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

Summary 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/MФ) 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 transcription factor, T-box expressed in T cells (T-bet), on Tim-3 expression in M/MФ in the setting of HCV infection. We demonstrate that T-bet is constitutively expressed in resting CD14+ M/MФ in the peripheral blood. M/MФ 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/MФ incubated with HCV+ Huh7.5 cells, as well as in primary M/MФ 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/MФ can be abrogated by incubating the cells with SP600125 - an inhibitor for JNK signaling pathway. Importantly, silencing T-bet gene expression decreases Tim-3 expression and enhances IL-12 secretion as well as STAT-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/MФ 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. This article is protected by copyright. All rights reserved.