T cell immunoglobulin- and mucin-domain-containing molecule-3 (Tim-3) mediates natural killer cell suppression in chronic hepatitis B.
OBJECTIVE
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-gamma) production. Similarly, enhanced cytotoxicity was also observed in PBMCs or NK cells from CHB patients treated with the Tim-3 blockade ex vivo.


CONCLUSIONS
HBV infection can up-regulate Tim-3 expression in NK cells, which may in turn suppress NK-cell functions in CHB patients.
Ju
Ying
Y
Institute of Immunology, Key Laboratory for Experimental Teratology of Ministry of Education, Shandong University School of Medicine, #44 Wenhua Xi Road, Jinan, Shandong, PR China.
Hou
Nan
N
Meng
Jing
J
Wang
Xiaoyan
X
Zhang
Xiaoning
X
Zhao
Di
D
Liu
Ying
Y
Zhu
Faliang
F
Zhang
Lining
L
Sun
Wensheng
W
Liang
Xiaohong
X
Gao
Lifen
L
Ma
Chunhong
C
D000328:Adult; D000818:Animals; D001323:Autoantibodies / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D016022:Case-Control Studies; D002460:Cell Line; D005234:Fatty Liver / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D005260:Female; D000072597:Hepatitis A Virus Cellular Receptor 2; D006515:Hepatitis B virus / Q000235:genetics / Q000502:physiology; D019694:Hepatitis B, Chronic / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology*; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D007694:Killer Cells, Natural / Q000473:pathology / Q000502:physiology* / Q000821:virology*; D007963:Leukocytes, Mononuclear / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000378:metabolism / Q000473:pathology / Q000821:virology; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008214:Lymphocytes / Q000378:metabolism / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D008875:Middle Aged; D012189:Retrospective Studies; D015854:Up-Regulation / Q000502:physiology
D001323:Autoantibodies; C448908:HAVCR2 protein, human; D000072597:Hepatitis A Virus Cellular Receptor 2; D008565:Membrane Proteins; D007371:Interferon-gamma