Journal
IMMUNOLOGY
Volume 145, Issue 4, Pages 485-497Publisher
WILEY
DOI: 10.1111/imm.12463
Keywords
hepatitis C virus; interferon-gamma; microRNA-155; natural killer cells; signal transducer and activator of transcription-5; T-cell immunoglobulin and mucin domain protein-3
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Funding
- NIH NIDDK [R01DK093526]
- NIH NIAID [R01AI114748]
- NIAID [1R15AI103828-01]
- Beijing 302 Hospital, Beijing, China
- China Scholarship Council [CSC 201306590012]
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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-gamma production. Blocking Tim-3 signalling also enhanced interferon-gamma 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.
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