期刊
HEPATOLOGY
卷 61, 期 4, 页码 1163-1173出版社
WILEY-BLACKWELL
DOI: 10.1002/hep.27634
关键词
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资金
- National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases [R01DK093526]
- National Institutes of Health, National Institute of Allergy and Infectious Diseases [R01AI114748, R15AI072750]
- China Scholarship Council [CSC 201306590012]
- Guangzhou Municipal Health Bureau, China
- Guanghua Foundation of Xian Jiaotong University, China
- Beijing 302 Hospital, Beijing, China
T cells play a crucial role in viral clearance or persistence; however, the precise mechanisms that control their responses during viral infection remain incompletely understood. MicroRNA (miR) has been implicated as a key regulator controlling diverse biological processes through posttranscriptional repression. Here, we demonstrate that hepatitis C virus (HCV)-mediated decline of miR-181a expression impairs CD4(+) T-cell responses through overexpression of dual specific phosphatase 6 (DUSP6). Specifically, a significant decline of miR-181a expression along with overexpression of DUSP6 was observed in CD4(+) T cells from chronically HCV-infected individuals compared to healthy subjects, and the levels of miR-181a loss were found to be negatively associated with the levels of DUSP6 overexpression in these cells. Importantly, reconstitution of miR-181a or blockade of DUSP6 expression in CD4(+) T cells led to improved T-cell responses including enhanced CD25 and CD69 expression, increased interleukin-2 expression, and improved proliferation of CD4(+) T cells derived from chronically HCV-infected individuals. Conclusion: Since a decline of miR-181a concomitant with DUSP6 overexpression is the signature marker for age-associated T-cell senescence, these findings provide novel mechanistic insights into HCV-mediated premature T-cell aging through miR-181a-regulated DUSP6 signaling and reveal new targets for therapeutic rejuvenation of impaired T-cell responses during chronic viral infection. (Hepatology 2015;61:1163-1173)
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