T-bet-mediated Tim-3 expression dampens monocyte function during chronic hepatitis C virus infection

Area of Science:

• Immunology
• Virology
• Molecular Biology

Background:

• Hepatitis C virus (HCV) causes chronic infection by disrupting host immunity.
• T-cell immunoglobulin and mucin domain-3 (Tim-3) is upregulated on monocyte/macrophages (M/Mφ) during chronic HCV infection.
• The transcription factor controlling Tim-3 expression in M/Mφ during HCV infection is largely unknown.

Purpose of the Study:

• To investigate the role of the transcription factor T-box expressed in T cells (T-bet) in regulating Tim-3 expression in M/Mφ during HCV infection.
• To elucidate the molecular mechanisms underlying T-bet and Tim-3 upregulation in M/Mφ in the context of HCV.

Main Methods:

• Analysis of T-bet and Tim-3 expression in M/Mφ from healthy and chronically HCV-infected individuals.
• In vitro studies using M/Mφ or THP-1 cells exposed to HCV core protein or HCV+ cells.
• Investigation of the role of HCV core/gC1qR interaction and the JNK signaling pathway.
• Gene silencing of T-bet to assess its impact on Tim-3 expression and M/Mφ function.

Main Results:

• T-bet is constitutively expressed in resting M/Mφ and significantly increased in those from chronically HCV-infected individuals, correlating with elevated Tim-3 levels.
• HCV core protein exposure in vitro upregulates T-bet and Tim-3 in M/Mφ, a process dependent on HCV core/gC1qR interaction and the JNK pathway.
• Silencing T-bet reduced Tim-3 expression, enhanced IL-12 secretion, and increased STAT1 phosphorylation in M/Mφ.

Conclusions:

• T-bet, induced by HCV core/gC1qR interaction, promotes Tim-3 expression via the JNK pathway in M/Mφ.
• This T-bet-mediated upregulation of Tim-3 contributes to dampened M/Mφ function during chronic HCV infection.
• Targeting the T-bet/Tim-3 axis presents a potential therapeutic strategy against chronic HCV infection.