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

A Corrigendum to this article was published on 01 June 2008

This article has been updated

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 p110δ subunit of PI(3)K controlled CD62L proteolysis through mitogen-activated protein kinases, whereas control of CD62L transcription by p110δ 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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Figure 1: Shedding of CD62L from TCR-activated CD8+ T cells is PI(3)K dependent.
Figure 2: CD62L downregulation in effector CD8+ T cells is PI(3)K-dependent.
Figure 3: TCR-induced CD62L shedding is Erk dependent, whereas IL-2-induced downregulation of CD62L transcription is mTOR dependent.
Figure 4: Expression of KLF2 and S1P1 is regulated by PI(3)K and mTOR signaling.
Figure 5: Loss of PTEN is sufficient to downregulate CD62L expression.
Figure 6: CCR7 downregulation on activated T cells is dependent on PI(3)K and mTOR.

Change history

  • 19 May 2008

    In the version of this article initially published, the key for Figure 5b is incorrect. The black bars should be ‘CD4+ SP’ and the gray bars should be ’DP’. The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

We thank R. Clarke for assistance with flow cytometry and cell sorting; H. Akel for assistance with adoptive transfer; members of Biological Services Resource Unit for mouse care; and members of the Cantrell laboratory for critical reading of the manuscript. Supported by the Wellcome Trust (Programme Grant GR065975; Principal Research Fellowship to D.A.C.).

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Contributions

L.V.S., most in vitro assays and in vivo adoptive transfer; D.F., analysis of PTEN-KO(T) cells; C.F., real-time PCR; G.H.C., in vitro migration assay; A.G., PtdIns(3,4,5)P3 quantification; A.A., provision of CD62L transgenic mice and discussions; K.O., provision of p110δ(D910A)-transgenic mice; T.J.H. and H.S., provision of PTEN-KO(T) mice; D.A.C., conceptual design and manuscript authorship.

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Correspondence to Doreen A Cantrell.

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H.S. is an employee of Genentech, a biotechnology company that develops and markets drugs.

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Sinclair, L., Finlay, D., Feijoo, C. et al. Phosphatidylinositol-3-OH kinase and nutrient-sensing mTOR pathways control T lymphocyte trafficking. Nat Immunol 9, 513–521 (2008). https://doi.org/10.1038/ni.1603

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