T CELL SIGNALING · The spatiotemporal organization of T cell signaling as a regulator of T cell function

The spatiotemporal organization of T cell signaling as a regulator of T cell function

Cellular function is regulated by the integrated interactions between dozens of proteins. The positioning of proteins inside a cell determines how they function: Proteins that are close interact more efficiently. When studied at a sufficient scale localisation data thus provide unique insight into functional integration of groups of proteins. As most current investigations study individual proteins, often in isolation, insight into the integrated regulation of cellular function remains often inaccessible. This severely limits our understanding of cells, in particular how their behaviour changes in complex diseases such as autoimmunity, cancer or metabolic disease. We aim to use subcellular localisation data to understand how groups of proteins work together to regulate cell function. Prior to moving to the University of Bristol we had developed unique approaches to gain access to signaling as it occurs inside live primary cells in time and space, i.e. subcellular localization data, at a large scale. We use efficient live cell time-lapse fluorescence microscopy of the activation of primary T cells, the central regulators of the immune system. The key objectives of the Marie Curie CIG grant were to use unique strengths of the collaborative environment in Bristol, the United Kingdom and Europe to make progress in three areas. We proposed to integrate our imaging approaches with computational image analysis and an approach that can provide higher spatial resolution, electron microscopy. We proposed to further pursue scientific questions on the regulation of the efficiency of T cell activation. We proposed an extension of our studies to medically important questions. Computational image analysis routines and electron microscopy data are being generated in collaboration with Robert F. Murphy (Carnegie Mellon University, Pittsburgh and Freiburg Institute for Advanced Studies) and Paul Verkade (University of Bristol), respectively, as published. They have been used to address the regulation of T cell activation with an emphasis on the actin cytoskeleton, as published. Collaborative projects have been firmly established on applying our large-scale imaging approaches to T cell signalling to a murine model of multiple sclerosis and its therapy (David Wraith, University of Birmingham), to T cell signalling in tumour-infiltrating lymphocytes (David Morgan, University of Bristol and Awen Gallimore, University of Cardiff) and to the characterisation of a pharmaceutical lead compound (industrial collaboration). The Marie Curie CIG thus has greatly facilitated the integration of the principle investigator into his new environment and the application of his unique approaches to T cell signalling within this environment. Christoph Wuelfing, School of Cellular and Molecular Medicine, University of Bristol, University Walk, Bristol, BS8 1TD, United Kingdom, tel +44 117 3312364, email Christoph. Wuelfing@bristol.ac.uk, webpage http://www.bristol.ac.uk/cellmolmed/research/infect-immune/wuelfing/

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