title: Dysfunctional CD8+ T cells in hepatitis B and C are characterized by a lack of antigen-specific T-bet induction.
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.
authors.affiliation: Institute for Immunology, Ludwig-Maximilians-University, 80539 Munich, Germany Department of Medicine II, University Hospital Munich, 80539 Munich, Germany peter.kurktschiev@med.uni-muenchen.de.
authors.forename: Peter D
authors.initials: PD
authors.lastname: Kurktschiev
authors.affiliation: Institute for Immunology, Ludwig-Maximilians-University, 80539 Munich, Germany Department of Medicine II, University Hospital Munich, 80539 Munich, Germany.
authors.forename: Bijan
authors.initials: B
authors.lastname: Raziorrouh
authors.affiliation: Institute for Immunology, Ludwig-Maximilians-University, 80539 Munich, Germany Department of Medicine II, University Hospital Munich, 80539 Munich, Germany.
authors.forename: Winfried
authors.initials: W
authors.lastname: Schraut
authors.affiliation: Department of Medicine II, University Hospital Munich, 80539 Munich, Germany PiT - Praxis im Tal, 80331 Munich, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Backmund
authors.affiliation: Department of Medicine, Klinikum Schwabing, 81925 Munich, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Wächtler
authors.affiliation: Department of Medicine, Klinikum Schwabing, 81925 Munich, Germany.
authors.forename: Clemens-Martin
authors.initials: CM
authors.lastname: Wendtner
authors.affiliation: Department of Medicine II, University Hospital Freiburg, 79106 Freiburg, Germany.
authors.forename: Bertram
authors.initials: B
authors.lastname: Bengsch
authors.affiliation: Department of Medicine II, University Hospital Freiburg, 79106 Freiburg, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Thimme
authors.affiliation: Department of Medicine II, University Hospital Munich, 80539 Munich, Germany.
authors.forename: Gerald
authors.initials: G
authors.lastname: Denk
authors.affiliation: Department of Medicine II, University Hospital Munich, 80539 Munich, Germany.
authors.forename: Reinhart
authors.initials: R
authors.lastname: Zachoval
authors.affiliation: Laboratory of Immunogenetics and Molecular Diagnostics, 80539 Munich, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Dick
authors.affiliation: Laboratory of Immunogenetics and Molecular Diagnostics, 80539 Munich, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Spannagl
authors.affiliation: Division of Infection and Pathway Medicine, University of Edinburgh, Edinburgh EH16 4SB, Scotland, UK.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Haas
authors.affiliation: Department of Medicine II, University Hospital Munich, 80539 Munich, Germany.
authors.forename: Helmut M
authors.initials: HM
authors.lastname: Diepolder
authors.affiliation: Leberzentrum München, 80336 Munich, Germany.
authors.forename: Maria-Christina
authors.initials: MC
authors.lastname: Jung
authors.affiliation: Institute for Immunology, Ludwig-Maximilians-University, 80539 Munich, Germany Department of Medicine II, University Hospital Munich, 80539 Munich, Germany.
authors.forename: Norbert H
authors.initials: NH
authors.lastname: Gruener
mesh_terms: D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D005434:Flow Cytometry; D006509:Hepatitis B / Q000276:immunology*; D006526:Hepatitis C / Q000276:immunology*; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism; D010766:Phosphorylation; D050797:STAT4 Transcription Factor / Q000378:metabolism; D018709:Statistics, Nonparametric; D020825:T-Box Domain Proteins / Q000276:immunology / Q000378:metabolism*; D000098815:T-bet Transcription Factor
chemical_list: D050797:STAT4 Transcription Factor; C494090:STAT4 protein, human; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D018664:Interleukin-12; D007371:Interferon-gamma