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:

Transcription factor KLF2 regulates the migration of naive T cells by restricting chemokine receptor expression patterns

Nature Immunology volume 9, pages 292–300 (2008)Cite this article

Abstract

The migration patterns of naive and activated T cells are associated with the expression of distinct sets of chemokine receptors, but the molecular basis for this regulation is unknown. Here we identify Krupple-like factor 2 (KLF2) as a key transcriptional factor needed to prevent naive T cells from expressing inflammatory chemokine receptors and acquiring the migration patterns of activated T cells. Lineage-specific deletion of KLF2 resulted in fewer naive T cells in the blood and secondary lymphoid organs, whereas it expanded naive T cell numbers in nonlymphoid tissues; these effects were associated with altered expression of inflammatory chemokine receptors on naive T cells. KLF2 repressed the expression of several chemokine receptors, including CCR3 and CCR5. We thus conclude that KLF2 maintains proper T cell migration patterns by linking T cell movement and transcriptional regulation of chemokine receptor expression patterns.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1: Klf2−/−Vav-Cre+ mice have more mature thymocytes but many fewer T cells in the peripheral blood and lymphoid organs.
Figure 2: KLF2-deficient thymocytes and T cells do not undergo spontaneous apoptosis.
Figure 3: CD4+ T cell migration in response to S1P and inhibition of migration by FTY720 indicates the presence of peripheral KLF2-deficient T cells in Klf2fl/flVav-Cre− mice.
Figure 4: KLF2-deficient T cells trapped in lymph nodes by FTY720 treatment have a naive phenotype.
Figure 5: KLF2-deficient T cells home to nonlymphoid peripheral tissues.
Figure 6: Expression and function of inflammatory chemokine receptors by naive KLF2-deficient T cells.
Figure 7: Altered homing by KLF2-deficient T cells in vivo requires Gi protein–coupled chemokine receptor signaling.

Similar content being viewed by others

References

  1. Dang, D.T., Pevsner, J. & Yang, V.W. The biology of the mammalian Kruppel-like family of transcription factors. Int. J. Biochem. Cell Biol. 32, 1103–1121 (2000).

    Article  CAS  Google Scholar 

  2. Kaczynski, J., Cook, T. & Urrutia, R. Sp1- and Kruppel-like transcription factors. Genome Biol. 4, 206.1–206.8 (2003).

    Article  Google Scholar 

  3. Schober, S.L. et al. Expression of the transcription factor lung Kruppel-like factor is regulated by cytokines and correlates with survival of memory T cells in vitro and in vivo. J. Immunol. 163, 3662–3667 (1999).

    CAS  PubMed  Google Scholar 

  4. Kuo, C.T., Veselits, M.L. & Leiden, J.M. LKLF: A transcriptional regulator of single-positive T cell quiescence and survival. Science 277, 1986–1990 (1997).

    Article  CAS  Google Scholar 

  5. Kuo, C.T. et al. The LKLF transcription factor is required for normal tunica media formation and blood vessel stabilization during murine embryogenesis. Genes Dev. 11, 2996–3006 (1997).

    Article  CAS  Google Scholar 

  6. Wani, M.A., Means, R.T. Jr. & Lingrel, J.B. Loss of LKLF function results in embryonic lethality in mice. Transgenic Res. 7, 229–238 (1998).

    Article  CAS  Google Scholar 

  7. Lee, J.S. et al. Klf2 is an essential regulator of vascular hemodynamic forces in vivo. Dev. Cell 11, 845–857 (2006).

    Article  CAS  Google Scholar 

  8. Buckley, A.F., Kuo, C.T. & Leiden, J.M. Transcription factor LKLF is sufficient to program T cell quiescence via a c-Myc–dependent pathway. Nat. Immunol. 2, 698–704 (2001).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  10. Matloubian, M. et al. Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1. Nature 427, 355–360 (2004).

    Article  CAS  Google Scholar 

  11. Allende, M.L., Dreier, J.L., Mandala, S. & Proia, R.L. Expression of the sphingosine 1-phosphate receptor, S1P1, on T-cells controls thymic emigration. J. Biol. Chem. 279, 15396–15401 (2004).

    Article  CAS  Google Scholar 

  12. Teresa Sanchez, T.H. Structural and functional characteristics of S1P receptors. J. Cell. Biochem. 92, 913–922 (2004).

    Article  Google Scholar 

  13. Chiba, K., Matsuyuki, H., Maeda, Y. & Sugahara, K. Role of sphingosine 1-phosphate receptor type 1 in lymphocyte egress from secondary lymphoid tissues and thymus. Cell. Mol. Immunol. 3, 11–19 (2006).

    CAS  PubMed  Google Scholar 

  14. Stadtfeld, M. & Graf, T. Assessing the role of hematopoietic plasticity for endothelial and hepatocyte development by non-invasive lineage tracing. Development 132, 203–213 (2005).

    Article  CAS  Google Scholar 

  15. Kuo, C.T., Veselits, M.L. & Leiden, J.M. LKLF and FasL expression: correctiona and clarification. Science 278, 788–789 (1997).

    Article  CAS  Google Scholar 

  16. Lee, M.-J. et al. Sphingosine-1-phosphate as a ligand for the G protein-coupled receptor EDG-1. Science 279, 1552–1555 (1998).

    Article  CAS  Google Scholar 

  17. Liu, C.H. et al. Ligand-induced trafficking of the sphingosine-1-phosphate receptor EDG-1. Mol. Biol. Cell 10, 1179–1190 (1999).

    Article  CAS  Google Scholar 

  18. Graeler, M. & Goetzl, E.J. Activation-regulated expression and chemotactic function of sphingosine 1-phosphate receptors in mouse splenic T cells. FASEB J. 16, 1874–1878 (2002).

    Article  CAS  Google Scholar 

  19. Pappu, R. et al. Promotion of lymphocyte egress into blood and lymph by distinct sources of sphingosine-1-phosphate. Science 316, 295–298 (2007).

    Article  CAS  Google Scholar 

  20. Chiba, K. et al. FTY720, a novel immunosuppressant, induces sequestration of circulating mature lymphocytes by acceleration of lymphocyte homing in rats. I. FTY720 selectively decreases the number of circulating mature lymphocytes by acceleration of lymphocyte homing. J. Immunol. 160, 5037–5044 (1998).

    CAS  PubMed  Google Scholar 

  21. Graler, M.H. & Goetzl, E.J. The immunosuppressant FTY720 down-regulates sphingosine 1-phosphate G-protein-coupled receptors. FASEB J. 18, 551–553 (2004).

    Article  CAS  Google Scholar 

  22. Luster, A.D., Alon, R. & von Andrian, U.H. Immune cell migration in inflammation: present and future therapeutic targets. Nat. Immunol. 6, 1182–1190 (2005).

    Article  CAS  Google Scholar 

  23. 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 

  24. von Andrian, U.H. & Mempel, T.R. Homing and cellular traffic in lymph nodes. Nat. Rev. Immunol. 3, 867–878 (2003).

    Article  CAS  Google Scholar 

  25. 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 

  26. Liu, R., Zhao, X., Gurney, T. & Landau, N. Functional analysis of the proximal CCR5 promoter. AIDS Res. Hum. Retroviruses 14, 1509–1519 (1998).

    Article  CAS  Google Scholar 

  27. Guignard, F., Combadiere, C., Tiffany, H.L. & Murphy, P.M. Gene organization and promoter function for CC chemokine receptor 5 (CCR5). J. Immunol. 160, 985–992 (1998).

    CAS  PubMed  Google Scholar 

  28. Scotet, E., Schroeder, S. & Lanzavecchia, A. Molecular regulation of CC-chemokine receptor 3 expression in human T helper 2 cells. Blood 98, 2568–2570 (2001).

    Article  CAS  Google Scholar 

  29. Gonzalo, J.-A. et al. Mouse eotaxin expression parallels eosinophil accumulation during lung allergic inflammation but it is not restricted to a Th2-type response. Immunity 4, 1–14 (1996).

    Article  CAS  Google Scholar 

  30. Heath, H. et al. Chemokine receptor usage by human eosinophils. The importance of CCR3 demonstrated using an antagonistic monoclonal antibody. J. Clin. Invest. 99, 178–184 (1997).

    Article  CAS  Google Scholar 

  31. Apolinario, A. et al. Increased expression of T cell chemokines and their receptors in chronic hepatitis C: relationship with the histological activity of liver disease. Am. J. Gastroenterol. 97, 2861–2870 (2002).

    Article  CAS  Google Scholar 

  32. Murai, M. et al. Active participation of CCR5+CD8+ T lymphocytes in the pathogenesis of liver injury in graft-versus-host disease. J. Clin. Invest. 104, 49–57 (1999).

    Article  CAS  Google Scholar 

  33. Ajuebor, M.N., Hogaboam, C.M., Le, T., Proudfoot, A.E. & Swain, M.G. CCL3/MIP-1α is pro-inflammatory in murine T cell-mediated hepatitis by recruiting CCR1-expressing CD4+ T cells to the liver. Eur. J. Immunol. 34, 2907–2918 (2004).

    Article  CAS  Google Scholar 

  34. von Andrian, U.H. & Mackay, C.R. T-cell function and migration. Two sides of the same coin. N. Engl. J. Med. 343, 1020–1034 (2000).

    Article  CAS  Google Scholar 

  35. Rot, A. & von Andrian, U.H. Chemokines in innate and adaptive host defense: basic chemokinese grammar for immune cells. Annu. Rev. Immunol. 22, 891–928 (2004).

    Article  CAS  Google Scholar 

  36. Ebert, L.M., Schaerli, P. & Moser, B. Chemokine-mediated control of T cell traffic in lymphoid and peripheral tissues. Mol. Immunol. 42, 799–809 (2005).

    Article  CAS  Google Scholar 

  37. Rosen, S.D. Ligands for L-selectin: homing, inflammation, and beyond. Annu. Rev. Immunol. 22, 129–156 (2004).

    Article  CAS  Google Scholar 

  38. Daugherty, B. et al. Cloning, expression, and characterization of the human eosinophil eotaxin receptor. J. Exp. Med. 183, 2349–2354 (1996).

    Article  CAS  Google Scholar 

  39. Uguccioni, M. et al. High expression of the chemokine receptor CCR3 in human blood basophils. Role in activation by eotaxin, MCP-4, and other chemokines. J. Clin. Invest. 100, 1137–1143 (1997).

    Article  CAS  Google Scholar 

  40. Ochi, H. et al. T helper cell type 2 cytokine-mediated comitogenic responses and CCR3 expression during differentiation of human mast cells in vitro. J. Exp. Med. 190, 267–280 (1999).

    Article  CAS  Google Scholar 

  41. Sallusto, F., Lenig, D., Forster, R., Lipp, M. & Lanzavecchia, A. Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature 401, 708–712 (1999).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  43. Endrizzi, B.T. & Jameson, S.C. Differential role for IL-7 in inducing lung Kruppel-like factor (Kruppel-like factor 2) expression by naive versus activated T cells. Int. Immunol. 15, 1341–1348 (2003).

    Article  CAS  Google Scholar 

  44. Lee, P.P. et al. A critical role for Dnmt1 and DNA methylation in T cell development, function, and survival. Immunity 15, 763–774 (2001).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank J. Cyster and M. Zachariah for assistance with anti-S1P1 staining and for comments on the manuscript; T. Graf (Albert Einstein College of Medicine) for the use of Vav-Cre–transgenic mice; and G. Koretzky, J. Maltzman and B. Kleaveland for insights. The plasmid pcDNA-HA-KLF2 was a gift from laboratory of L.H. Glimcher (Harvard School of Public Health).

Author information

Author notes

  1. Eric Sebzda

    Present address: Present address: Department of Microbiology and Immunology, Vanderbilt University, Nashville, Tennessee 37232, USA.,

Authors and Affiliations

  1. Department of Medicine, University of Pennsylvania, Philadelphia, 19104, Pennsylvania, USA

    Eric Sebzda, Zhiying Zou, John S Lee, Tao Wang & Mark L Kahn

Authors
  1. Eric Sebzda
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zhiying Zou
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. John S Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tao Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mark L Kahn
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

E.S. designed and did experiments and wrote the manuscript; Z.Z., J.S.L. and T.W. designed and did experiments; and M.L.K. designed experiments and wrote the manuscript.

Corresponding authors

Correspondence to Eric Sebzda or Mark L Kahn.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–2 and Table 1 (PDF 389 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sebzda, E., Zou, Z., Lee, J. et al. Transcription factor KLF2 regulates the migration of naive T cells by restricting chemokine receptor expression patterns. Nat Immunol 9, 292–300 (2008). https://doi.org/10.1038/ni1565

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ni1565

This article is cited by

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