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T cell signal integration in signalling complexes


The activation of T lymphocytes is governed by the interaction of specific receptor/ligand pairs on T cell and antigen presenting cell (APC), respectively. The engagement of the T cell receptor (TCR) by peptide/MHC complexes on the APC and the interaction ofCD80/CD86 with their costimulatory or inhibitory receptors CD28 orCTLA-4 on the T cell are among the most important. Combinations of the signals are integrated by the T lymphocyte to mount a distinctive response, such as differentiation, proliferation, anergy, or cell death. T cell stimulation induces the formation of signaling protein complexes in the T cell plasma membrane domain in contact with the APC. This study seeks to investigate the effects of modulated T cell activation on the composition of these T cell signalling complexes and to correlate them with functional parameters of T cell activation. In the presence or absence of costimulatory molecules, various peptide/MHC complexes will be coupled to magnetic beads and used for activation of transgenic murine primary T cells. The formation and composition of these signaling complexes will be studied biochemically and by imaging techniques. In this project, I will enter the field of signal transduction. By working on the project, I will complement my knowledge of cell biological, immunological and biochemical methods with state of the art proteomic analysis and analysis of lipid membranes. The host, Thomas Harder, has developed a novel approach for immunoisolationg TCR-containig membrane domains and associated proteins, which will contribute to the understanding of the integration of TCR-mediated and costimulating signals at the level of signaling complexes and might very well lead to the identification of new components of TCR signalling assemblies. In this project, I will apply this method to the activation of primary T cells isolated from TCR transgenic mice. In my PhD studies, I have extensively studied the activation of murine primary T cells and their effector functions, so the areas of expertise of Thomas Harder and me optimally complement each other.


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United Kingdom