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T‐bet‐mediated Tim‐3 expression dampens monocyte function during chronic hepatitis C virus infection
Author(s) -
Yi Wenjing,
Zhang Peixin,
Liang Yan,
Zhou Yun,
Shen Huanjun,
Fan Chao,
Moorman Jonathan P.,
Yao Zhi Q.,
Jia Zhansheng,
Zhang Ying
Publication year - 2017
Publication title -
immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.297
H-Index - 133
eISSN - 1365-2567
pISSN - 0019-2805
DOI - 10.1111/imm.12686
Subject(s) - cd14 , biology , monocyte , stat protein , microbiology and biotechnology , hepatitis c virus , transcription factor , signal transduction , stat3 , immune system , virus , immunology , gene , biochemistry
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/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 CD 14 + 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 CD 14 + 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/ gC 1qR 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 SP 600125 – 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/ gC 1qR 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.

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