T-bet-mediated Tim-3 expression dampens monocyte function during chronic hepatitis C virus infection.
Hepatitis C virus (HCV) induces a high rate of chronic infection via dysregulation of host immunity. We have previously shown that T-cell immunoglobulin and mucin domain protein-3 (Tim-3) is up-regulated on monocyte/macrophages (M/Mφ) during chronic HCV infection; little is known, however, about the transcription factor that controls its expression in these cells. In this study, we investigated the role of transcription factor, T-box expressed in T cells (T-bet), in Tim-3 expression in M/Mφ in the setting of HCV infection. We demonstrate that T-bet is constitutively expressed in resting CD14+M/Mφ in the peripheral blood. M/Mφ from chronically HCV-infected individuals exhibit a significant increase in T-bet expression that positively correlates with an increased level of Tim-3 expression. Up-regulation of T-bet is also observed in CD14+M/Mφ incubated with HCV+Huh7.5 cells, as well as in primary M/Mφ or monocytic THP-1 cells exposed to HCV core protein in vitro, which is reversible by blocking HCV core/gC1qR interactions. Moreover, the HCV core-induced up-regulation of T-bet and Tim-3 expression in M/Mφ can be abrogated by incubating the cells with SP600125 - an inhibitor for the c-Jun N-terminal kinase (JNK) signalling pathway. Importantly, silencing T-bet gene expression decreases Tim-3 expression and enhances interleukin-12 secretion as well as signal transducer and activator of transcription 1 phosphorylation. These data suggest that T-bet, induced by the HCV core/gC1qR interaction, enhances Tim-3 expression via the JNK pathway, leading to dampened M/Mφ function during HCV infection. These findings reveal a novel mechanism for Tim-3 regulation via T-bet during HCV infection, providing new targets to combat this global epidemic viral disease.
Department of Infectious Diseases, Tangdu Hospital, Fourth Military Medical University, Xian, China.
Wenjing
W
Yi
Department of Infectious Diseases, Tangdu Hospital, Fourth Military Medical University, Xian, China.
Peixin
P
Zhang
Department of Infectious Diseases, Tangdu Hospital, Fourth Military Medical University, Xian, China.
Yan
Y
Liang
Department of Infectious Diseases, Tangdu Hospital, Fourth Military Medical University, Xian, China.
Yun
Y
Zhou
Department of Infectious Diseases, Tangdu Hospital, Fourth Military Medical University, Xian, China.
Huanjun
H
Shen
Department of Infectious Diseases, Tangdu Hospital, Fourth Military Medical University, Xian, China.
Chao
C
Fan
Department of Internal Medicine, Division of Infectious Diseases, James H. Quillen College of Medicine, Center of Excellence in Immunity, Inflammatory and Infectious Diseases, East Tennessee State University, Johnson City, TN, USA.
Jonathan P
JP
Moorman
Department of Internal Medicine, Division of Infectious Diseases, James H. Quillen College of Medicine, Center of Excellence in Immunity, Inflammatory and Infectious Diseases, East Tennessee State University, Johnson City, TN, USA.
Zhi Q
ZQ
Yao
Department of Infectious Diseases, Tangdu Hospital, Fourth Military Medical University, Xian, China.
Zhansheng
Z
Jia
Department of Infectious Diseases, Tangdu Hospital, Fourth Military Medical University, Xian, China.
Ying
Y
Zhang
D000328:Adult; D002460:Cell Line; D005260:Female; D016174:Hepacivirus / Q000502:physiology*; D000072597:Hepatitis A Virus Cellular Receptor 2 / Q000235:genetics / Q000378:metabolism*; D019698:Hepatitis C, Chronic / Q000276:immunology*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008264:Macrophages / Q000276:immunology* / Q000821:virology; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000276:immunology* / Q000821:virology; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000276:immunology; D020825:T-Box Domain Proteins / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D014758:Viral Core Proteins / Q000276:immunology; D055815:Young Adult; D000098815:T-bet Transcription Factor
C448908:HAVCR2 protein, human; D000072597:Hepatitis A Virus Cellular Receptor 2; D034741:RNA, Small Interfering; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D014758:Viral Core Proteins; D048031:JNK Mitogen-Activated Protein Kinases

hepatitis C virus
; T-bet; Tim-3; c-Jun N-terminal kinase pathway; monocyte/macrophages