T cell receptor signaling controls Foxp3 expression via PI3K, Akt, and mTOR

被引：715

作者：

Sauer, Stephan ^{[1
]}

Bruno, Ludovica ^{[1
]}

Hertweck, Arnulf ^{[1
]}

Finlay, David ^{[3
]}

Leleu, Marion ^{[1
]}

Spivakov, Mikhail ^{[1
]}

Knight, Zachary A. ^{[4
]}

Cobb, Bradley S. ^{[1
]}

Cantrell, Doreen ^{[3
]}

O'Connor, Eric ^{[2
]}

Shokat, Kevan M. ^{[4
]}

Fisher, Amanda G. ^{[1
]}

Merkenschlager, Matthias ^{[1
]}

机构：

[1] Univ London Imperial Coll Sci Technol & Med, Med Res Council Clin Sci Ctr, Lymphocyte Dev Grp, London W12 0NN, England

[2] Univ London Imperial Coll Sci Technol & Med, Med Res Council Clin Sci Ctr, Flow Cytometry Facil, London W12 0NN, England

[3] Univ Dundee, Coll Life Sci, Div Cell Biol & Immunol, Dundee DD1 5EH, Scotland

[4] Univ Calif San Francisco, Howard Hughes Med Inst, Dept Cellular & Mol Pharmacol, San Francisco, CA 94143 USA

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2008年 / 105卷 / 22期

基金：

英国医学研究理事会; 英国惠康基金;

关键词：

D O I：

10.1073/pnas.0800928105

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页码：7797 / 7802

页数：6

共 46 条

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