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/M φ) 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/M φ in the setting of HCV infection. We demonstrate that T-bet is constitutively expressed in resting CD14+ M/M φ in the peripheral blood. M/M φ 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/M φ incubated with HCV+ Huh7.5 cells, as well as in primary M/M φ 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/M φ 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/M φ 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. [ABSTRACT FROM AUTHOR]