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BACKGROUND AND AIM: Chronic hepatitis C (CHC) in humans caused by persistent hepatitis C virus (HCV) infection is a global public health problem. The functional exhaustion of HCV-specific CD8(+) T cells regulated by several inhibitory receptors has been shown to contribute to chronic HCV infection. Lymphocyte activation gene 3 (LAG-3), which is an inhibitory receptor, plays an important role in several chronic viral infections. However, its effect on the function of HCV-specific CD8(+) T cells is unclear. METHODS: The expression of LAG-3 on the CD8(+) T cells in intrahepatic and peripheral lymphocytes from 17 CHC patients and 15 HCV-negative patients was analyzed by flow cytometry. The LAG-3 expression in CD8(+) T cells was downregulated or upregulated by lentivirus LAG-3 shRNA or lentivirus overexpressing LAG-3. After HCV peptide stimulation, flow cytometry was used to detect cell proliferation and cytokine (γ-interferon IFN-γ, tumor necrosis factor-α TNF-α, granzyme B, and perforin) production of CD8(+) T cells. Cytotoxicity functions of HCV-specific CD8(+) T cells were measured using a (51) Cr release assay. RESULTS: The frequency of LAG-3-positive intrahepatic and peripheral CD8(+) T cells was higher in CHC patients, compared with HCV-negative patients. The cell proliferation, cytokine (IFN-γ, TNF-α, granzyme B, and perforin) expression and cytotoxicity function of HCV-specific CD8(+) T cells in CHC patients were increased by the knocking down and blockade of LAG-3. In the LAG-3 overexpressed CD8(+) T cells, cell proliferation, cytokine (IFN-γ, TNF-α, granzyme B, and perforin) expression, and cytotoxicity function were inhibited, while the LAG-3 blocking antibody reversed the inhibition. CONCLUSION: LAG-3 negatively regulated the function of HCV-specific CD8(+) T cells in CHC patients.
Chen et al. (Fri,) studied this question.