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Protection of CD4+ T cells from hepatitis C virus infection-associated senescence via ΔNp63-miR-181a-Sirt1 pathway.
J Leukoc Biol. 2016 Nov;100(5):1201-1211
Authors: Zhou Y, Li GY, Ren JP, Wang L, Zhao J, Ning SB, Zhang Y, Lian JQ, Huang CX, Jia ZS, Moorman JP, Yao ZQ
Abstract
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.
PMID: 27354409 [PubMed - indexed for MEDLINE]
from # All Medicine by Alexandros G. Sfakianakis via alkiviadis.1961 on Inoreader http://ift.tt/2eCQdft
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