Article abstract
Nature Immunology 9, 513 - 521 (2008)
Published online: 6 April 2008 | Corrected online: 19 May 2008 | doi:10.1038/ni.1603
There is a Corrigendum (June 2008) associated with this Article.
Phosphatidylinositol-3-OH kinase and nutrient-sensing mTOR pathways control T lymphocyte trafficking
Linda V Sinclair1, David Finlay1, Carmen Feijoo1, Georgina H Cornish2, Alex Gray3, Ann Ager4, Klaus Okkenhaug5, Thijs J Hagenbeek6, Hergen Spits6,7 & Doreen A Cantrell1
Abstract
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
subunit of PI(3)K controlled CD62L proteolysis through mitogen-activated protein kinases, whereas control of CD62L transcription by p110 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.
- Department of Cell Biology and Immunology, University of Dundee, Dundee DD1 5EH, UK.
- Immune Cell Biology, The National Institute for Medical Research, London NW7 1AA, UK.
- Division of Molecular Physiology, University of Dundee, Dundee DD1 5EH, UK.
- Department of Medical Biochemistry and Immunology, Cardiff University, Cardiff CF14 4XN, UK.
- Laboratory of Lymphocyte Signalling and Development, Babraham Institute, Cambridge CB2 4AT, UK.
- Department of Immunology, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.
- Department of Immunology Discovery, Genentech, South San Francisco, California 94080, USA.
Correspondence to: Doreen A Cantrell1 e-mail: d.a.cantrell@dundee.ac.uk
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