Sauer Stephan, Bruno Ludovica, Hertweck Arnulf, Finlay David, Leleu Marion, Spivakov Mikhail, Knight Zachary A, Cobb Bradley S, Cantrell Doreen, O'Connor Eric, Shokat Kevan M, Fisher Amanda G, Merkenschlager Matthias
Lymphocyte Development Group, Medical Research Council Clinical Sciences Centre, Imperial College London, Du Cane Road, London W12 0NN, United Kingdom.
Proc Natl Acad Sci U S A. 2008 Jun 3;105(22):7797-802. doi: 10.1073/pnas.0800928105. Epub 2008 May 28.
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 phosphatidyl inositol 3-kinase (PI3K) p110alpha, p110delta, 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.
调节性T（Treg）细胞可预防自身免疫和免疫病理。由于Treg细胞命运的决定因素尚未完全明确，我们已经描绘出了控制初始外周CD4 T细胞和胸腺细胞中Foxp3从头表达的信号事件。我们报告称，TCR信号的过早终止以及磷脂酰肌醇3激酶（PI3K）p110α、p110δ、蛋白激酶B（Akt）或雷帕霉素靶蛋白（mTOR）的抑制赋予了Foxp3表达和Treg样基因表达谱。相反，持续的TCR信号和组成型PI3K/Akt/mTOR活性则拮抗Foxp3的诱导。在染色质水平上，Foxp3转录起始位点（TSS）附近以及5'非翻译区（UTR）内组蛋白H3赖氨酸4的二甲基化和三甲基化（H3K4me2和-3）先于活跃的Foxp3表达，并且与Foxp3的诱导能力一样，在持续的TCR刺激下会丧失。这些数据表明PI3K/Akt/mTOR信号网络调节Foxp3的表达。
