of adults and 90% of children, which results in 1∼2 million people died annually worldwide due to HBV-related end-stage liver diseases, such as liver cirrhosis, hepatic failure, and hepatocellular carcinoma (Hoofnagle et al, 2007; Lok and McMahon, 2009; Lu and Zhuang, 2009)
Mixture of Hepatitis B surface antigen (HBsAg), hepatitis B e antigen (HBeAg), and HBcAg did not upregulate the expression of T-cell immunoglobulin domain and mucin domain-containing molecule-3 (Tim-3) on T cells in either asymptomatic HBV carriers (AsC) (P > 0.05, Figures 1D,E) and chronic hepatitis B (CHB) (P > 0.05, Figures 1F,G)
We provided the evidence to further insight into the mechanism of Tim-3 regulation in chronic HBV infection
Summary
Hepatitis B virus (HBV) leads to a chronic infection in 10% of adults and 90% of children, which results in 1∼2 million people died annually worldwide due to HBV-related end-stage liver diseases, such as liver cirrhosis, hepatic failure, and hepatocellular carcinoma (Hoofnagle et al, 2007; Lok and McMahon, 2009; Lu and Zhuang, 2009). Tim-3 Modulation in HBV Infection specific CD4+ and CD8+ T cells response is pivotal for controlling acute hepatitis B virus infection (Rehermann et al, 1995; Bertoletti and Naoumov, 2003). The inability of T cells results in the collapse of HBV-specific adaptive immune response in chronic hepatitis B (CHB) (Bertoletti and Naoumov, 2003; Chisari et al, 2010). Chronic HBV infection is not directly associated with liver inflammation, which is the results of interaction between virus and host immune response. Immune tolerant phase is characterized by high HBV DNA and normal ALT, which showed as asymmetric HBV carriers, while CHB patients reveal acute increase in ALT and continuing hepatic injury (Lian et al, 2014). The precise mechanisms corresponding to T cells tolerance and immune evasion in chronic HBV infection are still not fully elucidated
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