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 p110delta subunit of PI(3)K controlled CD62L proteolysis through mitogen-activated protein kinases, whereas control of CD62L transcription by p110delta 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.
Sinclair
Linda V
LV
Department of Cell Biology and Immunology, University of Dundee, Dundee DD1 5EH, UK.
Finlay
David
D
Feijoo
Carmen
C
Cornish
Georgina H
GH
Gray
Alex
A
Ager
Ann
A
Okkenhaug
Klaus
K
Hagenbeek
Thijs J
TJ
Spits
Hergen
H
Cantrell
Doreen A
DA
D000818:Animals; D002465:Cell Movement; D019041:L-Selectin / Q000378:metabolism; D008198:Lymph Nodes / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D011494:Protein Kinases / Q000502:physiology*; D054400:Receptors, CCR7 / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases
D019041:L-Selectin; D019869:Phosphatidylinositol 3-Kinases; D011494:Protein Kinases; D054400:Receptors, CCR7; D058570:TOR Serine-Threonine Kinases; C515371:Ccr7 protein, mouse; C546843:mTOR protein, mouse