Na Chen1, Yehong Liu1, Yonghong Guo2, Yunru Chen1, Xiaojing Liu1, Min Liu1. 1. Department of Infectious Diseases, First Affiliated Hospital, Medical College of Xi'an Jiaotong University, Xi'an, China. 2. Department of Infectious Diseases, Second Affiliated Hospital, Medical College of Xi'an Jiaotong University, Xi'an, China.
Abstract
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.
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 CHCpatients 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 CHCpatients, 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 CHCpatients 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 CHCpatients.
Authors: Stephanie E A Burnell; Lorenzo Capitani; Bruce J MacLachlan; Georgina H Mason; Awen M Gallimore; Andrew Godkin Journal: Immunother Adv Date: 2021-12-20