MicroRNA‐155 regulates interferon‐γ production in natural killer cells via Tim‐3 signalling in chronic hepatitis C virus infection

• Published in: Immunology Vol. 145; no. 4; pp. 485 - 497
• Main Authors: Cheng, Yong Q., Ren, Jun P., Zhao, Juan, Wang, Jia M., Zhou, Yun, Li, Guang Y., Moorman, Jonathan P., Yao, Zhi Q.
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Ltd 01-08-2015
• Subjects: Adult; Aged; Cell Line; Female; Hepatitis A Virus Cellular Receptor 2; hepatitis C virus; Hepatitis C, Chronic - immunology; Hepatitis C, Chronic - pathology; Hepatocytes - immunology; Hepatocytes - pathology; Humans; Interferon-gamma - immunology; interferon‐γ; Killer Cells, Natural - immunology; Killer Cells, Natural - pathology; Male; Membrane Proteins - immunology; MicroRNAs - immunology; microRNA‐155; Middle Aged; natural killer cells; Original; signal transducer and activator of transcription‐5; Signal Transduction - immunology; T-Box Domain Proteins - immunology; T‐cell immunoglobulin and mucin domain protein‐3; Up-Regulation - immunology; microRNA-155; hepatitis C virus; natural killer cells; interferon-γ; T-cell immunoglobulin and mucin domain protein-3; signal transducer and activator of transcription-5
• ISSN: 0019-2805; 1365-2567
• DOI: 10.1111/imm.12463

Summary
Host immune responses must be tightly regulated by an intricate balance between positive and negative signals while fighting pathogens; persistent pathogens may usurp these regulatory mechanisms to dampen host immunity to facilitate survival in vivo. Here we report that Tim‐3, a negative signalling molecule expressed on monocytes and T cells, is up‐regulated on natural killer (NK) cells in individuals chronically infected with hepatitis C virus (HCV). Additionally, the transcription factor T‐bet was also found to be up‐regulated and associated with Tim‐3 expression in NK cells during chronic HCV infection. MicroRNA‐155 (miR‐155), an miRNA that inhibits signalling proteins involved in immune responses, was down‐regulated in NK cells by HCV infection. This Tim‐3/T‐bet over‐expression and miR‐155 inhibition were recapitulated in vitro by incubating primary NK cells or NK92 cell line with Huh‐7 hepatocytes expressing HCV. Reconstitution of miR‐155 in NK cells from HCV‐infected patients led to a decrease in T‐bet/Tim‐3 expression and an increase in interferon‐γ production. Blocking Tim‐3 signalling also enhanced interferon‐γ production in NK cells by improving signal transducer and activator of transcription‐5 phosphorylation. These data indicate that HCV‐induced, miR‐155‐regulated Tim‐3 expression regulates NK cell function, suggesting a novel mechanism for balancing immune clearance and immune injury during chronic viral infection.