AMPK gets phosphorylated (and thus activated) after TCR ligation (α-CD3) in primary T cells.

Many cell types use AMPK (AMP-activated protein kinase) to signal that energy reserves are low so more energy generation is needed. But, say Tamás et al. on page 1665, T cells also use AMPK to signal that energy will be needed in the near future, for attacking target cells, proliferating or churning out cytokines.

When cellular energy is in short supply—due, for example, to nutrient deficiency or metabolic stress—rising levels of AMP and falling levels of ATP trigger the activation of AMPK. AMPK then activates ATP-generating pathways, such as fatty acid oxidation. Tamás and colleagues now show that this pathway is also activated in T cells when their energy reserves dwindle. This is the first demonstration of physiological AMPK regulation in T cells.

But T cells turned on AMPK not only in response to falling energy levels but also in anticipation of upcoming energy needs. “If a T cell fluxes calcium,” says senior author Doreen Cantrell, “it is indicating that it is about to activate and will need ATP.” And this Ca2+ flux, they found, triggered the activation of AMPK.

Ca2+-induced AMPK activation required upstream Ca2+/calmodulin-dependent protein kinase kinases, which were not needed for AMPK activation in response to rising AMP/ATP ratios. PI3 kinase (PI3K)—an enzyme required for cytokine- and costimulation-induced energy generation in T cells—was also dispensable for AMPK activation. Determining the importance of the AMPK pathway, relative to these other energy-boosting pathways, awaits the development of conditional AMPK-deficient mice.