In Jurkat cells the Shc adaptor protein has been demonstrated to play a role in mediating both TCR and CD4 signals to the Ras signaling pathway whose activity is essential for NF-AT activation. The Shc protein contains two protein phosphotyrosine binding domains, the SH2 domain and PTB domain, with different specificity. Truncated forms of the Shc protein containing only the SH2 domain or the PTB domain function as dominant inhibitors of CD4 and TCR/CD4 signaling respectively. The objective of this project is to study the role of Shc in transducing TCR and CD4 signals in T-cell subsets at differented stages of T-cell development. A transgenic mouse carrying a gene coding for the inhibitory SH2 domain has been obtained. The proliferative response of peripheral T-cells to mitogens is impaired in these mice however T-cell development appears normal. This mouse will be crossed with a transgenic mouse carrying the luciferase reporter under the control of an NF-AT dependent promoter in order to facilitate the analysis of TCR and CD4 signals in the presence of the dominant negative Shc. TCR and CD4 signals will be analyzed in different subsets of T-cells from these mice. A similar line of transgenic mice will be produced with the PTB domain which should inhibit both TCR and CD4 signals. The project will ensure a thorough training in modern signal transduction research using up to date technology. In addition the close links between the molecular biology aspects of the project with those of immunology give a cross-disciplinary quality to the project. Links with industry / industrial relevance (22)
The host institue is the research center of a biotechnology company dedicated to the design and development of innovative vaccines. Basic and applied research go hand in hand to achieve these goals.