Published September 15, 2014
The Rockefeller University Press, doi: 10.1084/jem.20131333 © 2014 Kurktschiev et al.
Dysfunctional CD8+ T cells in hepatitis B and C are characterized by a lack of antigen-specific T-bet induction - Peter D. Kurktschiev,1,2
- Bijan Raziorrouh,1,2
- Winfried Schraut,1,2
- Markus Backmund,2,3
- Martin Wächtler,4
- Clemens-Martin Wendtner,4
- Bertram Bengsch,5
- Robert Thimme,5
- Gerald Denk,2
- Reinhart Zachoval,2
- Andrea Dick,6
- Michael Spannagl,6
- Jürgen Haas,7
- Helmut M. Diepolder,2
- Maria-Christina Jung,8 and
- Norbert H. Gruener1,2
- Author Affiliations - 1Institute for Immunology, Ludwig-Maximilians-University, 80539 Munich, Germany
- 2Department of Medicine II, University Hospital Munich, 80539 Munich, Germany
- 3PiT – Praxis im Tal, 80331 Munich, Germany
- 4Department of Medicine, Klinikum Schwabing, 81925 Munich, Germany
- 5Department of Medicine II, University Hospital Freiburg, 79106 Freiburg, Germany
- 6Laboratory of Immunogenetics and Molecular Diagnostics, 80539 Munich, Germany
- 7Division of Infection and Pathway Medicine, University of Edinburgh, Edinburgh EH16 4SB, Scotland, UK
- 8Leberzentrum München, 80336 Munich, Germany
Abstract The transcription factor T-bet regulates the production of interferon-γ and cytotoxic molecules in effector CD8 T cells, and its expression correlates with improved control of chronic viral infections. However, the role of T-bet in infections with differential outcome remains poorly defined. Here, we report that high expression of T-bet in virus-specific CD8 T cells during acute hepatitis B virus (HBV) and hepatitis C virus (HCV) infection was associated with spontaneous resolution, whereas T-bet deficiency was more characteristic of chronic evolving infection. T-bet strongly correlated with interferon-γ production and proliferation of virus-specific CD8 T cells, and its induction by antigen and IL-2 stimulation partially restored functionality in previously dysfunctional T-bet–deficient CD8 T cells. However, restoration of a strong interferon-γ response required additional stimulation with IL-12, which selectively induced the phosphorylation of STAT4 in T-bet+ CD8 T cells. The observation that T-bet expression rendered CD8 T cells responsive to IL-12 suggests a stepwise mechanism of T cell activation in which T-bet facilitates the recruitment of additional transcription factors in the presence of key cytokines. These findings support a critical role of T-bet for viral clearance and suggest T-bet deficiency as an important mechanism behind chronic infection.
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