title: Lymphocyte activation gene 3 negatively regulates the function of intrahepatic hepatitis C virus-specific CD8+ T cells.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  LAG-3 negatively regulated the function of HCV-specific CD8(+) T cells in CHC patients.
authors.affiliation: Department of Infectious Diseases, First Affiliated Hospital, Medical College of Xi'an Jiaotong University, Xi'an, China.
authors.forename: Na
authors.initials: N
authors.lastname: Chen
authors.affiliation: Department of Infectious Diseases, First Affiliated Hospital, Medical College of Xi'an Jiaotong University, Xi'an, China.
authors.forename: Yehong
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Infectious Diseases, Second Affiliated Hospital, Medical College of Xi'an Jiaotong University, Xi'an, China.
authors.forename: Yonghong
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Department of Infectious Diseases, First Affiliated Hospital, Medical College of Xi'an Jiaotong University, Xi'an, China.
authors.forename: Yunru
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Infectious Diseases, First Affiliated Hospital, Medical College of Xi'an Jiaotong University, Xi'an, China.
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Infectious Diseases, First Affiliated Hospital, Medical College of Xi'an Jiaotong University, Xi'an, China.
authors.forename: Min
authors.initials: M
authors.lastname: Liu
mesh_terms: D000368:Aged; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000821:virology*; D016207:Cytokines / Q000378:metabolism; D003602:Cytotoxicity, Immunologic; D005260:Female; D005434:Flow Cytometry; D015870:Gene Expression; D019698:Hepatitis C, Chronic / Q000276:immunology* / Q000821:virology*; D006801:Humans; D016086:Lentivirus / Q000235:genetics / Q000276:immunology; D008099:Liver / Q000166:cytology / Q000276:immunology; D008213:Lymphocyte Activation / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D000093322:Lymphocyte Activation Gene 3 Protein
chemical_list: D015703:Antigens, CD; D016207:Cytokines; D000093322:Lymphocyte Activation Gene 3 Protein
keywords: CD8+ T cells; HCV; LAG-3.; immunology