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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 (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 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 Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted April 4, 2006 Accepted April 20, 2006 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* Department of Microbiology and Immunology and the Walther Oncology Center, Indiana University Department of Microbiology-Immunology, Northwestern University Department of Biochemistry, Indiana University Department of Experimental Medicine, University of Perugia * Corresponding author; email: mkaplan2{at}iupui.edu. 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. While 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 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 as Tbx21-/- Th1 cultures maintain the IL-17 secreting phenotype after two 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. R. Lees, Y. Iwakura, and J. H. Russell Host T Cells Are the Main Producers of IL-17 within the Central Nervous System during Initiation of Experimental Autoimmune Encephalomyelitis Induced by Adoptive Transfer of Th1 Cell Lines J. Immunol., June 15, 2008; 180(12): 8066 - 8072. [Abstract] [Full Text] [PDF] G. Jiang, Y. Ke, D. Sun, G. Han, H. J. Kaplan, and H. Shao Reactivation of Uveitogenic T Cells by Retinal Astrocytes Derived from Experimental Autoimmune Uveitis-Prone B10RIII Mice Invest. Ophthalmol. Vis. Sci., January 1, 2008; 49(1): 282 - 289. [Abstract] [Full Text] [PDF] E. Smith, A. Zarbock, M. A. Stark, T. L. Burcin, A. C. Bruce, P. Foley, and K. Ley IL-23 Is Required for Neutrophil Homeostasis in Normal and Neutrophilic Mice J. Immunol., December 15, 2007; 179(12): 8274 - 8279. [Abstract] [Full Text] [PDF] J. Moisan, R. Grenningloh, E. Bettelli, M. Oukka, and I-C. Ho Ets-1 is a negative regulator of Th17 differentiation J. Exp. Med., November 26, 2007; 204(12): 2825 - 2835. [Abstract] [Full Text] [PDF] F. 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. Biol., May 1, 2007; 81(5): 1258 - 1268. [Abstract] [Full Text] [PDF] S. Nakae, H. Suto, G. J. Berry, and S. J. Galli Mast cell-derived TNF can promote Th17 cell-dependent neutrophil recruitment in ovalbumin-challenged OTII mice Blood, May 1, 2007; 109(9): 3640 - 3648. [Abstract] [Full Text] [PDF] A. N. Mathur, H.-C. Chang, D. G. Zisoulis, G. L. Stritesky, Q. Yu, J. T. O'Malley, R. Kapur, D. E. Levy, G. S. Kansas, and M. H. Kaplan Stat3 and Stat4 Direct Development of IL-17-Secreting Th Cells J. Immunol., April 15, 2007; 178(8): 4901 - 4907. [Abstract] [Full Text] [PDF]

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