Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

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

Nature Immunology volume 9, pages 513–521 (2008)Cite this article

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.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others

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.

References

  1. Fruman, D.A. Phosphoinositide 3-kinase and its targets in B-cell and T-cell signaling. Curr. Opin. Immunol. 16, 314–320 (2004).

    Article  CAS  Google Scholar 

  2. Costello, P.S., Gallagher, M. & Cantrell, D.A. Sustained and dynamic inositol lipid metabolism inside and outside the immunological synapse. Nat. Immunol. 3, 1082–1089 (2002).

    Article  CAS  Google Scholar 

  3. Garcon, F. et al. CD28 provides T-cell costimulation and enhances PI3K activity at the immune synapse independently of its capacity to interact with the p85/p110 heterodimer. Blood 111, 1464–1471 (2008).

    Article  CAS  Google Scholar 

  4. Harriague, J. & Bismuth, G. Imaging antigen-induced PI3K activation in T cells. Nat. Immunol. 3, 1090–1096 (2002).

    Article  CAS  Google Scholar 

  5. Jones, R.G. & Thompson, C.B. Revving the engine: signal transduction fuels T cell activation. Immunity 27, 173–178 (2007).

    Article  CAS  Google Scholar 

  6. Reif, K., Nobes, C.D., Thomas, G., Hall, A. & Cantrell, D.A. Phosphatidylinositol 3-kinase signals activate a selective subset of Rac/Rho-dependent effector pathways. Curr. Biol. 6, 1445–1455 (1996).

    Article  CAS  Google Scholar 

  7. Reif, K. et al. Cutting edge: differential roles for phosphoinositide 3-kinases, p110γ and p110δ, in lymphocyte chemotaxis and homing. J. Immunol. 173, 2236–2240 (2004).

    Article  CAS  Google Scholar 

  8. Ward, S.G. T lymphocytes on the move: chemokines, PI 3-kinase and beyond. Trends Immunol. 27, 80–87 (2006).

    Article  CAS  Google Scholar 

  9. Matheu, M.P., Deane, J.A., Parker, I., Fruman, D.A. & Cahalan, M.D. Class IA phosphoinositide 3-kinase modulates basal lymphocyte motility in the lymph node. J. Immunol. 179, 2261–2269 (2007).

    Article  CAS  Google Scholar 

  10. Asperti-Boursin, F., Real, E., Bismuth, G., Trautmann, A. & Donnadieu, E. CCR7 ligands control basal T cell motility within lymph node slices in a phosphoinositide 3-kinase-independent manner. J. Exp. Med. 204, 1167–1179 (2007).

    Article  CAS  Google Scholar 

  11. Cyster, J.G. Chemokines, sphingosine-1-phosphate, and cell migration in secondary lymphoid organs. Annu. Rev. Immunol. 23, 127–159 (2005).

    Article  CAS  Google Scholar 

  12. Mora, J.R. & von Andrian, U.H. T-cell homing specificity and plasticity: new concepts and future challenges. Trends Immunol. 27, 235–243 (2006).

    Article  CAS  Google Scholar 

  13. Springer, T.A. Traffic signals for lymphocyte recirculation and leukocyte emigration: the multistep paradigm. Cell 76, 301–314 (1994).

    Article  CAS  Google Scholar 

  14. Arbones, M.L. et al. Lymphocyte homing and leukocyte rolling and migration are impaired in L-selectin-deficient mice. Immunity 1, 247–260 (1994).

    Article  CAS  Google Scholar 

  15. Tang, M.L., Steeber, D.A., Zhang, X.Q. & Tedder, T.F. Intrinsic differences in L-selectin expression levels affect T and B lymphocyte subset-specific recirculation pathways. J. Immunol. 160, 5113–5121 (1998).

    CAS  PubMed  Google Scholar 

  16. Lefrancois, L. Development, trafficking, and function of memory T-cell subsets. Immunol. Rev. 211, 93–103 (2006).

    Article  CAS  Google Scholar 

  17. Jung, T.M., Gallatin, W.M., Weissman, I.L. & Dailey, M.O. Down-regulation of homing receptors after T cell activation. J. Immunol. 141, 4110–4117 (1988).

    CAS  PubMed  Google Scholar 

  18. Chao, C.C., Jensen, R. & Dailey, M.O. Mechanisms of L-selectin regulation by activated T cells. J. Immunol. 159, 1686–1694 (1997).

    CAS  PubMed  Google Scholar 

  19. Preece, G., Murphy, G. & Ager, A. Metalloproteinase-mediated regulation of L-selectin levels on leucocytes. J. Biol. Chem. 271, 11634–11640 (1996).

    Article  CAS  Google Scholar 

  20. Ley, K. & Kansas, G.S. Selectins in T-cell recruitment to non-lymphoid tissues and sites of inflammation. Nat. Rev. Immunol. 4, 325–335 (2004).

    Article  CAS  Google Scholar 

  21. Venturi, G.M. et al. Leukocyte migration is regulated by L-selectin endoproteolytic release. Immunity 19, 713–724 (2003).

    Article  CAS  Google Scholar 

  22. Kaech, S.M., Hemby, S., Kersh, E. & Ahmed, R. Molecular and functional profiling of memory CD8 T cell differentiation. Cell 111, 837–851 (2002).

    Article  CAS  Google Scholar 

  23. Manjunath, N. et al. Effector differentiation is not prerequisite for generation of memory cytotoxic T lymphocytes. J. Clin. Invest. 108, 871–878 (2001).

    Article  CAS  Google Scholar 

  24. Weninger, W., Crowley, M.A., Manjunath, N. & von Andrian, U.H. Migratory properties of naive, effector, and memory CD8+ T cells. J. Exp. Med. 194, 953–966 (2001).

    Article  CAS  Google Scholar 

  25. Cornish, G.H., Sinclair, L.V. & Cantrell, D.A. Differential regulation of T-cell growth by IL-2 and IL-15. Blood 108, 600–608 (2006).

    Article  CAS  Google Scholar 

  26. Galkina, E. et al. L-selectin shedding does not regulate constitutive T cell trafficking but controls the migration pathways of antigen-activated T lymphocytes. J. Exp. Med. 198, 1323–1335 (2003).

    Article  CAS  Google Scholar 

  27. Li, Y., Brazzell, J., Herrera, A. & Walcheck, B. ADAM17 deficiency by mature neutrophils has differential effects on L-selectin shedding. Blood 108, 2275–2279 (2006).

    Article  CAS  Google Scholar 

  28. Vanhaesebroeck, B., Ali, K., Bilancio, A., Geering, B. & Foukas, L.C. Signalling by PI3K isoforms: insights from gene-targeted mice. Trends Biochem. Sci. 30, 194–204 (2005).

    Article  CAS  Google Scholar 

  29. Okkenhaug, K. et al. Impaired B and T cell antigen receptor signaling in p110δ PI 3-kinase mutant mice. Science 297, 1031–1034 (2002).

    CAS  PubMed  Google Scholar 

  30. Okkenhaug, K. et al. The p110δ isoform of phosphoinositide 3-kinase controls clonal expansion and differentiation of Th cells. J. Immunol. 177, 5122–5128 (2006).

    Article  CAS  Google Scholar 

  31. Kelly, A.P. et al. Notch-induced T cell development requires phosphoinositide-dependent kinase 1. EMBO J. 26, 3441–3450 (2007).

    Article  CAS  Google Scholar 

  32. Fan, H. & Derynck, R. Ectodomain shedding of TGF-α and other transmembrane proteins is induced by receptor tyrosine kinase activation and MAP kinase signaling cascades. EMBO J. 18, 6962–6972 (1999).

    Article  CAS  Google Scholar 

  33. Borroto, A. et al. Impaired trafficking and activation of tumor necrosis factor-α-converting enzyme in cell mutants defective in protein ectodomain shedding. J. Biol. Chem. 278, 25933–25939 (2003).

    Article  CAS  Google Scholar 

  34. Diaz-Rodriguez, E., Montero, J.C., Esparis-Ogando, A., Yuste, L. & Pandiella, A. Extracellular signal-regulated kinase phosphorylates tumor necrosis factor α-converting enzyme at threonine 735: a potential role in regulated shedding. Mol. Biol. Cell 13, 2031–2044 (2002).

    Article  CAS  Google Scholar 

  35. Soond, S.M., Everson, B., Riches, D.W. & Murphy, G. ERK-mediated phosphorylation of Thr735 in TNFα-converting enzyme and its potential role in TACE protein trafficking. J. Cell Sci. 118, 2371–2380 (2005).

    Article  CAS  Google Scholar 

  36. Fingar, D.C. & Blenis, J. Target of rapamycin (TOR): an integrator of nutrient and growth factor signals and coordinator of cell growth and cell cycle progression. Oncogene 23, 3151–3171 (2004).

    Article  CAS  Google Scholar 

  37. Sebzda, E., Zou, Z., Lee, J.S., Wang, T. & Kahn, M.L. Transcription factor KLF2 regulates the migration of naive T cells by restricting chemokine receptor expression patterns. Nat. Immunol. 9, 292–300 (2008).

    Article  CAS  Google Scholar 

  38. Bai, A., Hu, H., Yeung, M. & Chen, J. Kruppel-like factor 2 controls T cell trafficking by activating L-selectin (CD62L) and sphingosine-1-phosphate receptor 1 transcription. J. Immunol. 178, 7632–7639 (2007).

    Article  CAS  Google Scholar 

  39. Carlson, C.M. et al. Kruppel-like factor 2 regulates thymocyte and T-cell migration. Nature 442, 299–302 (2006).

    Article  CAS  Google Scholar 

  40. Hagenbeek, T.J. et al. The loss of PTEN allows TCR αβ lineage thymocytes to bypass IL-7 and pre-TCR-mediated signaling. J. Exp. Med. 200, 883–894 (2004).

    Article  CAS  Google Scholar 

  41. Unsoeld, H., Voehringer, D., Krautwald, S. & Pircher, H. Constitutive expression of CCR7 directs effector CD8 T cells into the splenic white pulp and impairs functional activity. J. Immunol. 173, 3013–3019 (2004).

    Article  CAS  Google Scholar 

  42. Venturi, G.M., Conway, R.M., Steeber, D.A. & Tedder, T.F. CD25+CD4+ regulatory T cell migration requires L-selectin expression: L-selectin transcriptional regulation balances constitutive receptor turnover. J. Immunol. 178, 291–300 (2007).

    Article  CAS  Google Scholar 

  43. Richards, H., Longhi, M.P., Wright, K., Gallimore, A. & Ager, A. CD62L down-regulation does not affect memory T cell distribution but failure to shed compromises anti-viral Immunity. J. Immunol. 180, 198–206 (2008).

    Article  CAS  Google Scholar 

  44. Sarbassov, D.D., Ali, S.M. & Sabatini, D.M. Growing roles for the mTOR pathway. Curr. Opin. Cell Biol. 17, 596–603 (2005).

    Article  CAS  Google Scholar 

  45. Battaglia, M., Stabilini, A. & Roncarolo, M.G. Rapamycin selectively expands CD4+CD25+FoxP3+ regulatory T cells. Blood 105, 4743–4748 (2005).

    Article  CAS  Google Scholar 

  46. Zheng, X.X. et al. Favorably tipping the balance between cytopathic and regulatory T cells to create transplantation tolerance. Immunity 19, 503–514 (2003).

    Article  CAS  Google Scholar 

  47. Guarda, G. et al. L-selectin-negative CCR7− effector and memory CD8+ T cells enter reactive lymph nodes and kill dendritic cells. Nat. Immunol. 8, 743–752 (2007).

    Article  CAS  Google Scholar 

  48. Pircher, H., Burki, K., Lang, R., Hengartner, H. & Zinkernagel, R.M. Tolerance induction in double specific T-cell receptor transgenic mice varies with antigen. Nature 342, 559–561 (1989).

    Article  CAS  Google Scholar 

  49. Gray, A., Olsson, H., Batty, I.H., Priganica, L. & Peter Downes, C. Nonradioactive methods for the assay of phosphoinositide 3-kinases and phosphoinositide phosphatases and selective detection of signaling lipids in cell and tissue extracts. Anal. Biochem. 313, 234–245 (2003).

    Article  CAS  Google Scholar 

Download references

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.).

Author information

Authors and Affiliations

  1. Department of Cell Biology and Immunology, University of Dundee, Dundee, DD1 5EH, UK

    Linda V Sinclair, David Finlay, Carmen Feijoo & Doreen A Cantrell

  2. Immune Cell Biology, The National Institute for Medical Research, London, NW7 1AA, UK

    Georgina H Cornish

  3. Division of Molecular Physiology, University of Dundee, Dundee, DD1 5EH, UK

    Alex Gray

  4. Department of Medical Biochemistry and Immunology, Cardiff University, Cardiff, CF14 4XN, UK

    Ann Ager

  5. Laboratory of Lymphocyte Signalling and Development, Babraham Institute, Cambridge, CB2 4AT, UK

    Klaus Okkenhaug

  6. Department of Immunology, The Netherlands Cancer Institute, Amsterdam, 1066 CX, The Netherlands

    Thijs J Hagenbeek & Hergen Spits

  7. Department of Immunology Discovery, Genentech, South San Francisco, California, 94080, USA

    Hergen Spits

Authors
  1. Linda V Sinclair
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. David Finlay
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Carmen Feijoo
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. Georgina H Cornish
    View author publications

    You can also search for this author inPubMed Google Scholar

  5. Alex Gray
    View author publications

    You can also search for this author inPubMed Google Scholar

  6. Ann Ager
    View author publications

    You can also search for this author inPubMed Google Scholar

  7. Klaus Okkenhaug
    View author publications

    You can also search for this author inPubMed Google Scholar

  8. Thijs J Hagenbeek
    View author publications

    You can also search for this author inPubMed Google Scholar

  9. Hergen Spits
    View author publications

    You can also search for this author inPubMed Google Scholar

  10. Doreen A Cantrell
    View author publications

    You can also search for this author inPubMed Google Scholar

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.

Corresponding author

Correspondence to Doreen A Cantrell.

Ethics declarations

Competing interests

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

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–3 and Methods (PDF 717 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ni.1603

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing