Abstract
Background and objectiveT-cell immunoglobulin domain and mucin domain-containing molecule-3 (Tim-3) represents a novel mechanism of T-cell dysfunction in chronic viral diseases. However, the role of Tim-3 in the pathogenesis of chronic hepatitis B (CHB) is not well understood. We investigated Tim-3 expression on peripheral T cell subsets and analyzed the relationship between Tim-3 expression and disease progression in HBV infection.Methodsperipheral blood samples were obtained from CHB patients (n = 40), including 23 patients with moderate CHB [MCHB] and 17 with severe CHB [SCHB]. Control samples were obtained from nine acute hepatitis B patients (AHB) and 26 age-matched healthy subjects. The expression of Tim-3 on T cells was determined by flow cytometry.ResultsTim-3 expression was elevated on peripheral CD4+ and CD8+ T cells from AHB and CHB patients compared to those from healthy controls. The percentage of Tim-3+ T cells was further increased in SCHB patients relative to MCHB patients and showed a positive correlation with conventional markers for liver injury (alanine aminotransferase (ALT), aspartate transaminase (AST), total bilirubin (TB) and international normalized ratio (INR) level). The frequency of Tim-3-expressing T cells was negatively correlated with T-bet mRNA expression and plasma interferon-gamma (INF-gamma) levels. Further, Tim-3 expression on CD4+ or CD8+ T cells was reduced in CHB patients with disease remission after antiviral treatment and in AHB patients during the convalescence phase.ConclusionsOur results suggest that over-expression of Tim-3 is involved in disease progression of CHB and that Tim-3 may participate in skewing of Th1/Tc1 response, which contributes to persistency of HBV infection.
Highlights
Chronic hepatitis B virus (HBV) infection is a global health burden with 350-400 million people infected worldwide
An elevated frequency of T-cell immunoglobulin domain and mucin domain-containing molecule-3 (Tim-3)-positive CD4+ cells was observed in subjects with acute HBV infection (AHB) and chronic hepatitis B (CHB) compared to non-infected controls
We found that the frequency of Tim-3+ CD4+ or CD8+ T cells significantly correlated with levels of alanine aminotransferase (ALT), aspartate transaminase (AST), international normalized ratio (INR), and total bilirubin (Figure 2)
Summary
Chronic hepatitis B virus (HBV) infection is a global health burden with 350-400 million people infected worldwide. Patients chronically infected with HBV present impaired T helper 1 cells (Th1) response and impaired cytotoxic T lymphocyte (Tc1) priming, which results in viral persistence and liver damage [3]. Programmed cell death-1 (PD-1), a member of the CD28 family, was found to be up-regulated on the surfaces of exhausted T cells during chronic lymphocytic choriomeningitis virus (LCMV) [4], human immunodeficiency virus (HIV) [5], hepatitis C virus (HCV) [6] and HBV infections [7]. Blockade of this pathway ex vivo or in vivo significantly improved T-cell function. We investigated Tim-3 expression on peripheral T cell subsets and analyzed the relationship between Tim-3 expression and disease progression in HBV infection
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