T cell receptor signaling controls Foxp3 expression via PI3K, Akt, and mTOR
T cell receptor signaling controls Foxp3 expression via PI3K, Akt, and mTOR
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DOI：
10.1073/pnas.0800928105
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发表时间：
2008-06-03
影响因子：
11.1
通讯作者：
Merkenschlager, Matthias
中科院分区：
文献类型：
--
作者：
Sauer, Stephan;Bruno, Ludovica;Merkenschlager, Matthias
调节性T（Treg）细胞保护自身免疫和免疫病理。由于Treg细胞命运的决定因素还不完全清楚，我们已经描述了控制初始外周CD 4 T细胞和胸腺细胞中Foxp 3从头表达的信号传导事件。我们报道了TCR信号的提前终止和磷脂酰肌醇3-激酶（PI 3 K）p110 α、p110 δ、蛋白激酶B（Akt）或哺乳动物雷帕霉素靶蛋白（mTOR）的抑制赋予Foxp 3表达和Treg样基因表达谱。相反，持续的TCR信号传导和组成型PI 3 K/Akt/mTOR活性拮抗Foxp 3诱导。在染色质水平，Foxp 3转录起始位点（TSS）附近和5'非翻译区（UTR）内的组蛋白H3的赖氨酸4（H3 K4 me 2和-3）的二-和三甲基化先于活性Foxp 3表达，并且与Foxp 3诱导一样，在持续TCR刺激后丧失。这些数据表明PI 3 K/ Akt/mTOR信号网络调节Foxp 3表达。
Regulatory T (Treg) cells safeguard against autoimmunity and immune pathology. Because determinants of the Treg cell fate are not completely understood, we have delineated signaling events that control the de novo expression of Foxp3 in naive peripheral CD4 T cells and in thymocytes. We report that premature termination of TCR signaling and inibition of phosphaticlyl inositol 3-kinase (PI3K) p110 alpha, p110 delta, protein kinase B (Akt), or mammalian target of rapamycin (mTOR) conferred Foxp3 expression and Treg-like gene expression profiles. Conversely, continued TCR signaling and constitutive PI3K/Akt/mTOR activity antagonised Foxp3 induction. At the chromatin level, di- and trimethylation of lysine 4 of histone H3 (H3K4me2 and -3) near the Foxp3 transcription start site (TSS) and within the 5' untranslated region (UTR) preceded active Foxp3 expression and, like Foxp3 inducibility, was lost upon continued TCR stimulation. These data demonstrate that the PI3K/ Akt/mTOR signaling network regulates Foxp3 expression.