Doreen Cantrell

Professor Doreen Cantrell

Position: Professor of Cellular Immunology, Wellcome Trust Principal Research Fellow and Vice Principal and Head of College
Division: Cell Signalling and Immunology
Address: College of Life Sciences, University of Dundee, Dundee
Telephone: +44 1382 385047, int ext. 85047
Fax: +44 1382 385783
Email: d.a.cantrell@dundee.ac.uk

T-lymphocyte signal transduction

Research

Analysis of signal transduction pathways that control T lymphocyte metabolism, migration and differentiation

These images (frames taken every 15 seconds) show the change in the subcellular 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. 

Teaching


Publications

  1. Sinclair, L.V., Finlay, D., Feijoo, C., Cornish, G.H., Gray, A., Ager, A., Okkenhaug, K., Hagenbeek, T.J., Spits, H. and Cantrell, D.A. (2008) Phosphatidylinositol-3-OH kinase and nutrient-sensing mTOR pathways control T lymphocyte trafficking. Nature Immunology 9 (5), 513-521

  2. Finlay, D.K., Sinclair, L.V., Feijoo, C., Waugh, C.M., Hagenbeek, T.J., Spits, H. and Cantrell, D.A. (2009) Phosphoinositide-dependent kinase 1 controls migration and malignant transformation but not  cell growth and proliferation in PTEN-null lymphocytes. Journal Exp Med 206 (11), 2441-2454

  3. Waugh, C., Sinclair, L., Finlay, D., Bayascas, J.R. and Cantrell, D. (2009) Phosphoinositide (3,4,5)-triphosphate binding to phosphoinositide-dependent kinase 1 regulates a protein kinase B/Akt signaling threshold that dictates T-cell migration, not proliferation. Molecular Cell Biology 29 (21), 5952-5962

  4. Tamás, P., Macintyre, A., Finlay, D., Clarke, R., Feijoo-Carnero, C., Ashworth, A. and Cantrell D. (2010) LKB1 is essential for the proliferation of T-cell progenitors and mature peripheral T cells.  Eur J Immunology 40 (1), 242-253

  5. Matthews, S.A., Navarro, M.N., Sinclair, L.V., Emslie, E., Feijoo-Carnero, C. and Cantrell, D.A. (2010) Unique functions for protein kinase D1 and protein kinase D2 in mammalian cells. Biochemical Journal 432 (1), 153-163

  6. Finlay, D.K., Kelly, A.P., Clarke, R., Sinclair, L.V., Deak, M., Alessi, D.R. and Cantrell, D.A. (2010) Temporal differences in the dependency on phosphoinositide-dependent kinase 1 distinguish the development of invariant Valpha14 NKT cells and conventional T cells. Journal of Immunology 185 (10), 5973-5982

  7. Finlay, D. and Cantrell, D.A. (2011) Metabolism, migration and memory in cytotoxic T cells. Nature Review Immunology 11 (2), 109-17

  8. 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

  9. 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

  10. 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. Biochemical Journal doi:10.1042/BJ20111700

  11. Konopatskaya, O., Matthews, S.A., Harper, M.T., Gilio, K., Cosemans, J.M.,Williams, C.M., Navarro, M.N., Carter, D.A., Heemskerk, J.W., Leitges, M., Cantrell, D.A. and Poole, A.W. (2011) Protein kinase C mediates platelet secretion and thrombus formation through protein kinase D2. Blood 118, 416-424 doi: 10.1182/blood-2010-10-312199

  12. Matthews, S.A., Lek, H.S., Morrison, V.L., Mackenzie, M.G., Zarrouk, M., Cantrell, D.A and Fagerholm, S.C. (2012) Protein kinase D isoforms are dispensable for integrin-mediated lymphocyte adhesion and homing to lymphoid tissues. Eur J Immunol doi: 10.1002/eji.201142004