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Lymphocyte activation gene 3 negatively regulates the function of intrahepatic hepatitis C virus‐specific CD8 + T cells
Author(s) -
Chen Na,
Liu Yehong,
Guo Yonghong,
Chen Yunru,
Liu Xiaojing,
Liu Min
Publication year - 2015
Publication title -
journal of gastroenterology and hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.214
H-Index - 130
eISSN - 1440-1746
pISSN - 0815-9319
DOI - 10.1111/jgh.13017
Subject(s) - medicine , cd8 , virology , t lymphocyte , hepatitis c virus , lymphocyte , virus , lymphocyte subsets , hepatitis a virus , immunology , immune system
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.