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γ-H2AX+CD8+ T lymphocytes cannot respond to IFN-α, IL-2 or IL-6 in chronic hepatitis C virus infection
- Source :
-
Journal of Hepatology . May2013, Vol. 58 Issue 5, p868-874. 7p. - Publication Year :
- 2013
-
Abstract
- Background & Aims: Age is the dominant prognostic factor influencing the natural history of hepatitis C virus (HCV) infection and treatment response. Accelerated lymphocyte telomere shortening in HCV infection correlates with adverse clinical outcomes. Critical telomere shortening generates double-stranded DNA breaks (DSB) inducing the DNA damage response, leading to replicative senescence. The phenotype and function of CD8+ T lymphocytes and the in vitro response to IFN-α in relation to the DNA damage response were investigated in patients with chronic HCV infection. Methods: CD8+ T lymphocytes with DSB were identified by expression of γ-H2AX (Ser-139) in 134 HCV-exposed subjects and 27 controls. Telomere length was determined by flow-FISH; cytokine expression by intracellular cytokine staining; in vitro responses to IFN-α, IL-2 or IL-6 by phospho-STAT1 (Y701) or phospho-STAT5 (Y694) expression. Results: The proportion of circulating CD8+γ-H2AX+ T lymphocytes rose with increasing fibrosis stage (p= 0.0023). CD8+γ-H2AX+ T lymphocytes were enriched in liver compared to blood (p= 0.03). CD8+γ-H2AX+ T lymphocytes demonstrated increased IFN-γ (p= 0.02) and reduced IL-2 expression (p= 0.02). CD8+γ-H2AX+ T lymphocytes failed to phosphorylate STAT1 in response to IFN-α compared to unfractionated CD8+ T lymphocytes (p <0.0001). More widespread failure of Jak/Stat signalling in CD8+γ-H2AX+ T lymphocytes was suggested by impaired phosphorylation of STAT1 with IL-6 (p= 0.002) and STAT5 with IL-2 (p= 0.0039) compared to unfractionated CD8+ T-lymphocytes. Conclusions: In chronic HCV infection, CD8+γ-H2AX+ T lymphocytes are highly differentiated with shortened telomeres, are more frequent within the liver, are associated with severe fibrosis and fail to activate Jak/Stat pathways in response to IFN-α, IL-2 or IL-6, perhaps explaining treatment failure in those with severe fibrosis. [Copyright &y& Elsevier]
Details
- Language :
- English
- ISSN :
- 01688278
- Volume :
- 58
- Issue :
- 5
- Database :
- Academic Search Index
- Journal :
- Journal of Hepatology
- Publication Type :
- Academic Journal
- Accession number :
- 87013845
- Full Text :
- https://doi.org/10.1016/j.jhep.2012.12.009