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Science 292 (5523): 1907-1910

Copyright © 2001 by the American Association for the Advancement of Science

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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   Abstract »    Full Text »    PDF »
Transcriptional Activators of Helper T Cell Fate Are Required for Establishment but Not Maintenance of Signature Cytokine Expression.
G. A. Martins, A. S. Hutchins, and S. L. Reiner (2005)
J. Immunol. 175, 5981-5985
   Abstract »    Full Text »    PDF »
Upregulation of T-bet expression in peripheral blood mononuclear cells during Vogt-Koyanagi-Harada disease.
B Li, P Yang, H Zhou, X Huang, H Jin, L Chu, Y Gao, L Zhu, and A Kijlstra (2005)
Br J Ophthalmol 89, 1410-1412
   Abstract »    Full Text »    PDF »
Expression of T-bet by CD4 T Cells Is Essential for Resistance to Salmonella Infection.
R. Ravindran, J. Foley, T. Stoklasek, L. H. Glimcher, and S. J. McSorley (2005)
J. Immunol. 175, 4603-4610
   Abstract »    Full Text »    PDF »
A Role for IL-27 in Early Regulation of Th1 Differentiation.
T. Owaki, M. Asakawa, N. Morishima, K. Hata, F. Fukai, M. Matsui, J. Mizuguchi, and T. Yoshimoto (2005)
J. Immunol. 175, 2191-2200
   Abstract »    Full Text »    PDF »
Asthmatic changes in mice lacking T-bet are mediated by IL-13.
S. Finotto, M. Hausding, A. Doganci, J. H. Maxeiner, H. A. Lehr, C. Luft, P. R. Galle, and L. H. Glimcher (2005)
Int. Immunol. 17, 993-1007
   Abstract »    Full Text »    PDF »
The Functional Heterogeneity of Type 1 Effector T Cells in Response to Infection Is Related to the Potential for IFN-{gamma} Production.
K. D. Mayer, K. Mohrs, S. R. Crowe, L. L. Johnson, P. Rhyne, D. L. Woodland, and M. Mohrs (2005)
J. Immunol. 174, 7732-7739
   Abstract »    Full Text »    PDF »
Regulation of IFN-{gamma} Production by B Effector 1 Cells: Essential Roles for T-bet and the IFN-{gamma} Receptor.
D. P. Harris, S. Goodrich, A. J. Gerth, S. L. Peng, and F. E. Lund (2005)
J. Immunol. 174, 6781-6790
   Abstract »    Full Text »    PDF »
TGF-{beta}1 Uses Distinct Mechanisms to Inhibit IFN-{gamma} Expression in CD4+ T Cells at Priming and at Recall: Differential Involvement of Stat4 and T-bet.
J. T. Lin, S. L. Martin, L. Xia, and J. D. Gorham (2005)
J. Immunol. 174, 5950-5958
   Abstract »    Full Text »    PDF »
Protective Immunity to Genital Herpes Simpex Virus Type 2 Infection Is Mediated by T-bet.
A. Svensson, I. Nordstrom, J.-B. Sun, and K. Eriksson (2005)
J. Immunol. 174, 6266-6273
   Abstract »    Full Text »    PDF »
Epigenetic control in the immune response.
S. L. Reiner (2005)
Hum. Mol. Genet. 14, R41-R46
   Abstract »    Full Text »    PDF »
Maintenance of Pulmonary Th1 Effector Function in Chronic Tuberculosis Requires Persistent IL-12 Production.
C. G. Feng, D. Jankovic, M. Kullberg, A. Cheever, C. A. Scanga, S. Hieny, P. Caspar, G. S. Yap, and A. Sher (2005)
J. Immunol. 174, 4185-4192
   Abstract »    Full Text »    PDF »
Ets-1, a functional cofactor of T-bet, is essential for Th1 inflammatory responses.
R. Grenningloh, B. Y. Kang, and I-C. Ho (2005)
J. Exp. Med. 201, 615-626
   Abstract »    Full Text »    PDF »
Different Competitive Capacities of Stat4- and Stat6-Deficient CD4+ T Cells during Lymphophenia-Driven Proliferation.
V. Sanchez-Guajardo, J. A. M. Borghans, M.-E. Marquez, S. Garcia, and A. A. Freitas (2005)
J. Immunol. 174, 1178-1187
   Abstract »    Full Text »    PDF »
Polarized Development of Memory Cell-Like IFN-{gamma}-Producing Cells in the Absence of TCR {zeta}-Chain.
L. Krymskaya, W.-H. Lee, L. Zhong, and C.-P. Liu (2005)
J. Immunol. 174, 1188-1195
   Abstract »    Full Text »    PDF »
TLR Ligands Can Activate Dendritic Cells to Provide a MyD88-Dependent Negative Signal for Th2 Cell Development.
J. Sun, M. Walsh, A. V. Villarino, L. Cervi, C. A. Hunter, Y. Choi, and E. J. Pearce (2005)
J. Immunol. 174, 742-751
   Abstract »    Full Text »    PDF »
Abnormal Th1 Cell Differentiation and IFN-{gamma} Production in T Lymphocytes from Motheaten Viable Mice Mutant for Src Homology 2 Domain-Containing Protein Tyrosine Phosphatase-1.
W.-M. Yu, S. Wang, A. D. Keegan, M. S. Williams, and C.-K. Qu (2005)
J. Immunol. 174, 1013-1019
   Abstract »    Full Text »    PDF »

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