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.
- 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(1):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(15):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. Mol Cell Proteomics 13(12) 3544-3557
- Navarro, M.N., Feijoo-Carnero, C., Gonzalez Arandilla, A., Trost, M. and Cantrell, D.A (2014) Protein kinase D2: a switch-like amplifier of T cell receptor diacylglycerol signalling in naïve CD8 T cells. Science Signaling 7 (348)
- 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) AMPKα1: A glucose sensor that controls CD8 T-cell memory. European Journal of Immunology 43(4):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 (13) 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. Biochem J. 442, 649-659
- Navarro, M.N., Goebel, J., Feijoo-Carnero, C., Morrice, N. and Cantrell, D.A. (2011) Phosphoproteomic analysis reveals an intrinsic pathway for the regulation of histone deacetylase 7 that controls the function of cytotoxic T lymphocytes. Nature Immunology - 12 (4), 352-361
- Macintyre, A.N., Finlay, D., Preston, G., Sinclair, L.V., Waugh, C.M., Tamas, P., Feijoo, C., Okkenhaug, K., and Cantrell, D.A. (2011) Protein kinase B controls transcriptional programs that direct cytotoxic T cell fate but is dispensable for T cell metabolism. Immunity 25; 34 (2) 224-236