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Move to metabolism

Nature Reviews Immunology volume 19, page 270 (2019)Cite this article

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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.

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References

Original article

  • Hawley, S. A. et al. Calmodulin-dependent protein kinase kinase-β is an alternative upstream kinase for AMP-activated protein kinase. Cell Metab. 2, 9–19 (2005)

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Further reading

  • Tamás, P. et al. Regulation of the energy sensor AMP-activated protein kinase by antigen receptor and Ca2+ in T lymphocytes. J. Exp. Med. 203, 1665–1670 (2006)

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  1. University of Dundee, Dundee, UK

    Doreen A. Cantrell

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  1. Doreen A. Cantrell
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Correspondence to Doreen A. Cantrell.

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Cantrell, D.A. Move to metabolism. Nat Rev Immunol 19, 270 (2019). https://doi.org/10.1038/s41577-019-0157-0

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