The role of Zap70 in T-cell homeostasis
Dr. Benedict Seddon - Division of Infection & Immunity/NIMR
National Institute for Medical Research (Mill Hill)
Description of Project:
T cells play a central role in cell-mediated adaptive immune responses. Throughout life the size of the various T-cell populations are maintained constant, as a result of tight homeostatic control of peripheral cell survival and proliferation. Cytokine and T cell receptor (TCR) signalling are crucial to both T cell development and peripheral homeostasis. Recently, the expression Zap70, an essential target of TCR signalling, was found to be upregulated during positive selection of T cells in the thymus. The first aim of my PhD will be to investigate the control mechanisms of Zap70 expression during positive selection and in peripheral T cells. We plan to identify key regulatory regions of the Zap70 gene by mapping the histone code of the Zap70 locus throughout T cell development. We will then test the importance of possible regulatory regions required for constitutive and inducible expression in vitro in Jurkat cells and in vivo. The survival of naïve T cells in the periphery is also thought to depend on TCR signalling. However, the nature of a TCR dependent survival signal remains controversial. The second aim of my PhD will be to investigate the role of Zap70 in transducing a TCR dependent survival signal in naïve T cells. We will use mice, which conditionally express Zap70 to test whether naïve T cell survival depends requires Zap70 expression. Should Zap70 be required for survival of naïve T cells, we will attempt to investigate the mechanism of Zap70 dependent T cell survival using mice that express a mutated form of Zap70 that has reduced adaptor function.
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