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

Stephan Sauer, Ludovica Bruno, Arnulf Hertweck, David Finlay, Marion Leleu, Mikhail Spivakov, Zachary A. Knight, Bradley S. Cobb, Doreen Cantrell, Eric O'Connor, Kevan M. Shokat, Amanda G. Fisher, Matthias Merkenschlager

    Research output: Contribution to journalArticle

    596 Citations (Scopus)

    Abstract

    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.

    Original languageEnglish
    Pages (from-to)7797-7802
    Number of pages6
    JournalProceedings of the National Academy of Sciences of the United States of America
    Volume105
    Issue number22
    DOIs
    Publication statusPublished - 3 Jun 2008

    Keywords

    • Transcription factor Foxp3
    • De novo generation
    • Retinoic acid
    • Antigen receptor
    • Cutting edge
    • B-cell
    • Growth
    • P110-delta
    • Induction
    • Self

    Cite this

    Sauer, S., Bruno, L., Hertweck, A., Finlay, D., Leleu, M., Spivakov, M., Knight, Z. A., Cobb, B. S., Cantrell, D., O'Connor, E., Shokat, K. M., Fisher, A. G., & Merkenschlager, M. (2008). T cell receptor signaling controls Foxp3 expression via PI3K, Akt, and mTOR. Proceedings of the National Academy of Sciences of the United States of America, 105(22), 7797-7802. https://doi.org/10.1073/pnas.0800928105