LAUSR

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.