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

Abstract

SummaryHost 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. , 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 HCVinfected patients led to a decrease in T-bet/Tim-3 expression and an increase in interferon-c production. Blocking Tim-3 signalling also enhanced interferon-c 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.Keywords: hepatitis C virus; interferon-c; microRNA-155; natural killer cells; signal transducer and activator of transcription-5; T-cell immunoglobulin and mucin domain protein-3.

Role of Tim-3 in hepatitis B virus infection: An overview

“…Some studies have demonstrated that Tim-3 expression is elevated in NKs and that Tim-3 over-expression tends to result from down-regulated miR-155 in NKs during HCV infection, similarly to chronic HBV infection. Blocking Tim-3 can rescue the function of NKs, whereas reconstituting miR-155 can down-regulate Tim-3 [65] . However, a recent study has reported the opposite results.…”

T cell immunoglobulin and mucin domain‐containing molecule 3 on CD14+ monocytes serves as a novel biological marker for diabetes duration in type 2 diabetes mellitus

“…Recently, Tim‐3 was also shown to play important roles in activated T helper 17, cytotoxic T cell 1, macrophages/monocytes, dendritic cells and natural killer cells. A strong correlation between Tim‐3 expression and some chronic diseases has been recently confirmed, such as atherosclerosis and chronic viral infection. Recent data showed that Tim‐3 has a potential relationship with type 2 diabetes.…”

An update on the role of miRNA-155 in pathogenic microbial infections

“…This is likely to occur by interfering with the TLR7 signaling pathway, upstream of the IFN-a-activated JAK/STAT pathway. The complex balance of immune responses is further illustrated by the finding that, during chronic HCV infections, miR-155 is actually down-regulated in NK cells [30]. This was found to be linked to the up-regulation of Tim-3 and the transcription factor T-bet, with the consequence of a reduction in IFN-g production by these cells.…”