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

Publisher: Blackwell Scientific Publications Country of Publication: England NLM ID: 0374672 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1365-2567 (Electronic) Linking ISSN: 00192805 NLM ISO Abbreviation: Immunology Subsets: MEDLINE

Original Publication: Oxford : Blackwell Scientific Publications

Hepatitis C, Chronic/*immunology ; Interferon-gamma/*immunology ; Killer Cells, Natural/*immunology ; Membrane Proteins/*immunology ; MicroRNAs/*immunology ; Signal Transduction/*immunology ; Up-Regulation/*immunology; Adult ; Aged ; Cell Line ; Female ; Hepatitis A Virus Cellular Receptor 2 ; Hepatitis C, Chronic/pathology ; Hepatocytes/immunology ; Hepatocytes/pathology ; Humans ; Killer Cells, Natural/pathology ; Male ; Middle Aged ; T-Box Domain Proteins/immunology

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.
(© 2015 John Wiley & Sons Ltd.)

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R01AI114748 United States AI NIAID NIH HHS; R15 AI103828 United States AI NIAID NIH HHS; 1R15AI103828-01 United States AI NIAID NIH HHS; R01 AI114748 United States AI NIAID NIH HHS; I01 BX002670 United States BX BLRD VA; R01DK093526 United States DK NIDDK NIH HHS; R15 AG050456 United States AG NIA NIH HHS; R01 DK093526 United States DK NIDDK NIH HHS

Keywords: T-cell immunoglobulin and mucin domain protein-3; hepatitis C virus; interferon-γ; microRNA-155; natural killer cells; signal transducer and activator of transcription-5

0 (HAVCR2 protein, human)
0 (Hepatitis A Virus Cellular Receptor 2)
0 (IFNG protein, human)
0 (MIRN155 microRNA, human)
0 (Membrane Proteins)
0 (MicroRNAs)
0 (T-Box Domain Proteins)
0 (T-box transcription factor TBX21)
82115-62-6 (Interferon-gamma)

Date Created: 20150317 Date Completed: 20150918 Latest Revision: 20220309

20240628

PMC4515129

10.1111/imm.12463

25772938