Research Article
γ-H2AX + CD8+ T lymphocytes cannot respond to IFN-α, IL-2 or IL-6 in chronic hepatitis C virus infection

https://doi.org/10.1016/j.jhep.2012.12.009Get rights and content
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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.

Abbreviations

HCV
Hepatitis C virus
DSB
double-stranded DNA breaks
ATM
ataxia telangiectasia-mutated
IFN-α
interferon-α
PBMC
peripheral blood mononuclear cells
DDR
DNA damage response
SOCS
suppressor of cytokine signalling

Keywords

Hepatitis C
T-lymphocytes
Senescence
Interferon-alpha
γ-H2AX

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Present address: CRUK Cambridge Research Institute, Robinson Way, Cambridge CB2 0RE, UK.