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Science 8 June 2001:
Vol. 292. no. 5523, pp. 1907 - 1910
DOI: 10.1126/science.1059835
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Reports

Role of T-bet in Commitment of TH1 Cells Before IL-12-Dependent Selection

Alan C. Mullen,1 Frances A. High,1 Anne S. Hutchins,1 Hubert W. Lee,1 Alejandro V. Villarino,1 David M. Livingston,2 Andrew L. Kung,2 Nezih Cereb,3 Tso-Pang Yao,4 Soo Y. Yang,3 Steven L. Reiner1*

How cytokines control differentiation of helper T (TH) cells is controversial. We show that T-bet, without apparent assistance from interleukin 12 (IL-12)/STAT4, specifies TH1 effector fate by targeting chromatin remodeling to individual interferon-gamma (IFN-gamma ) alleles and by inducing IL-12 receptor beta 2 expression. Subsequently, it appears that IL-12/STAT4 serves two essential functions in the development of TH1 cells: as growth signal, inducing survival and cell division; and as trans-activator, prolonging IFN-gamma synthesis through a genetic interaction with the coactivator, CREB-binding protein. These results suggest that a cytokine does not simply induce TH fate choice but instead may act as an essential secondary stimulus that mediates selective survival of a lineage.

1 Abramson Family Cancer Research Institute and Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104-6160, USA.
2 Dana Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA.
3 Histogenetics, Inc., and Center for Genetic Polymorphism, Hawthorne, NY 10532, USA.
4 Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA.
*   To whom correspondence should be addressed: sreiner{at}mail.med.upenn.edu

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Cutting Edge: Innate Production of IFN-{gamma} by NK Cells Is Independent of Epigenetic Modification of the IFN-{gamma} Promoter.
C. M. Tato, G. A. Martins, F. A. High, C. B. DiCioccio, S. L. Reiner, and C. A. Hunter (2004)
J. Immunol. 173, 1514-1517
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Loss of T-bet, But Not STAT1, Prevents the Development of Experimental Autoimmune Encephalomyelitis.
E. Bettelli, B. Sullivan, S. J. Szabo, R. A. Sobel, L. H. Glimcher, and V. K. Kuchroo (2004)
J. Exp. Med. 200, 79-87
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STAT4 activation in smokers and patients with chronic obstructive pulmonary disease.
A. Di Stefano, G. Caramori, A. Capelli, I. Gnemmi, F.L. Ricciardolo, T. Oates, C.F. Donner, K.F. Chung, P.J. Barnes, and I.M. Adcock (2004)
Eur. Respir. J. 24, 78-85
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Low Dose Leishmania major Promotes a Transient T Helper Cell Type 2 Response That Is Down-regulated by Interferon {gamma}-producing CD8+ T Cells.
J. E. Uzonna, K. L. Joyce, and P. Scott (2004)
J. Exp. Med. 199, 1559-1566
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Early Target Genes of IL-12 and STAT4 Signaling in Th Cells.
R. J. Lund, Z. Chen, J. Scheinin, and R. Lahesmaa (2004)
J. Immunol. 172, 6775-6782
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Cutting Edge: Early IL-4 Production Governs the Requirement for IL-27-WSX-1 Signaling in the Development of Protective Th1 Cytokine Responses following Leishmania major Infection.
D. Artis, L. M. Johnson, K. Joyce, C. Saris, A. Villarino, C. A. Hunter, and P. Scott (2004)
J. Immunol. 172, 4672-4675
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Cellular FLIP Long Form-Transgenic Mice Manifest a Th2 Cytokine Bias and Enhanced Allergic Airway Inflammation.
W. Wu, L. Rinaldi, K. A. Fortner, J. Q. Russell, J. Tschopp, C. Irvin, and R. C. Budd (2004)
J. Immunol. 172, 4724-4732
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Kinetic analysis of genomewide gene expression reveals molecule circuitries that control T cell activation and Th1/2 differentiation.
B. Lu, P. Zagouras, J. E. Fischer, J. Lu, B. Li, and R. A. Flavell (2004)
PNAS 101, 3023-3028
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STAT1 Is Essential for Antimicrobial Effector Function but Dispensable for Gamma Interferon Production during Toxoplasma gondii Infection.
L. C. Gavrilescu, B. A. Butcher, L. Del Rio, G. A. Taylor, and E. Y. Denkers (2004)
Infect. Immun. 72, 1257-1264
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IL-4-mediated inhibition of IFN-{gamma} production by CD4+ T cells proceeds by several developmentally regulated mechanisms.
O. Wurtz, M. Bajenoff, and S. Guerder (2004)
Int. Immunol. 16, 501-508
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Specific Regulation of T Helper Cell 1-mediated Murine Colitis by CEACAM1.
H. Iijima, M. F. Neurath, T. Nagaishi, J. N. Glickman, E. E. Nieuwenhuis, A. Nakajima, D. Chen, I. J. Fuss, N. Utku, D. N. Lewicki, et al. (2004)
J. Exp. Med. 199, 471-482
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A Distal Enhancer in the Interferon-{gamma} (IFN-{gamma}) Locus Revealed by Genome Sequence Comparison.
D. U. Lee, O. Avni, L. Chen, and A. Rao (2004)
J. Biol. Chem. 279, 4802-4810
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A mechanism underlying STAT4-mediated up-regulation of IFN-{gamma} induction inTCR-triggered T cells.
W.-R. Park, M. Nakahira, N. Sugimoto, Y. Bian, Y. Yashiro-Ohtani, X.-Y. Zhou, Y.-F. Yang, T. Hamaoka, and H. Fujiwara (2004)
Int. Immunol. 16, 295-302
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Potential Targets of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitor for Multiple Sclerosis Therapy.
N. Nath, S. Giri, R. Prasad, A. K. Singh, and I. Singh (2004)
J. Immunol. 172, 1273-1286
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Up-Regulation of Hlx in Immature Th Cells Induces IFN-{gamma} Expression.
W.-p. Zheng, Q. Zhao, X. Zhao, B. Li, M. Hubank, D. G. Schatz, and R. A. Flavell (2004)
J. Immunol. 172, 114-122
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Homing to Nonlymphoid Tissues Is Not Necessary for Effector Th1 Cell Differentiation.
M. Bajenoff and S. Guerder (2003)
J. Immunol. 171, 6355-6362
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