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

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.

Keywords: Tim-3, Natural killer cells, Hepatitis B, Suppression

Abbreviations: HBV, hepatitis B virus, NK cells, natural killer cells, Tim-3, T cell immunoglobulin- and mucin-domain-containing molecule-3, IFN-γ, interferon-gamma, NKT, natural killer T cells, CHB, chronic hepatitis B, FLD, fatty liver disease, HCV, hepatitis C virus, HDV, hepatitis D virus, HGV, hepatitis G virus, HIV, human immunodeficiency virus, MNC, mononuclear cell, RT-PCR, reverse transcription polymerase chain reaction, PBMC, peripheral blood mononuclear cell, LILs, liver infiltrating lymphocytes, MFI, median fluorescence intensity