The Journal of Experimental Medicine
StemCell Technologies
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Published online 6 March 2006 doi:10.1084/jem.20052165
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 203, Number 3, 755-766
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ARTICLE

 T-bet regulates Th1 responses through essential effects on GATA-3 function rather than on IFNG gene acetylation and transcription

Takashi Usui1, Jan C. Preiss1, Yuka Kanno2, Zheng Ju Yao2, Jay H. Bream2, John J. O'Shea2, and Warren Strober1

1 Mucosal Immunity Section, Laboratory of Host Defenses, National Institute of Allergy and Infectious Disease (NIAID), and 2 Molecular Immunology and Inflammation Branch, National Institute of Arthritis, Musculoskeletal and Skin Diseases, National Institutes of Health (NIH), Bethesda, MD 20892

CORRESPONDENCE Warren Strober: wstrober{at}niaid.nih.gov

T helper type 1 (Th1) development is facilitated by interrelated changes in key intracellular factors, particularly signal transducer and activator of transcription (STAT)4, T-bet, and GATA-3. Here we show that CD4+ cells from T-bet–/– mice are skewed toward Th2 differentiation by high endogenous GATA-3 levels but exhibit virtually normal Th1 differentiation provided that GATA-3 levels are regulated at an early stage by anti–interleukin (IL)-4 blockade of IL-4 receptor (R) signaling. In addition, under these conditions, Th1 cells from T-bet–/– mice manifest IFNG promotor accessibility as detected by histone acetylation and deoxyribonuclease I hypersensitivity. In related studies, we show that the negative effect of GATA-3 on Th1 differentiation in T-bet–/– cells arises from its ability to suppress STAT4 levels, because if this is prevented by a STAT4-expressing retrovirus, normal Th1 differentiation is observed. Finally, we show that retroviral T-bet expression in developing and established Th2 cells leads to down-regulation of GATA-3 levels. These findings lead to a model of T cell differentiation that holds that naive T cells tend toward Th2 differentiation through induction of GATA-3 and subsequent down-regulation of STAT4/IL-12Rß2 chain unless GATA-3 levels or function is regulated by T-bet. Thus, the principal function of T-bet in developing Th1 cells is to negatively regulate GATA-3 rather than to positively regulate the IFNG gene.

Abbreviations used: ChIP, chromatin immunoprecipitation; MFI, mean fluorescence intensity.


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