Programmed Cell Death 1 (PD-1) and Cytotoxic T Lymphocyte-Associated Antigen 4 (CTLA-4) in Viral Hepatitis

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.

Expressions of inhibitory checkpoint molecules in acute and chronic HBV and HCV infections: Implications for therapeutic monitoring and personalized therapy

“…High expressions are generally believed to be markers of exhausted T cells during the chronic stage. While previous studies and reviews concentrated on “classical” ICs of PD‐1 and CTLA‐4, emerging studies unravel crucial roles of “the next generation” ICs of TIGIT, LAG‐3, BTLA, and other ICs in chronic viral infections, which will be the focus of this section.…”

The Reduction in CD8+PD-1+ T Cells in Liver Histological Tissue is Related to Pegylated IFN-α Therapy Outcomes in Chronic Hepatitis B Patients

“…12 Studies showed that the upregulation of PD-1 is associated with T cell exhaustion and persistent viral infection. 13 Our past study showed that in PEG-IFN-α therapy responders, PD-1 levels decreased in CD4 + and CD8 + T cells from peripheral blood, while in non-responders, CD4 + PD-1 + T and CD8 + PD-1 + T cells had no signi cant reduction. 6 In this study, CD8 + PD-1 + T cells signi cantly decreased in liver tissue in the FIER group after treating with PEG-IFN-α for 6 months, while CD8 + PD-1 -T cells did not change signi cantly.…”

Immune Checkpoint Inhibitors in Hepatocellular Carcinoma: Opportunities and Challenges

“…Immune dysregulation regulates almost the whole process of HBV‐associated liver diseases including HCC, especially with T‐cell dysfunction in patients overexpressing PD‐1 and CTLA‐4 . The phenomenon that PD‐1 and CTLA‐4 are up‐ or downregulated along with virus relapse or recovery indicates that they have protective effects that involve suppressing cytotoxic T cells, which induce the harmful destruction of infected hepatocytes in self‐limited viral hepatitis.…”