Regulatory T cells (Tregs) play an important role in immune regulation. Their development in the thymus requires interaction of their TCR with self-peptide-MHC and the induction of Foxp3. The downstream signals from the TCR that lead to commitment to the regulatory lineage and subsequent up-regulation of Foxp3 are unclear. The development of regulatory T cells has been shown to occur at the DP stage of thymocyte development where positive and negative selection occurs and it is thought that Tregs differentiate from positively selected thymocytes. The three classical MAPK cascades and their targets have been implicated in both positive and negative selection. Thus they represent an opportunity to gain further insights into the development of regulatory T cells. Here I have compared the requirements of positive selection and regulatory T cell development through the use of knockout and transgenic animals defective in Raf signalling, and components of the SRF regulatory network including the ternary complex factors (TCFs) and SRF itself. Whilst the TCF deficient mice display severe defects in positive selection, Treg development was unimpaired. However depletion of SRF resulted in a complete block in positive selection and Treg development suggesting that positive selection consists of both TCF-dependent and TCF-independent events. Inhibition of Raf signalling by the dominant interfering DN Raf derivative reduced both Foxp3+ and Foxp3" CD4+ populations. TCR crosslinking efficiently induced ERK activation in regulatory T cells but induction of the TCF target gene was impaired. Nevertheless, both TCF-deficient and DN Raf CD4+CD25+ Tregs effectively suppressed CD4+CD25" T cell proliferation in vitro. Finally SAP-l"7" CD4XD25" Tregs are functional in an in vivo model of colitis. Thus the signalling requirements for development of Tregs in the thymus are distinct from those required for conventional T cell positive selection.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:499112 |
| Date | January 2008 |
| Creators | Willoughby, Jane |
| Publisher | University College London (University of London) |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://discovery.ucl.ac.uk/1446200/ |
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