Abstract
Virus-specific cluster of differentiation 8 (CD8+) cytotoxic T cells (CTL) recognize viral antigens presented on major histocompatibility complex (MHC) class I chains on infected hepatocytes, with help from CD4+ T cells. However, this CTL response is frequently weak or undetectable in patients with chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infection. Programmed cell death 1 (PD-1) and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) are receptors in the CD28 family of costimulatory molecules, providing inhibitory signals to T cells. The overexpressions of PD-1 and CTLA-4 in patients with viral infection have been shown to associate with functional impairment of virus-specific T cells. In acute viral hepatitis, PD-1 and CTLA-4 are up-regulated during the symptomatic phase, and then down-regulated after recovery. These findings suggest that PD-1 and CTLA-4 have protective effects as inhibitory molecules to suppress cytotoxic T cells which induce harmful destruction of viral infected hepatocytes in self-limited viral hepatitis. In chronic viral hepatitis, the extended upregulations of PD-1 and CTLA-4 are associated with T cell exhaustion and persistent viral infection, suggesting positive correlations between expression of immune inhibitory factors and the chronicity of viral disease. In this review, we summarize recent literature relating to PD-1, CTLA-4, and other inhibitory receptors in antigen-specific T cell exhaustion in viral hepatitis, including hepatitis A, B, C, and others.
Highlights
Programmed cell death 1 (PD-1) and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) are major inhibitory molecules that reduce T cell activation
We review the current understanding of immune inhibitory receptors such as PD-1, CTLA-4, CD244, Lymphocyte activation gene 3 (LAG-3), T cell immunoglobulin domain and mucin domain-3 (Tim-3), and CD160
Several mechanisms seem to contribute to the dysfunction of hepatitis B virus (HBV)-specific T cells, including suppressive cytokine production (IL-10, TGF-β) and an increased number of Tregs and co-inhibitory receptors, such as PD-1, T cell immunoglobulin domain and mucin domain-3 (TIM-3), CTLA-4, and CD244 (2B4), which result in a progressive loss of T cell function [49,71,80,81,82]
Summary
Programmed cell death 1 (PD-1) and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) are major inhibitory molecules that reduce T cell activation. A number of studies have reported overexpression of PD-1 and CTLA-4 on antigen-specific cluster of differentiation 4 (CD4+) or CD8+ T cells during chronic viral infections, including those by hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV), and lymphocytic choriomeningitis virus (LCMV). HBV and HCV persist with functionally-impaired, virus-specific peripheral T cells as well as intrahepatic T cells that over-express PD-1 and CTLA-4. We review the current understanding of immune inhibitory receptors such as PD-1, CTLA-4, CD244, Lymphocyte activation gene 3 (LAG-3), T cell immunoglobulin domain and mucin domain-3 (Tim-3), and CD160 (expressed on virus-specific T cells in hepatitis)
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