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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-\u03b3 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\u2013deficient CD8 T cells. However, restoration of a strong interferon-\u03b3 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.<\/jats:p>","DOI":"10.1084\/jem.20131333","type":"journal-article","created":{"date-parts":[[2014,9,16]],"date-time":"2014-09-16T07:56:27Z","timestamp":1410854187000},"page":"2047-2059","update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":98,"title":["Dysfunctional CD8+ T cells in hepatitis B and C are characterized by a lack of antigen-specific T-bet induction"],"prefix":"10.1084","volume":"211","author":[{"given":"Peter D.","family":"Kurktschiev","sequence":"first","affiliation":[{"name":"Institute for Immunology, Ludwig-Maximilians-University, 80539 Munich, Germany 1"},{"name":"Department of Medicine II, University Hospital Munich, 80539 Munich, Germany 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bijan","family":"Raziorrouh","sequence":"additional","affiliation":[{"name":"Institute for Immunology, Ludwig-Maximilians-University, 80539 Munich, Germany 1"},{"name":"Department of Medicine II, University Hospital Munich, 80539 Munich, Germany 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Winfried","family":"Schraut","sequence":"additional","affiliation":[{"name":"Institute for Immunology, Ludwig-Maximilians-University, 80539 Munich, Germany 1"},{"name":"Department of Medicine II, University Hospital Munich, 80539 Munich, Germany 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markus","family":"Backmund","sequence":"additional","affiliation":[{"name":"Department of Medicine II, University Hospital Munich, 80539 Munich, Germany 2"},{"name":"PiT \u2013 Praxis im Tal, 80331 Munich, Germany 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"W\u00e4chtler","sequence":"additional","affiliation":[{"name":"Department of Medicine, Klinikum Schwabing, 81925 Munich, Germany 4"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clemens-Martin","family":"Wendtner","sequence":"additional","affiliation":[{"name":"Department of Medicine, Klinikum Schwabing, 81925 Munich, Germany 4"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bertram","family":"Bengsch","sequence":"additional","affiliation":[{"name":"Department of Medicine II, University Hospital Freiburg, 79106 Freiburg, Germany 5"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Thimme","sequence":"additional","affiliation":[{"name":"Department of Medicine II, University Hospital Freiburg, 79106 Freiburg, Germany 5"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerald","family":"Denk","sequence":"additional","affiliation":[{"name":"Department of Medicine II, University Hospital Munich, 80539 Munich, Germany 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reinhart","family":"Zachoval","sequence":"additional","affiliation":[{"name":"Department of Medicine II, University Hospital Munich, 80539 Munich, Germany 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Dick","sequence":"additional","affiliation":[{"name":"Laboratory of Immunogenetics and Molecular Diagnostics, 80539 Munich, Germany 6"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Spannagl","sequence":"additional","affiliation":[{"name":"Laboratory of Immunogenetics and Molecular Diagnostics, 80539 Munich, Germany 6"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00fcrgen","family":"Haas","sequence":"additional","affiliation":[{"name":"Division of Infection and Pathway Medicine, University of Edinburgh, Edinburgh EH16 4SB, Scotland, UK 7"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helmut M.","family":"Diepolder","sequence":"additional","affiliation":[{"name":"Department of Medicine II, University Hospital Munich, 80539 Munich, Germany 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria-Christina","family":"Jung","sequence":"additional","affiliation":[{"name":"Leberzentrum M\u00fcnchen, 80336 Munich, Germany 8"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norbert H.","family":"Gruener","sequence":"additional","affiliation":[{"name":"Institute for Immunology, Ludwig-Maximilians-University, 80539 Munich, Germany 1"},{"name":"Department of Medicine II, University Hospital Munich, 80539 Munich, Germany 2"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2014,9,15]]},"reference":[{"key":"2023072601520411100_bib1","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1002\/(SICI)1096-9071(199803)54:3&lt;167::AID-JMV4&gt;3.0.CO;2-3","article-title":"Double-blind, randomized controlled trial of interleukin-2 treatment of chronic hepatitis B","volume":"54","author":"Artillo","year":"1998","journal-title":"J. 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