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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 105; no. 22; pp. 7797 - 7802
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 03.06.2008; National Acad Sciences
• Subjects: 5' Untranslated Regions - metabolism; Animals; Antigen presenting cells; Biological Sciences; Cells; Chromatin; Cultured cells; Drug regulation; Forkhead Transcription Factors - genetics; Forkhead Transcription Factors - metabolism; Gene expression; Histones - metabolism; Immunology; Isoenzymes - metabolism; Kinases; Methylation; Mice; Mice, Inbred Strains; MicroRNA; MicroRNAs - metabolism; Phosphatidylinositol 3-Kinases - metabolism; Phosphoinositide-3 Kinase Inhibitors; Protein Kinases - metabolism; Proto-Oncogene Proteins c-akt - antagonists & inhibitors; Proto-Oncogene Proteins c-akt - metabolism; Receptors, Antigen, T-Cell - agonists; Receptors, Antigen, T-Cell - metabolism; Signal Transduction; Stem cells; T cell antigen receptors; T cell receptors; T lymphocytes; T-Lymphocytes, Regulatory - drug effects; T-Lymphocytes, Regulatory - immunology; Thymocytes; TOR Serine-Threonine Kinases; Transcription Initiation Site; Transforming Growth Factor beta - metabolism
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0800928105

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) p110α, p110δ, 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.