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?-H2AX+CD8+ T lymphocytes cannot respond to IFN-?, IL-2 or IL-6 in chronic hepatitis C virus infection.

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-? 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 ?-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-?, IL-2 or IL-6 by phospho-STAT1 (Y701) or phospho-STAT5 (Y694) expression. RESULTS:The proportion of circulating CD8+?-H2AX+ T lymphocytes rose with increasing fibrosis stage (p=0.0023). CD8+?-H2AX+ T lymphocytes were enriched in liver compared to blood (p=0.03). CD8+?-H2AX+ T lymphocytes demonstrated increased IFN-? (p=0.02) and reduced IL-2 expression (p=0.02). CD8+?-H2AX+ T lymphocytes failed to phosphorylate STAT1 in response to IFN-? compared to unfractionated CD8+ T lymphocytes (p <0.0001). More widespread failure of Jak/Stat signalling in CD8+?-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+?-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-?, IL-2 or IL-6, perhaps explaining treatment failure in those with severe fibrosis.

SUBMITTER: Hoare M

PROVIDER: S-EPMC3625113 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature

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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.

Hoare Matthew M Shankar Arun A Shah Meera M Rushbrook Simon S Gelson William W Davies Susan S Akbar Arne A Alexander Graeme J M GJ

Journal of hepatology 20121217 5

<h4>Background & aims</h4>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 ...[more]

PMID: 23257612

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?-H2AX+CD8+ T lymphocytes cannot respond to IFN-?, IL-2 or IL-6 in chronic hepatitis C virus infection.

Publications

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

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