Phosphatidylinositol-3-OH kinase and nutrient-sensing mTOR pathways control T lymphocyte trafficking

Phosphatidylinositol-3-OH kinase (PI(3) K) and the nutrient sensor mTOR are evolutionarily conserved regulators of cell metabolism. Here we show that PI(3) K and mTOR determined the repertoire of adhesion and chemokine receptors expressed by T lymphocytes. The key lymph node-homing receptors CD62L (L-selectin) and CCR7 were highly expressed on naive T lymphocytes but were downregulated after immune activation. CD62L downregulation occurred through ectodomain proteolysis and suppression of gene transcription. The p110 delta subunit of PI(3) K controlled CD62L proteolysis through mitogen-activated protein kinases, whereas control of CD62L transcription by p110d was mediated by mTOR through regulation of the transcription factor KLF2. PI(3) K-mTOR nutrient-sensing pathways also determined expression of the chemokine receptor CCR7 and regulated lymphocyte trafficking in vivo. Hence, lymphocytes use PI(3) K and mTOR to match metabolism and trafficking.