Protection of CD4+ T cells from hepatitis C virus infection-associated senescence via ΔNp63–miR-181a–Sirt1 pathway
| Autor: | Zhi Q. Yao, Zhan S. Jia, Jonathan P. Moorman, Jun P. Ren, Ying Zhang, Guang Y. Li, Yun Zhou, Chang X. Huang, Shun B. Ning, Jian Q. Lian, Ling Wang, Juan Zhao |
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| Rok vydání: | 2016 |
| Předmět: |
Adult
CD4-Positive T-Lymphocytes Male 0301 basic medicine Interleukin 2 T cell Immunology Translational & Clinical Immunology Biology Transfection TCIRG1 03 medical and health sciences Interleukin 21 0302 clinical medicine Sirtuin 1 Genes Reporter medicine Humans Immunology and Allergy Cytotoxic T cell IL-2 receptor Cellular Senescence Telomere Shortening Aged Tumor Suppressor Proteins ZAP70 virus diseases FOXP3 Cell Biology Hepatitis C Chronic Middle Aged Up-Regulation Cell biology MicroRNAs 030104 developmental biology medicine.anatomical_structure Case-Control Studies Interleukin-2 Female hormones hormone substitutes and hormone antagonists Signal Transduction Transcription Factors 030215 immunology medicine.drug |
| Zdroj: | Journal of Leukocyte Biology. 100:1201-1211 |
| ISSN: | 1938-3673 0741-5400 |
| DOI: | 10.1189/jlb.5a0316-119rr |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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