Dysfunctional CD8(+) T cells in hepatitis B and C are characterized by a lack of antigen-specific T-bet induction

Peter D. Kurktschiev*, Bijan Raziorrouh, Winfried Schraut, Markus Backmund, Martin Waechtler, Clemens-Martin Wendtner, Bertram Bengsch, Robert Thimme, Gerald Denk, Reinhart Zachoval, Andrea Dick, Michael Spannagl, Juergen Haas, Helmut M. Diepolder, Maria-Christina Jung, Norbert H. Gruener

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

The transcription factor T-bet regulates the production of interferon-gamma 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-gamma 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-gamma 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.

Original languageEnglish
Pages (from-to)2047-2059
Number of pages13
JournalJournal of Experimental Medicine
Volume211
Issue number10
DOIs
Publication statusPublished - 15 Sep 2014

Keywords

  • RECOMBINANT HUMAN INTERLEUKIN-12
  • VIRUS-INFECTION
  • TRANSCRIPTION FACTOR
  • VIRAL CLEARANCE
  • PHASE I/II
  • RESPONSES
  • EFFECTOR
  • DIFFERENTIATION
  • EXPRESSION
  • PROLIFERATION

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