MicroRNA-155 Regulates Interferon-γ Production in Natural Killer Cells via Tim-3 Signalling in Chronic Hepatitis C Virus Infection
Document Type
Article
Publication Date
8-1-2015
Description
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.
Citation Information
Cheng, Yong Q.; Ren, Jun P.; Zhao, Juan; Wang, Jia M.; Zhou, Yun; Li, Guang Y.; Moorman, Jonathan P.; and Yao, Zhi Q.. 2015. MicroRNA-155 Regulates Interferon-γ Production in Natural Killer Cells via Tim-3 Signalling in Chronic Hepatitis C Virus Infection. Immunology. Vol.145(4). 485-497. https://doi.org/10.1111/imm.12463 PMID: 25772938 ISSN: 0019-2805