Linked Life Data

16520391

Source:http://linkedlifedata.com/resource/pubmed/id/16520391

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pubmed-article:16520391pubmed:abstractTextT 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-12Rbeta2 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.lld:pubmed
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pubmed-article:16520391pubmed:authorpubmed-author:StroberWarren...lld:pubmed
pubmed-article:16520391pubmed:authorpubmed-author:UsuiTakashiTlld:pubmed
pubmed-article:16520391pubmed:authorpubmed-author:KannoYukaYlld:pubmed
pubmed-article:16520391pubmed:authorpubmed-author:BreamJay HJHlld:pubmed
pubmed-article:16520391pubmed:authorpubmed-author:PreissJan CJClld:pubmed
pubmed-article:16520391pubmed:authorpubmed-author:YaoZheng JuZJlld:pubmed
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pubmed-article:16520391pubmed:dateRevised2009-11-18lld:pubmed
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