Move to metabolism

In 2002, with the support of the Wellcome Trust, my laboratory moved to the University of Dundee, a leading centre for cell signalling research and the perfect environment in which to explore how serine/threonine kinases control T cell-mediated immune responses. What we had not appreciated was that many of our new colleagues worked on fundamental issues of how protein phosphorylation controls basic metabolic pathways. We found ourselves in a new community, one in which people asked questions about how cells sense changes in energy metabolism. We inevitably started to think about how T cells sense nutrients and modulate their metabolism to meet the energy demands of clonal expansion and effector function. One clear connection came from a paper published in 2005 by one of our colleagues, Grahame Hardie.

Grahame had previously discovered the energy-sensing AMP-activated protein kinase (AMPK), which is activated by an increased intracellular AMP:ATP ratio and functions to restore energy balance by inhibiting ATP-consuming processes and stimulating ATP-generating pathways. The revelation that this might be important in T cells came when Grahame showed that Ca²⁺–calmodulin-dependent protein kinase kinases (CaMKKs) could phosphorylate and activate AMPK. This established a biochemical link between Ca²⁺ signalling and a kinase that evolved to control the conservation and production of ATP. We immediately knew this would be relevant to T cells because it is well established that triggering of the T cell receptor induces a rapid increase in intracellular Ca²⁺ concentration and CaMKK activation. A collaboration with the Hardie group established that Ca²⁺ signalling in T cells activates AMPK (Tamás et al., 2006) and highlighted how antigen receptor signalling could control the activity of a key metabolic enzyme.

a biochemical link between Ca²⁺ signalling and a kinase that evolved to control the conservation and production of ATP

Metabolism is a relatively new focus for immunologists and is currently in the spotlight of research activities. My appreciation of its importance started with a move to Dundee, where a spirit of collaboration and the inspirational work of my colleagues opened my mind to the concept that immune cells can sense nutrients and that nutrient sensing is coupled to signal transduction pathways that determine cell fate.