Protection of CD4+ T cells from hepatitis C virus infection‐associated senescence via ΔNp63–miR‐181a–Sirt1 pathway

Acceleration of HCV infection‐associated T cell senescence is counter‐regulated by the ΔNp63‐miR181a‐Sirt1 pathway. T cell dysfunction has a crucial role in establishing and maintaining viral persistence. We have previously shown a decline in miR‐181a, which regulates CD4+ T cell responses via DUSP6...

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Published in:	Journal of leukocyte biology Vol. 100; no. 5; pp. 1201 - 1211
Main Authors:	Zhou, Yun, Li, Guang Y., Ren, Jun P., Wang, Ling, Zhao, Juan, Ning, Shun B., Zhang, Ying, Lian, Jian Q., Huang, Chang X., Jia, Zhan S., Moorman, Jonathan P., Yao, Zhi Q.
Format:	Journal Article
Language:	English
Published:	United States Society for Leukocyte Biology 01-11-2016
Subjects:	Adult Aged Case-Control Studies CD4-Positive T-Lymphocytes - immunology Cellular Senescence Female Genes, Reporter hepatitis C Hepatitis C, Chronic - immunology Humans Interleukin-2 - biosynthesis Interleukin-2 - genetics Male MicroRNAs - biosynthesis MicroRNAs - genetics MicroRNAs - physiology microRNA‐181a Middle Aged Signal Transduction - immunology Sirtuin 1 Sirtuin 1 - biosynthesis Sirtuin 1 - genetics Sirtuin 1 - physiology T cell senescence Telomere Shortening transcription factor p63 Transcription Factors - biosynthesis Transcription Factors - genetics Transcription Factors - physiology Transfection Translational & Clinical Immunology Tumor Suppressor Proteins - biosynthesis Tumor Suppressor Proteins - genetics Tumor Suppressor Proteins - physiology Up-Regulation T cell senescence microRNA-181a transcription factor p63 Sirtuin 1 hepatitis C
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Summary:	Acceleration of HCV infection‐associated T cell senescence is counter‐regulated by the ΔNp63‐miR181a‐Sirt1 pathway. T cell dysfunction has a crucial role in establishing and maintaining viral persistence. We have previously shown a decline in miR‐181a, which regulates CD4+ T cell responses via DUSP6 overexpression, in individuals with hepatitis C virus (HCV) infection. Here, we describe accelerated T cell senescence in HCV‐infected individuals compared with age‐ and sex‐matched healthy subjects. Mechanistic studies revealed that up‐regulation of transcription factor ΔNp63 led to the decline of miR‐181a expression, resulting in an overexpression of the antiaging protein Sirt1, in CD4+ T cells from HCV‐infected individuals. Either reconstituting miR‐181a or silencing ΔNp63 or Sirt1 expression in CD4+ T cells led to accelerated T cell senescence, as evidenced by an increased senescence‐associated β‐galactosidase (SA‐β‐gal) expression, shortened telomere length, and decreased EdU incorporation; this suggests that HCV‐induced T cell senescence is counterregulated by the ΔNp63–miR‐181a–Sirt1 pathway. An increase of IL‐2 production was observed in these senescent CD4+ T cells and was driven by a markedly reduced frequency of Foxp3+ regulatory T (Treg) cells and increased number of Foxp3− effector T (Teff) cells upon manipulating the ΔNp63–miR‐181a–Sirt1 pathway. In conclusion, these findings provide novel mechanistic insights into how HCV uses cellular senescent pathways to regulate T cell functions, revealing new targets for rejuvenating impaired T cell responses during chronic viral infection.
Bibliography:	These authors contributed equally to this work. ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0741-5400 1938-3673
DOI:	10.1189/jlb.5A0316-119RR