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

• DOI: 10.1016/j.jhep.2009.12.005
• Publication Date: 2010-01-07T09:16:40Z
• Authors: Ying Ju; Nan Hou; Jing Meng; Xiaoyan Wang; Xiaoning Zhang; Di Zhao; Ying Liu; Faliang Zhu; Lining Zhang; Wensheng Sun; Xiaohong Liang; Lifen Gao; Chunhong Ma
• Keywords: Adult; Male; Hepatitis B virus; Carcinoma, Hepatocellular; Liver Neoplasms; Membrane Proteins; Cell Line; 3. Good health; Fatty Liver; Killer Cells, Natural; Interferon-gamma; 03 medical and health sciences; Hepatitis B, Chronic; 0302 clinical medicine; Liver; Case-Control Studies; Leukocytes, Mononuclear; Animals; Humans; Female; Lymphocytes; Hepatitis A Virus Cellular Receptor 2; Autoantibodies

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.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.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-gamma) production. Similarly, enhanced cytotoxicity was also observed in PBMCs or NK cells from CHB patients treated with the Tim-3 blockade ex vivo.HBV infection can up-regulate Tim-3 expression in NK cells, which may in turn suppress NK-cell functions in CHB patients.