T cell immunoglobulin- and mucin-domain-containing molecule-3 (Tim-3) mediates natural killer cell suppression in chronic hepatitis B

• Published in: Journal of hepatology Vol. 52; no. 3; pp. 322 - 329
• Main Authors: Ju, Ying, Hou, Nan, Meng, Jing, Wang, Xiaoyan, Zhang, Xiaoning, Zhao, Di, Liu, Ying, Zhu, Faliang, Zhang, Lining, Sun, Wensheng, Liang, Xiaohong, Gao, Lifen, Ma, Chunhong
• Format: Journal Article
• Language: English
• Published: Kidlington Elsevier B.V 01.03.2010; Elsevier
• Subjects: Adult; Animals; Autoantibodies - pharmacology; Biological and medical sciences; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; Carcinoma, Hepatocellular - physiopathology; Case-Control Studies; Cell Line; Fatty Liver - metabolism; Fatty Liver - pathology; Fatty Liver - physiopathology; Female; Gastroenterology and Hepatology; Gastroenterology. Liver. Pancreas. Abdomen; Hepatitis A Virus Cellular Receptor 2; Hepatitis B; Hepatitis B virus - genetics; Hepatitis B virus - physiology; Hepatitis B, Chronic - immunology; Hepatitis B, Chronic - pathology; Hepatitis B, Chronic - physiopathology; Human viral diseases; Humans; Infectious diseases; Interferon-gamma - metabolism; Killer Cells, Natural - pathology; Killer Cells, Natural - physiology; Killer Cells, Natural - virology; Leukocytes, Mononuclear - metabolism; Leukocytes, Mononuclear - pathology; Liver - metabolism; Liver - pathology; Liver - virology; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Liver Neoplasms - physiopathology; Lymphocytes - metabolism; Lymphocytes - pathology; Male; Medical sciences; Membrane Proteins - genetics; Membrane Proteins - immunology; Membrane Proteins - physiology; Mice; Mice, Inbred BALB C; Mice, Transgenic; Middle Aged; Natural killer cells; Retrospective Studies; Suppression; Tim-3; Up-Regulation - physiology; Viral diseases; Viral hepatitis; hepatitis G virus; MNC; Suppression; hepatitis B virus; LILs; liver infiltrating lymphocytes; Tim-3; fatty liver disease; MFI; IFN-γ; RT-PCR; hepatitis C virus; Natural killer cells; HDV; HBV; interferon-gamma; chronic hepatitis B; NK cells; T cell immunoglobulin- and mucin-domain-containing molecule-3; PBMC; natural killer T cells; median fluorescence intensity; HIV; hepatitis D virus; NKT; HGV; mononuclear cell; human immunodeficiency virus; reverse transcription polymerase chain reaction; HCV; CHB; peripheral blood mononuclear cell; Hepatitis B; FLD; Immunoglobulins; Hepatic disease; Infection; Natural killer cell; Viral hepatitis B; Mucin; Immunological investigation; Viral disease; Gastroenterology; T-Lymphocyte; Digestive diseases
• ISSN: 0168-8278; 1600-0641
• DOI: 10.1016/j.jhep.2009.12.005

Background & Aims T cell immunoglobulin- and mucin-domain-containing molecule-3 (Tim-3) has been shown to influence autoimmune diseases; however, its function in viral infection has not been well-defined. We therefore investigated the expression and regulatory function of Tim-3 in natural killer (NK) cells in chronic Hepatitis B (CHB) infection. Methods Seventy-six CHB patients, 38 healthy controls, and 18 patients with fatty liver disease (FLD) were tested for Tim-3 expression on peripheral blood mononuclear cells (PBMCs) and in the liver tissue by flow cytometry and immunohistochemical stainning. The effects of HBV infection on Tim-3 expression in NK cells and the roles of Tim-3 in regulation of NK-cell function were also studied. Results There was a significant increase of Tim-3 expression in PBMCs, circulating NK cells and liver infiltrating lymphocytes (LILs) from CHB patients compared to that of healthy controls and FLD patients. Increased Tim-3 expression was also detected in NK92 cells that had been transfected with a HBV expression vector and NK cells isolated from the liver of HBV transgenic mice. Importantly, blockage of Tim-3 signaling with anti-Tim-3 antibodies or Tim-3-Fc fusion proteins resulted in an increased cytotoxicity for NK92 cells compared to HepG2 and HepG2.2.15 cells, as well as an elevated interferon-gamma (IFN-γ) production. Similarly, enhanced cytotoxicity was also observed in PBMCs or NK cells from CHB patients treated with the Tim-3 blockade ex vivo. Conclusion HBV infection can up-regulate Tim-3 expression in NK cells, which may in turn suppress NK-cell functions in CHB patients.