title: MicroRNA-155 regulates interferon-γ production in natural killer cells via Tim-3 signalling in chronic hepatitis C virus infection.
abstract: 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.
authors.affiliation: Center for Inflammation, Infectious Disease and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA.|International Centre for Diagnosis and Treatment of Liver Diseases, Beijing, China.
authors.forename: Yong Q
authors.initials: YQ
authors.lastname: Cheng
authors.affiliation: Center for Inflammation, Infectious Disease and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA.
authors.forename: Jun P
authors.initials: JP
authors.lastname: Ren
authors.affiliation: Center for Inflammation, Infectious Disease and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA.
authors.forename: Juan
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Center for Inflammation, Infectious Disease and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA.|Department of Biochemistry and Molecular Biology, Soochow University School of Medicine, Suzhou, China.
authors.forename: Jia M
authors.initials: JM
authors.lastname: Wang
authors.affiliation: Center for Inflammation, Infectious Disease and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA.|Centre of Diagnosis and Treatment for Infectious Diseases of Chinese PLA, Tangdu Hospital, Fourth Military Medical University, Xian, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Center for Inflammation, Infectious Disease and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA.
authors.forename: Guang Y
authors.initials: GY
authors.lastname: Li
authors.affiliation: Center for Inflammation, Infectious Disease and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA.|HCV/HIV Program, James H. Quillen VA Medical Center, Johnson City, TN, USA.
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Moorman
authors.affiliation: Center for Inflammation, Infectious Disease and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA.|HCV/HIV Program, James H. Quillen VA Medical Center, Johnson City, TN, USA.
authors.forename: Zhi Q
authors.initials: ZQ
authors.lastname: Yao
mesh_terms: D000328:Adult; D000368:Aged; D002460:Cell Line; D005260:Female; D000072597:Hepatitis A Virus Cellular Receptor 2; D019698:Hepatitis C, Chronic / Q000276:immunology* / Q000473:pathology; D022781:Hepatocytes / Q000276:immunology / Q000473:pathology; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology* / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000276:immunology*; D035683:MicroRNAs / Q000276:immunology*; D008875:Middle Aged; D015398:Signal Transduction / Q000276:immunology*; D020825:T-Box Domain Proteins / Q000276:immunology; D015854:Up-Regulation / Q000276:immunology*; D000098815:T-bet Transcription Factor
chemical_list: C448908:HAVCR2 protein, human; D000072597:Hepatitis A Virus Cellular Receptor 2; C573415:IFNG protein, human; C524942:MIRN155 microRNA, human; D008565:Membrane Proteins; D035683:MicroRNAs; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D007371:Interferon-gamma
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