Frontiers in Immunology (Jun 2015)

Type I Interferon Elevates Co-regulatory Receptor Expression on CMV- and EBV-specific CD8 T cells in Chronic Hepatitis C

  • Solomon eOwusu Sekyere,
  • Pothakamuri Venkata Suneetha,
  • Svenja eHardtke,
  • Christine Susanne Falk,
  • Julia eHengst,
  • Michael Peter Manns,
  • Markus eCornberg,
  • Heiner eWedemeyer,
  • Verena eSchlaphoff

DOI
https://doi.org/10.3389/fimmu.2015.00270
Journal volume & issue
Vol. 6

Abstract

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Hepatitis C virus (HCV) readily sets up persistence in a large fraction of infected hosts. Mounting epidemiological and immunological evidence suggest that HCV’s persistence could influence immune responses towards unrelated pathogens and vaccines. Nonetheless, the fundamental contribution of the inflammatory milieu during persistent HCV infection in impacting immune cells specific for common pathogens such as CMV and EBV has not been fully studied. As the co-regulatory receptors PD-1, Tim-3, and 2B4 have all been shown to be vital in regulating CD8+ T cell function, we assessed their expression on CMV/EBV-specific CD8+ T cells from patients with chronic hepatitis C (CHC) and healthy controls ex vivo and upon stimulation with virus-specific peptides in vitro. Total and CMV/EBV-specific CD8+ T cells expressing PD-1, Tim-3 and 2B4 were highly enriched in patients with CHC compared to healthy individuals ex vivo. In vitro peptide stimulation further potentiated the differential co-regulatory receptor expression of PD-1, Tim-3 and 2B4 which then culminated in an enhanced functionality of CMV/EBV-specific CD8+ T cells in CHC patients. Comprehensively analyzing plasma cytokines between the two cohorts, we observed that not only was IFNα-2a dominant among 21 other inflammatory mediators elevated in CHC patients, but it also correlated with PD-1 and Tim-3 expressions ex vivo. Importantly, IFNα-2a further caused up-regulation of these markers upon in vitro peptide stimulation. Finally we could prospectively study patients receiving novel IFN-free antiviral therapy. Here we observed that treatment-induced clearance of HCV resulted in a partial reversion of the phenotype of CMV/EBV-specific CD8+ T cells in patients with CHC. These data reveal an alteration of the plasma concentrations of IFNα-2a together with other inflammatory mediators during chronic hepatitis C, which appeared to pervasively influence co-regulatory receptor expression on CMV/EBV-specific CD8+ T cells.

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