TCR signalling is crucial to both T cell development and naive T cell homeostasis. Naïve T cell survival in the periphery is thought to depend on both cytokine signalling and constitutive TCR signalling. The nature of this TCR dependent survival signal remains controversial. The tyrosine kinase, Zap70, is essential for TCR signalling. The aim of this project is to investigate the role of Zap70 in the transduction of survival signals in naïve T cells. Using mice that conditionally express Zap70 by means of a tetracycline-inducible system, we found that Zap70 is absolutely required for the maintenance of naïve T cells in the periphery. Loss of Zap70 resulted in a dramatic and rapid reduction in mature naive CD8 T cells in the blood and peripheral organs consistent with a naïve T cell survival defect. This survival defect could not be accounted for by cell-intrinsic differences in IL-7Rα or Bcl-2 expression. Analysis of T cell survival in vitro revealed no differences in responses to IL-7 between F5 T cells with or without Zap70. Survival in vitro was found to be enhanced by the presence of CD1 1 c+ enriched splenocytes but not T or B cells. Survival of F5 T cells in these cultures was dependent on Zap70 expression and also required intact MEK signalling. In addition, we also tested the ability of previously described Zap70 mutants, Zap70 SKG and Zap70YYAA, to transduce homeostatic TCR survival signals in vivo. Both mutants were unable to support the development, survival or antigen-induced expansion of F5 T cells. Additionally, we found evidence that Zap70Y YAA had a dominant negative effect on T cell development and reconstitution in F5 TetZap70 mice. In conclusion, we find that Zap70 is essential for transmission of signals required for naive T cell survival and requires both full expression and functionality of Zap70.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:626511 |
| Date | January 2013 |
| Creators | Schim Van Der Loeff, I. C. D. |
| 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/1419150/ |
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