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T lymphocyte signal transduction: analysis of the biochemistry and biology of Rho family GTPases and the serine kinase Protein Kinase D in T cells
The regulation of T lymphocyte biology is essential for the adaptive immune response. The research objective of the laboratory is the characterization of signal transduction pathways in T lymphocytes with the aim of understanding how evolutionarily conserved signalling molecules control immune functions. The laboratory has defined signal transduction pathways that control T lymphocyte survival, differentiation and proliferation in vivo and has positioned Rho GTPases and key serine kinases on the map of antigen receptor lymphocyte signal transduction. We have also characterised the spatial and temporal kinetics of Diacylglycerol (DAG) and Phosphatidylinositol (3,4,5) triphosphate production in single T cells responding to antigenic peptides presented by MHC molecules on the surface of antigen presenting cells (APC). This work has produced fundamental insights about the dynamics of inositol lipid metabolism in T cells responding to physiological stimuli. One current research topic in the laboratory is the role of the Protein Kinase D family of serine/threonine kinases. PKDs are expressed ubiquitously but are particularly abundant in lymphocytes where they are selectively activated by triggering of antigen receptors. PKDs show different patterns of intracellular localization in different cell types, cell lineage specific functions and requirements for activation. The laboratory has made significant contributions in understanding PKD regulation, PKD localisation, PKD function and PKD substrates in lymphocytes and continues to study the function of these enzymes. Other research ongoing in the laboratory stems from the identification of important functions for the serine kinases Phospholipid dependent kinase 1(PDK1) and LKB1 in T cell progenitors in the thymus; the discovery that TCR-induced Ca2+ signals are linked to AMP-activated protein kinase (AMPK), an evolutionarily conserved serine kinase that regulates energy metabolism by controlling the conservation and production of ATP. The role of these latter serine kinases in peripheral T lymphocytes is under investigation.
These images (frames taken every 15 seconds) show the change in the subcellular localisation of a probe for the lipid PIP3 as naïve T cells contact antigen primed antigen presenting cells. The data show rapid and sustained accumulation of PIP3 at T cell plasma membrane as T cells undergo immune stimulation.