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Blood, 1 September 2006, Vol. 108, No. 5, pp. 1595-1601. Prepublished online as a Blood First Edition Paper on May 2, 2006; DOI 10.1182/blood-2006-04-015016. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2006-04-015016v1 108/5/1595    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Mathur, A. N. Articles by Kaplan, M. H. Search for Related Content PubMed PubMed Citation Articles by Mathur, A. N. Articles by Kaplan, M. H. Related Collections Immunobiology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY T-bet is a critical determinant in the instability of the IL-17-secreting T-helper phenotype Anubhav N. Mathur, Hua-Chen Chang, Dimitrios G. Zisoulis, Reuben Kapur, Maria Laura Belladonna, Geoffrey S. Kansas, and Mark H. Kaplan From the Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis; the Walther Oncology Center, Indiana University School of Medicine, Indianapolis; the Department of Biochemistry, Indiana University School of Medicine, Indianapolis; the Department of Pediatrics, Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis; the Walther Cancer Institute, Indianapolis; the Department of Microbiology-Immunology, Northwestern University Medical School, Chicago IL; and the Department of Experimental Medicine, University of Perugia, Italy. IL-23, an IL-12-related cytokine, induces an IL-17-secreting T-helper phenotype that is involved in autoimmune diseases and host defense against certain pathogens. Although the transcription factors required for development of IL-23-stimulated cells are unknown, we show that T-bet is a critical negative regulator of the IL-23-primed T-cell phenotype, which we term Th1. Th1 or Th1 Tbx21-/- cultures secrete higher than WT levels of IL-17 in response to T-cell receptor (TCR) or IL-23 + IL-18 stimulation. Ectopic T-bet expression in Th1 cells promotes IFN- secretion but decreases IL-17 production. Although antigen-receptor stimulation of Th1 cells stimulates IL-17 production, it also induces the IFN--independent expression of T-bet and progression to a Th1 cytokine secretion pattern. T-bet is required for the progression to the Th1 phenotype, because Tbx21-/- Th1 cultures maintain the IL-17-secreting phenotype after 2 weeks of culture. Addition of IFN- to Tbx21-/- Th1 cultures cannot recover the progression to the Th1 phenotype, suggesting T-bet, rather than IFN-, mediates Th1 to Th1 progression. The transient nature of the Th1 phenotype suggests that these cells are a component of type I immunity and that T-bet expression is a critical determinant of Th1 versus Th1 cell fate. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: J. Das, G. Ren, L. Zhang, A. I. Roberts, X. Zhao, A. L.M. Bothwell, L. Van Kaer, Y. Shi, and G. Das Transforming growth factor {beta} is dispensable for the molecular orchestration of Th17 cell differentiation J. Exp. Med., October 26, 2009; 206(11): 2407 - 2416. [Abstract] [Full Text] [PDF] D. M. Durrant, S. L. Gaffen, E. P. Riesenfeld, C. G. Irvin, and D. W. Metzger Development of Allergen-Induced Airway Inflammation in the Absence of T-bet Regulation Is Dependent on IL-17 J. Immunol., October 15, 2009; 183(8): 5293 - 5300. [Abstract] [Full Text] [PDF] M. El-behi, B. Ciric, S. Yu, G.-X. Zhang, D. C. Fitzgerald, and A. Rostami Differential Effect of IL-27 on Developing versus Committed Th17 Cells J. Immunol., October 15, 2009; 183(8): 4957 - 4967. [Abstract] [Full Text] [PDF] S. R. Good, V. T. Thieu, A. N. Mathur, Q. Yu, G. L. Stritesky, N. Yeh, J. T. O'Malley, N. B. Perumal, and M. H. Kaplan Temporal Induction Pattern of STAT4 Target Genes Defines Potential for Th1 Lineage-Specific Programming J. Immunol., September 15, 2009; 183(6): 3839 - 3847. [Abstract] [Full Text] [PDF] S. Guo, D. Cobb, and R. B. Smeltz T-bet Inhibits the In Vivo Differentiation of Parasite-Specific CD4+ Th17 Cells in a T Cell-Intrinsic Manner J. Immunol., May 15, 2009; 182(10): 6179 - 6186. [Abstract] [Full Text] [PDF] B. Ciric, M. El-behi, R. Cabrera, G.-X. Zhang, and A. Rostami IL-23 Drives Pathogenic IL-17-Producing CD8+ T Cells J. Immunol., May 1, 2009; 182(9): 5296 - 5305. [Abstract] [Full Text] [PDF] X. Yuan, J. Paez-Cortez, I. Schmitt-Knosalla, F. D'Addio, B. Mfarrej, M. Donnarumma, A. Habicht, M. R. Clarkson, J. Iacomini, L. H. Glimcher, et al. A novel role of CD4 Th17 cells in mediating cardiac allograft rejection and vasculopathy J. Exp. Med., December 22, 2008; 205(13): 3133 - 3144. [Abstract] [Full Text] [PDF] Y. Wang, D. Feng, G. Liu, Q. Luo, Y. Xu, S. Lin, J. Fei, and L. Xu {gamma}-Aminobutyric Acid Transporter 1 Negatively Regulates T Cell-Mediated Immune Responses and Ameliorates Autoimmune Inflammation in the CNS J. Immunol., December 15, 2008; 181(12): 8226 - 8236. [Abstract] [Full Text] [PDF] Y. Yang, J. Xu, Y. Niu, J. S. Bromberg, and Y. Ding T-bet and Eomesodermin Play Critical Roles in Directing T Cell Differentiation to Th1 versus Th17 J. Immunol., December 15, 2008; 181(12): 8700 - 8710. [Abstract] [Full Text] [PDF] T Kobayashi, S Okamoto, T Hisamatsu, N Kamada, H Chinen, R Saito, M T Kitazume, A Nakazawa, A Sugita, K Koganei, et al. 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Annunziato, L. Cosmi, V. Santarlasci, L. Maggi, F. Liotta, B. Mazzinghi, E. Parente, L. Fili, S. Ferri, F. Frosali, et al. Phenotypic and functional features of human Th17 cells J. Exp. Med., August 6, 2007; 204(8): 1849 - 1861. [Abstract] [Full Text] [PDF] C. A. Williams, S. E. Murray, A. D. Weinberg, and D. C. Parker OX40-Mediated Differentiation to Effector Function Requires IL-2 Receptor Signaling but Not CD28, CD40, IL-12Rbeta2, or T-bet J. Immunol., June 15, 2007; 178(12): 7694 - 7702. [Abstract] [Full Text] [PDF] A. F. Sheibanie, J.-H. Yen, T. Khayrullina, F. Emig, M. Zhang, R. Tuma, and D. Ganea The Proinflammatory Effect of Prostaglandin E2 in Experimental Inflammatory Bowel Disease Is Mediated through the IL-23->IL-17 Axis J. Immunol., June 15, 2007; 178(12): 8138 - 8147. [Abstract] [Full Text] [PDF] S. Nakae, Y. Iwakura, H. Suto, and S. J. Galli Phenotypic differences between Th1 and Th17 cells and negative regulation of Th1 cell differentiation by IL-17 J. Leukoc. 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