T-lymphocyte signal transduction

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. 

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. 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

3. 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 of Experimental Medicine 206 (11), 2441-54

4. 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

5. 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

6. 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 34 (2), 224-236

7. 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

8. 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 442 (3), 649-659

9. 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. J Exp Med. 209 (13), 2441-2453

10. 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

11. 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 (5), 500-508

12. Zarrouk, M., Rolf, J. and Cantrell, D.A. (2013) LKB1 Mediates the Development of Conventional and Innate T Cells via AMP-Dependent Kinase Autonomous Pathways. PLoS One. 8 (3) e60217