title: T-bet regulates Th1 responses through essential effects on GATA-3 function rather than on IFNG gene acetylation and transcription.
abstract: 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-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.
authors.affiliation: Mucosal Immunity Section, Laboratory of Host Defenses, National Institute of Allergy and Infectious Disease (NIAID), National Institutes of Health (NIH), Bethesda, MD 20892, USA.
authors.forename: Takashi
authors.initials: T
authors.lastname: Usui
authors.forename: Jan C
authors.initials: JC
authors.lastname: Preiss
authors.forename: Yuka
authors.initials: Y
authors.lastname: Kanno
authors.forename: Zheng Ju
authors.initials: ZJ
authors.lastname: Yao
authors.forename: Jay H
authors.initials: JH
authors.lastname: Bream
authors.forename: John J
authors.initials: JJ
authors.lastname: O'Shea
authors.forename: Warren
authors.initials: W
authors.lastname: Strober
mesh_terms: D000107:Acetylation; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology*; D050990:GATA3 Transcription Factor / Q000235:genetics / Q000276:immunology*; D050991:GATA4 Transcription Factor / Q000235:genetics / Q000276:immunology; D006657:Histones / Q000235:genetics / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D011499:Protein Processing, Post-Translational / Q000235:genetics / Q000276:immunology; D018123:Receptors, Interleukin / Q000235:genetics / Q000276:immunology; D053707:Receptors, Interleukin-12; D012190:Retroviridae; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D020825:T-Box Domain Proteins; D018417:Th1 Cells / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology; D014157:Transcription Factors / Q000172:deficiency / Q000276:immunology*; D014158:Transcription, Genetic / Q000235:genetics / Q000276:immunology; D014161:Transduction, Genetic / Q000379:methods; D000098815:T-bet Transcription Factor
chemical_list: D050990:GATA3 Transcription Factor; D050991:GATA4 Transcription Factor; C494748:Gata3 protein, mouse; D006657:Histones; D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D014157:Transcription Factors; D007371:Interferon-gamma