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

Linda V. Sinclair; David Finlay; Carmen Feijoo; Georgina H. Cornish; Alex Gray; Ann Ager; Klaus Okkenhaug; Thijs J. Hagenbeek; Hergen Spits; Doreen A. Cantrell

doi:10.1038/ni.1603

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

Linda V. Sinclair
, David Finlay
, Carmen Feijoo
, Georgina H. Cornish
, Alex Gray
, Ann Ager
, Klaus Okkenhaug
, Thijs J. Hagenbeek
, Hergen Spits
, Doreen A. Cantrell (Lead / Corresponding author)

Research output: Contribution to journal › Article › peer-review

350 Citations (Scopus)

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 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.

Original language	English
Pages (from-to)	513-521
Number of pages	9
Journal	Nature Immunology
Volume	9
Issue number	5
DOIs	https://doi.org/10.1038/ni.1603
Publication status	Published - May 2008

Keywords

Animals
Cell Movement
L-Selectin
Lymph Nodes
Lymphocyte Activation
Mice
Mice, Inbred C57BL
Mice, Transgenic
Phosphatidylinositol 3-Kinases
Protein Kinases
Receptors, CCR7
Signal Transduction
T-Lymphocytes
TOR Serine-Threonine Kinases

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10.1038/ni.1603

http://www.nature.com/ni/journal/v9/n5/full/ni.1603.html

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title = "Phosphatidylinositol-3-OH kinase and nutrient-sensing mTOR pathways control T lymphocyte trafficking",

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 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.",

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author = "Sinclair, \{Linda V.\} and David Finlay and Carmen Feijoo and Cornish, \{Georgina H.\} and Alex Gray and Ann Ager and Klaus Okkenhaug and Hagenbeek, \{Thijs J.\} and Hergen Spits and Cantrell, \{Doreen A.\}",

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AU - Sinclair, Linda V.

AU - Finlay, David

AU - Feijoo, Carmen

AU - Cornish, Georgina H.

AU - Gray, Alex

AU - Ager, Ann

AU - Okkenhaug, Klaus

AU - Hagenbeek, Thijs J.

AU - Spits, Hergen

AU - Cantrell, Doreen A.

PY - 2008/5

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N2 - 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.

AB - 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.

KW - Animals

KW - Cell Movement

KW - L-Selectin

KW - Lymph Nodes

KW - Lymphocyte Activation

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Transgenic

KW - Phosphatidylinositol 3-Kinases

KW - Protein Kinases

KW - Receptors, CCR7

KW - Signal Transduction

KW - T-Lymphocytes

KW - TOR Serine-Threonine Kinases

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M3 - Article

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VL - 9

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EP - 521

JO - Nature Immunology

JF - Nature Immunology

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ER -

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

Abstract

Keywords

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Corrigendum: Phosphatidylinositol-3-OH kinase and nutrient-sensing mTOR pathways control T lymphocyte trafficking (Nature Immunology (2008) vol. 9(6) (513-521))

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