Yu Qing, Sharma Archna, Oh Sun Young, Moon Hyung-Geun, Hossain M Zulfiquer, Salay Theresa M, Leeds Karen E, Du Hansen, Wu Beibei, Waterman Marian L, Zhu Zhou, Sen Jyoti Misra
Lymphocyte Development Unit, Laboratory of Immunology, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, USA.
Nat Immunol. 2009 Sep;10(9):992-9. doi: 10.1038/ni.1762. Epub 2009 Aug 2.
The differentiation of activated CD4(+) T cells into the T helper type 1 (T(H)1) or T(H)2 fate is regulated by cytokines and the transcription factors T-bet and GATA-3. Whereas interleukin 12 (IL-12) produced by antigen-presenting cells initiates the T(H)1 fate, signals that initiate the T(H)2 fate are not completely characterized. Here we show that early GATA-3 expression, required for T(H)2 differentiation, was induced by T cell factor 1 (TCF-1) and its cofactor beta-catenin, mainly from the proximal Gata3 promoter upstream of exon 1b. This activity was induced after T cell antigen receptor (TCR) stimulation and was independent of IL-4 receptor signaling through the transcription factor STAT6. Furthermore, TCF-1 blocked T(H)1 fate by negatively regulating interferon-gamma (IFN-gamma) expression independently of beta-catenin. Thus, TCF-1 initiates T(H)2 differentiation of activated CD4(+) T cells by promoting GATA-3 expression and suppressing IFN-gamma expression.
活化的CD4(+) T细胞向1型辅助性T细胞（T(H)1）或2型辅助性T细胞（T(H)2）命运的分化受细胞因子以及转录因子T-bet和GATA-3的调控。抗原呈递细胞产生的白细胞介素12（IL-12）启动T(H)1命运，而启动T(H)2命运的信号尚未完全明确。我们在此表明，T(H)2分化所需的早期GATA-3表达由T细胞因子1（TCF-1）及其辅因子β-连环蛋白诱导，主要来自外显子1b上游的近端Gata3启动子。这种活性在T细胞抗原受体（TCR）刺激后被诱导，且独立于通过转录因子STAT6的IL-4受体信号传导。此外，TCF-1通过独立于β-连环蛋白负向调节干扰素-γ（IFN-γ）表达来阻断T(H)1命运。因此，TCF-1通过促进GATA-3表达和抑制IFN-γ表达来启动活化的CD4(+) T细胞的T(H)2分化。
