Professor Doreen Cantrell CBE FRS FRSE FMedSci
Analysis of signal transduction pathways that control T lymphocyte metabolism, migration and differentiation
The laboratory explores how antigen receptors and cytokines control the development and immune activation of T lymphocytes; key cells in the adaptive immune system. The strategy is to rigorously interrogate T cell biology at the fundamental level of biochemical signal transduction. The integration of mouse molecular genetics, cell biology and microscopy is then used to define the contribution of a particular biochemical pathway to T cell activation. This work has defined how thymocytes and T lymphocytes use networks of guanine nucleotide binding proteins and serine kinases to interpret information from antigens and cytokines to make appropriate responses that control T cell development and peripheral T cell function. The laboratory has made considerable progress mapping serine/threonine kinase mediated signaling pathways in thymocytes and peripheral T cells and has identified essential regulators of T cell metabolism, cytotoxic T cell effector function and CD8 T cell migration/trafficking.
The future research program will adopt a multidisciplinary approach and combine biochemistry, cell biology and in vivo mouse immunology to explore the how protein phosphorylation controls T cell function. A key focus is the regulation of the metabolism of normal and malignant lymphocytes. One important component of the work is a discovery based program to use high resolution mass spectrometry to systematically define the phosphoproteome of naïve and effector CD4 and CD8 T lymphocyte subpopulations. Phosphoproteomic analysis of cytotoxic T cells has already identified links between serine/threonine kinases and chromatin regulators; the future program will address how phosphorylation of these chromatin regulators controls CTL transcriptional programs and explore the role of key cytokines on the CD8 T cell phosphoproteome. This work will generate a molecular understanding of how signal transduction pathways control T cell function. In particular, the studies will provide new insights about pharmacological strategies that might manipulate immune responses to ensure effective vaccination and/or restrain the T cell pathology caused by effector T cells.
Ross, S. H., Rollings, C., Anderson, K. E., Hawkins, P. T., Stephens, L. R. and Cantrell, D. A. (2016) Phosphoproteomic Analyses of Interleukin 2 Signaling Reveal Integrated JAK Kinase-Dependent and -Independent Networks in CD8(+) T Cells. Immunity. 45, 685-700
Swamy, M., Pathak, S., Grzes, K. M., Damerow, S., Sinclair, L. V., van Aalten, D. M. and Cantrell, D. A. (2016) Glucose and glutamine fuel protein O-GlcNAcylation to control T cell self-renewal and malignancy. Nature immunology. 17, 712-720
Hukelmann, J. L., Anderson, K. E., Sinclair, L. V., Grzes, K. M., Murillo, A. B., Hawkins, P. T., Stephens, L. R., Lamond, A. I. and Cantrell, D. A. (2016) The cytotoxic T cell proteome and its shaping by the kinase mTOR. Nature immunology. 17, 104-112
Preston, G. C., Sinclair, L. V., Kaskar, A., Hukelmann, J. L., Navarro, M. N., Ferrero, I., MacDonald, H. R., Cowling, V. H. and Cantrell, D. A. (2015) Single cell tuning of Myc expression by antigen receptor signal strength and interleukin-2 in T lymphocytes. The EMBO journal. 34, 2008-2024
Navarro, M. N., Goebel, J., Hukelmann, J. L. and Cantrell, D. A. (2014) Quantitative phosphoproteomics of cytotoxic T cells to reveal protein kinase d 2 regulated networks. Molecular & cellular proteomics : MCP. 13, 3544-3557
Navarro, M. N., Feijoo-Carnero, C., Arandilla, A. G., Trost, M. and Cantrell, D. A. (2014) Protein kinase D2 is a digital amplifier of T cell receptor-stimulated diacylglycerol signaling in naive CD8(+) T cells. Science signaling. 7, ra99
Sinclair, L. V., Rolf, J., Emslie, E., Shi, Y. B., Taylor, P. M. and Cantrell, D. A. (2013) Control of amino-acid transport by antigen receptors coordinates the metabolic reprogramming essential for T cell differentiation. Nature immunology. 14, 500-508
Rolf, J., Zarrouk, M., Finlay, D. K., Foretz, M., Viollet, B. and Cantrell, D. A. (2013) AMPKalpha1: a glucose sensor that controls CD8 T-cell memory. European journal of immunology. 43, 889-896
Finlay, D. K., Rosenzweig, E., Sinclair, L. V., Feijoo-Carnero, C., Hukelmann, J. L., Rolf, J., Panteleyev, A. A., Okkenhaug, K. and Cantrell, D. A. (2012) PDK1 regulation of mTOR and hypoxia-inducible factor 1 integrate metabolism and migration of CD8+ T cells. The Journal of experimental medicine. 209, 2441-2453
Navarro, M. N., Sinclair, L. V., Feijoo-Carnero, C., Clarke, R., Matthews, S. A. and Cantrell, D. A. (2012) Protein kinase D2 has a restricted but critical role in T-cell antigen receptor signalling in mature T-cells. The Biochemical journal. 442, 649-659