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Title: mTOR signalling and the regulation of FOXP3 expression
Author: Peter, Christian
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2012
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Regulatory T-cells (Treg) are essential for the establishment of self-tolerance and they can be identified by the expression of FOXP3, the "master" transcription factor for the development of Treg. A number of essential Signals, namely TCR engagement, TGF~, as well as the inhibition of the kinase mTOR, have been shown to be crucial for the induction of FOXP3 in the peripheral immune system. Despite recent progress, the molecular mechanisms for induction of FOXP3 remains elusive due, at least in part, to the lack of a cell line that mimics the behavior of primary CD4+ T-cells. Here we report the isolation of a clone B02 from the mouse lymphoma line EL4 that can be induced to express high levels of FOXP3 in up to 50% of the cells. Pharmacological inhibition of mTOR and EAA depletion synergized with TGF~ in the induction, and led to reduced activity of both mTORCl and mTORC2, which seemed to independently contribute to the enhanced FOXP3 expression. Luciferase reporter assays using Foxp3 promoter and enhancer sequences indicated that the mTOR inhibition-mediated increase in FOXP3 expression resulted primarily from enhanced transcriptional activity. In addition to the enhancement of FOXP3 induction, mTOR inhibition reduced the levels of lL-17A, presumably by SOCS-mediated inactivation of STAT3, which could also have accounted for increased Foxp3 transcription. Although the precise targets of mTOR inhibition involved in the regulation of FOXP3 expression have yet to be identified, both luciferase assays and mass spectrometry-based quantitative phospho-proteomics using SILAC labelled B02 cells, have identified promising candidates. This unique EL4 clone could represent a special resource for investigating the signaling events leading to the induction of FOXP3 as well as events downstream of FOXP3 expression.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available