Friend of GATA is expressed in naive Th cells and functions as a repressor of GATA-3-mediated Th2 cell development.
The commitment of naive T cells to polarized Th cells requires specific changes in their transcription factors. Retrovirally overexpressed GATA-3 has been reported to induce the Th2 cytokine profile in developing Th1 cells. In this study, we examined the role of the N-terminal finger (Nf) of GATA-3 in Th2 cell development. The Nf, as well as the C-terminal finger and the transactivation domain, is critical for the induction of the Th2 phenotype. Using the GATA-3-Nf as a bait, our yeast two-hybrid screening identified friend of GATA (FOG) in the Th2 cell-specific library. Naive T cells express significant levels of FOG mRNA, which was rapidly down-regulated upon commitment to both Th1 and Th2 lineages. In reporter assays, FOG blocked the GATA-3-mediated activation of several cytokine promoters. Finally, retroviral expression of FOG in developing Th2 cells suppressed both IL-4 and IL-5 and allowed for IFN-gamma production, which was accompanied by a significant level of T-bet mRNA expression. Serial deletion mutation analysis indicated that the N-terminal region, but not the consensus C-terminal binding protein-binding motif, of FOG is critical for the effects. Our results clearly indicate that 1) FOG is a repressor of GATA-3 in naive T cells and 2) the down-regulation of FOG induces Th2 cell differentiation by releasing GATA-3 from its repression.
Kurata
Hirokazu
H
Department of Immunology, DNAX Research Institute of Molecular and Cellular Biology, Palo Alto, CA 94304, USA. hirokazu.kurata@dnax.org
Lee
Hyun-Jun
HJ
McClanahan
Terri
T
Coffman
Robert L
RL
O'Garra
Anne
A
Arai
Naoko
N
D000818:Animals; D002352:Carrier Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D050990:GATA3 Transcription Factor; D019672:Genes, T-Cell Receptor; D007371:Interferon-gamma / Q000096:biosynthesis; D007700:Kinetics; D051379:Mice; D008822:Mice, Transgenic; D009687:Nuclear Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology*; D009928:Organ Specificity; D011401:Promoter Regions, Genetic; D017434:Protein Structure, Tertiary; D012097:Repressor Proteins / Q000235:genetics / Q000502:physiology; D012190:Retroviridae / Q000235:genetics; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology*; D015534:Trans-Activators / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D014157:Transcription Factors; D014158:Transcription, Genetic; D014161:Transduction, Genetic
D002352:Carrier Proteins; D016207:Cytokines; D004268:DNA-Binding Proteins; D050990:GATA3 Transcription Factor; C494748:Gata3 protein, mouse; D009687:Nuclear Proteins; D012097:Repressor Proteins; D015534:Trans-Activators; D014157:Transcription Factors; C107310:Zfpm1 protein, mouse; D007371:Interferon-gamma