University of Dundee

Professor Doreen Cantrell CBE FRS FRSE FMedSci

T-lymphocyte signal transduction
Position: 
Professor of Cellular Immunology and Wellcome Trust Principal Research Fellow
Address: 
School of Life Sciences, University of Dundee, Dundee
Full Telephone: 
+44 (0) 1382 385156, int ext 85156
Email: 

Research

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.

Publications

Sinclair, LV, Howden, A, Brenes Murillo, A, Spinelli, L, Hukelmann, J, Macintyre, AN, Liu, X, Thomson, S, Taylor, P, Rathmell, JC, Locasale, JW, Lamond, A & Cantrell, DA 2019, 'Antigen receptor control of methionine metabolism in T cells' eLife, vol. 8, e44210. https://doi.org/10.7554/eLife.44210

Cantrell, DA 2019, 'Move to metabolism' Nature Reviews Immunology. https://doi.org/10.1038/s41577-019-0157-0

Vara Ciruelos, D, Dandapani, M, Russell, F, Grzes, KM, Atrih, A, Foretz, M, Viollet, B, Lamont, D, Cantrell, D & Hardie, G 2019, 'Phenformin, but not metformin, delays development of T-cell acute lymphoblastic leukemia/lymphoma via cell-autonomous AMPK activation' Cell Reports, vol. 27, no. 3, pp. 690-698.e4. https://doi.org/10.1016/j.celrep.2019.03.067

Loftus, RM, Assmann, N, Kedia-Mehta, N, O'Brien, KL, Garcia, A, Gillespie, C, Hukelmann, JL, Oefner, PJ, Lamond, AI, Gardiner, CM, Dettmer, K, Cantrell, DA, Sinclair, LV & Finlay, DK 2018, 'Amino acid-dependent cMyc expression is essential for NK cell metabolic and functional responses in mice' Nature Communications, vol. 9, no. 1, 2341, pp. 1-15. https://doi.org/10.1038/s41467-018-04719-2

Rollings, C, Sinclair, L, Brady, HJM, Cantrell, D & Ross, S 2018, 'Interleukin-2 shapes the cytotoxic T cell proteome and immune environment sensing programs' Science Signaling, vol. 11, no. 526, eaap8112, pp. 1-16. https://doi.org/10.1126/scisignal.aap8112

Ross, SH & Cantrell, DA 2018, 'Signaling and Function of Interleukin-2 in T Lymphocytes' Annual Review of Immunology, vol. 36, pp. 411-433. https://doi.org/10.1146/annurev-immunol-042617-053352

Sinclair, L, Neyens, D, Ramsay, G, Taylor, P & Cantrell, D 2018, 'Single cell analysis of kynurenine and System L amino acid transport in T cells' Nature Communications, vol. 9, no. 1, 1981 (2018). https://doi.org/10.1038/s41467-018-04366-7

Grzes, KM, Swamy, M, Hukelmann, JL, Emslie, E, Sinclair, LV & Cantrell, DA 2017, 'Control of amino-acid transport coordinates metabolic reprogramming in T cell malignancy' Leukemia, vol. 31, pp. 2771-2779. https://doi.org/10.1038/leu.2017.160

Swamy, M, Pathak, S, Grzes, KM, Damerow, S, Sinclair, LV, van Aalten, DMF & Cantrell, DA 2016, 'Glucose and glutamine fuel protein O-GlcNAcylation to control T cell self-renewal and malignancy' Nature Immunology, vol. 17, no. 6, pp. 712-720. https://doi.org/10.1038/ni.3439

Eftimie, R, Gillard, JJ & Cantrell, DA 2016, 'Mathematical models for immunology: current state of the art and future research directions' Bulletin of Mathematical Biology, vol. 78, no. 10, pp. 2091-2134. https://doi.org/10.1007/s11538-016-0214-9

Ross, SH, Rollings, C, Anderson, KE, Hawkins, PT, Stephens, LR & Cantrell, DA 2016, 'Phosphoproteomic Analyses of Interleukin 2 Signaling Reveal Integrated JAK Kinase-Dependent and -Independent Networks in CD8+ T Cells' Immunity, vol. 45, no. 3, pp. 685-700. https://doi.org/10.1016/j.immuni.2016.07.022

Frost, J, Galdeano, C, Soares, P, Gadd, MS, Grzes, KM, Ellis, L, Epemolu, O, Shimamura, S, Bantscheff, M, Grandi, P, Read, KD, Cantrell, DA, Rocha, S & Ciulli, A 2016, 'Potent and selective chemical probe of hypoxic signaling downstream of HIF-α hydroxylation via VHL inhibition' Nature Communications, vol. 7, 13312, pp. 1-12. https://doi.org/10.1038/ncomms13312

Hukelmann, JL, Anderson, KE, Sinclair, LV, Grzes, KM, Brenes Murillo, A, Hawkins, PT, Stephens, LR, Lamond, AI & Cantrell, DA 2016, 'The cytotoxic T cell proteome and its shaping by the kinase mTOR' Nature Immunology, vol. 17, no. 1, pp. 104-112. https://doi.org/10.1038/ni.3314