The peripheral T cell compartment is maintained at a constant size, resulting from a balance of cell development, survival, proliferation and death. Transmission of signals through the TCR and IL-7R on the T cell surface is involved in regulating all these processes, however the precise manner in which these signals together maintain T cell homeostasis is unclear. To investigate the contribution of TCR and IL-7 signals to naive T cell homeostatic responses we established two model systems. To specifically address the role of homeostatic TCR signalling in the development and maintenance of the T cell compartment, we generated transgenic mice that conditionally express the Syk family tyrosine kinase Zap70. The transduction of TCR signals by Zap70 is essential for thymic development and T cell activation. Given the importance of Zap70 expression in T cell antigen receptor signalling, we investigated whether Zap70 was also essential for the transmission of TCR signals, required for the steady state survival of the peripheral naive T cell compartments. Zap70 deficient mice exhibit a complete block in thymopoiesis at the DP stage in the thymus and as a consequence lack mature peripheral T cells. For this reason we generated mice that express Zap70 in a conditional manner, using the tetracycline responsive gene regulatory system. Thymic selection proceeded normally in these mice, however ablation of Zap70 expression resulted in the disappearance in the peripheral naive CD4+ and CD8+ T cells, with the naive CD8+ T cell compartment appearing most affected by the loss of Zap70 expression. This data suggests an important role for Zap70 signalling in the transmission of homeostatic TCR survival signals. Unexpectedly we also found that TCR signals transmitted by Zap70 had the capacity to influence IL-7R expression and importantly revealed a novel role for positive selection signals in the regulation of peripheral IL-7R expression and therefore the competitive fitness of peripheral T cell clones. The second model system examined the homeostatic responses of class I MHC restricted F5+/+ TCR transgenic Rag1A CD8+ T cells following transfer into MHC class I or IL-7 deficient hosts, to specifically quantify the contribution of TCR and IL-7 signals in naive T cell homeostasis. Our data reveals that IL-7 signals are more essential than homeostatic TCR signals for the survival of the naive T cell compartment in conditions of lymphopenia. Interestingly we also demonstrate that IL-7 may exert part of its homeostatic effects by modulating TCR engagement with MHC ligands by regulating T cell - APC interactions in vivo. In conclusion the data presented in this thesis confirms that TCR and IL-7 signals are essential for naive T cell homeostasis, but also reveals extensive cross-talk between homeostatic TCR and IL7 signals in the control of peripheral T cell homeostasis.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:498899 |
| Date | January 2008 |
| Creators | Saini, Manoj |
| 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/1446076/ |
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