The group connected nutrient status with trafficking when they noticed that stimuli that decrease T cells' cache of nutrient receptors boost levels of CCR7 and L-selectin, which help keep T cells in lymph nodes. When nutrients are plentiful, metabolism is dialed up by the mTOR/PI3K pathway, which the group now shows reduces L-selectin levels via two routes.
In one route, PI3K and its PIP3 lipid product led to the rapid cleavage of L-selectin on the T cell surface. A later-acting path prevented the transcription of CCR7 and new L-selectin.
L-selectin and CCR7 levels are normally turned down when T cells are activated by antigen in the lymph nodes. The loss allows foreigner-fighting T cells to leave the node and head to remote tissues. The new results suggest that this exit does not occur in starved cells, which cannot turn on mTOR; inhibiting mTOR/PI3K in mouse cells restored L-selectin levels and retained T cells in lymph nodes.
“The system ensures that a T cell does not leave the node,” says Cantrell, “until it is in a metabolic state to do its job. It's like explorers making a dash for the North Pole. They need to be well fed before they go. And if they're not, they should return to base camp.”