T cell receptor signaling controls Foxp3 expression via PI3K, Akt, and mTOR.
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.
Lymphocyte Development Group, Medical Research Council Clinical Sciences Centre, Imperial College London, Du Cane Road, London W12 0NN, United Kingdom.
Stephan
S
Sauer
Ludovica
L
Bruno
Arnulf
A
Hertweck
David
D
Finlay
Marion
M
Leleu
Mikhail
M
Spivakov
Zachary A
ZA
Knight
Bradley S
BS
Cobb
Doreen
D
Cantrell
Eric
E
O'Connor
Kevan M
KM
Shokat
Amanda G
AG
Fisher
Matthias
M
Merkenschlager
D020121:5' Untranslated Regions / Q000378:metabolism; D000818:Animals; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism; D008745:Methylation; D051379:Mice; D008815:Mice, Inbred Strains; D035683:MicroRNAs / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011494:Protein Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000819:agonists / Q000378:metabolism*; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology; D058570:TOR Serine-Threonine Kinases; D024363:Transcription Initiation Site; D016212:Transforming Growth Factor beta / Q000378:metabolism
D020121:5' Untranslated Regions; D051858:Forkhead Transcription Factors; D006657:Histones; D007527:Isoenzymes; D035683:MicroRNAs; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011494:Protein Kinases; D051057:Proto-Oncogene Proteins c-akt; D011948:Receptors, Antigen, T-Cell; D058570:TOR Serine-Threonine Kinases; D016212:Transforming Growth Factor beta; C498833:Foxp3 protein, mouse; C546843:mTOR protein, mouse