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 ELF4 controls the proliferation and homing of CD8+ T cells via the Krüppel-like factors KLF4 and KLF2

Nature Immunology volume 10, pages 618–626 (2009)Cite this article

Abstract

Transcription factors that regulate the quiescence, proliferation and homing of lymphocytes are critical for effective immune system function. Here we demonstrate that the transcription factor ELF4 directly activated the tumor suppressor KLF4 'downstream' of T cell antigen receptor signaling to induce cell cycle arrest in naive CD8+ T cells. Elf4- and Klf4-deficient mice accumulated CD8+CD44hi T cells during steady-state conditions and generated more memory T cells after immunization. The homeostatic population expansion of CD8+CD44hi T cells in Elf4-null mice resulted in a redistribution of cells to nonlymphoid tissue because of lower expression of the transcription factor KLF2 and the surface proteins CCR7 and CD62L. Our work describes the combinatorial effect of lymphocyte-intrinsic factors on the homeostasis, activation and homing of T cells.

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: ELF4 negatively regulates the proliferation of naive CD8+ T cells.
Figure 2: ELF4 restricts the homeostatic population expansion of CD8+ T cells with a memory-like phenotype.
Figure 3: The gradual expansion of Elf4−/− CD8+CD44hi T cell populations leads to lower CD62L expression.
Figure 4: ELF4 regulates the expression of KLF2 and CD62L solely in CD8+CD44hi T cells from older mice.
Figure 5: Elf4−/− CD8+ T cells generate more effector and memory T cells after immunization.
Figure 6: ELF4 inhibits T cell proliferation by activating KLF4 'downstream' of TCR signaling.
Figure 7: KLF4, a direct target of ELF4, negatively regulates the proliferation of naive CD8+ T cells.

Similar content being viewed by others

Accession codes

Accessions

Gene Expression Omnibus

References

  1. Tzachanis, D., Lafuente, E.M., Li, L. & Boussiotis, V.A. Intrinsic and extrinsic regulation of T lymphocyte quiescence. Leuk. Lymphoma 45, 1959–1967 (2004).

    Article  CAS  Google Scholar 

  2. Surh, C.D. & Sprent, J. Homeostasis of naive and memory T cells. Immunity 29, 848–862 (2008).

    Article  CAS  Google Scholar 

  3. Lacorazza, H.D. & Nimer, S.D. The emerging role of the myeloid Elf-1 like transcription factor in hematopoiesis. Blood Cells Mol. Dis. 31, 342–350 (2003).

    Article  CAS  Google Scholar 

  4. Liu, Y. et al. The ETS protein MEF is regulated by phosphorylation-dependent proteolysis via the protein-ubiquitin ligase SCFSkp2. Mol. Cell. Biol. 26, 3114–3123 (2006).

    Article  CAS  Google Scholar 

  5. Miyazaki, Y. et al. Cyclin A-dependent phosphorylation of the ETS-related protein, MEF, restricts its activity to the G1 phase of the cell cycle. J. Biol. Chem. 276, 40528–40536 (2001).

    Article  CAS  Google Scholar 

  6. Alcalay, M. et al. Acute myeloid leukemia fusion proteins deregulate genes involved in stem cell maintenance and DNA repair. J. Clin. Invest. 112, 1751–1761 (2003).

    Article  CAS  Google Scholar 

  7. Park, D.J., Vuong, P.T., de Vos, S., Douer, D. & Koeffler, H.P. Comparative analysis of genes regulated by PML/RARα and PLZF/RARα in response to retinoic acid using oligonucleotide arrays. Blood 102, 3727–3736 (2003).

    Article  CAS  Google Scholar 

  8. Muller-Tidow, C. et al. Translocation products in acute myeloid leukemia activate the Wnt signaling pathway in hematopoietic cells. Mol. Cell. Biol. 24, 2890–2904 (2004).

    Article  Google Scholar 

  9. Lacorazza, H.D. et al. The ETS protein MEF plays a critical role in perforin gene expression and the development of natural killer and NK-T cells. Immunity 17, 437–449 (2002).

    Article  CAS  Google Scholar 

  10. Lacorazza, H.D. et al. The transcription factor MEF/ELF4 regulates the quiescence of primitive hematopoietic cells. Cancer Cell 9, 175–187 (2006).

    Article  CAS  Google Scholar 

  11. Rowland, B.D., Bernards, R. & Peeper, D.S. The KLF4 tumour suppressor is a transcriptional repressor of p53 that acts as a context-dependent oncogene. Nat. Cell Biol. 7, 1074–1082 (2005).

    Article  CAS  Google Scholar 

  12. Wei, D., Kanai, M., Huang, S. & Xie, K. Emerging role of KLF4 in human gastrointestinal cancer. Carcinogenesis 27, 23–31 (2006).

    Article  CAS  Google Scholar 

  13. Zhao, W. et al. Identification of Kruppel-like factor 4 as a potential tumor suppressor gene in colorectal cancer. Oncogene 23, 395–402 (2004).

    Article  CAS  Google Scholar 

  14. Yasunaga, J. et al. Identification of aberrantly methylated genes in association with adult T-cell leukemia. Cancer Res. 64, 6002–6009 (2004).

    Article  CAS  Google Scholar 

  15. Takahashi, K. & Yamanaka, S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663–676 (2006).

    Article  CAS  Google Scholar 

  16. Nakagawa, M. et al. Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts. Nat. Biotechnol. 26, 101–106 (2008).

    Article  CAS  Google Scholar 

  17. Takahashi, K. et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131, 861–872 (2007).

    Article  CAS  Google Scholar 

  18. 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 

  19. Tzachanis, D. et al. Tob is a negative regulator of activation that is expressed in anergic and quiescent T cells. Nat. Immunol. 2, 1174–1182 (2001).

    Article  CAS  Google Scholar 

  20. Medema, R.H., Kops, G.J., Bos, J.L. & Burgering, B.M. AFX-like Forkhead transcription factors mediate cell-cycle regulation by Ras and PKB through p27kip1. Nature 404, 782–787 (2000).

    Article  CAS  Google Scholar 

  21. Bista, P., Mele, D.A., Baez, D.V. & Huber, B.T. Lymphocyte quiescence factor Dpp2 is transcriptionally activated by KLF2 and TOB1. Mol. Immunol. 45, 3618–3623 (2008).

    Article  CAS  Google Scholar 

  22. Baksh, S. et al. NFATc2-mediated repression of cyclin-dependent kinase 4 expression. Mol. Cell 10, 1071–1081 (2002).

    Article  CAS  Google Scholar 

  23. Hou, S., Hyland, L., Ryan, K.W., Portner, A. & Doherty, P.C. Virus-specific CD8+ T-cell memory determined by clonal burst size. Nature 369, 652–654 (1994).

    Article  CAS  Google Scholar 

  24. Wherry, E.J. et al. Lineage relationship and protective immunity of memory CD8 T cell subsets. Nat. Immunol. 4, 225–234 (2003).

    Article  CAS  Google Scholar 

  25. Kaech, S.M. & Wherry, E.J. Heterogeneity and cell-fate decisions in effector and memory CD8+ T cell differentiation during viral infection. Immunity 27, 393–405 (2007).

    Article  CAS  Google Scholar 

  26. Marsden, V.S., Kappler, J.W. & Marrack, P.C. Homeostasis of the memory T cell pool. Int. Arch. Allergy Immunol. 139, 63–74 (2006).

    Article  Google Scholar 

  27. Cannarile, M.A. et al. Transcriptional regulator Id2 mediates CD8+ T cell immunity. Nat. Immunol. 7, 1317–1325 (2006).

    Article  CAS  Google Scholar 

  28. Joshi, N.S. et al. Inflammation directs memory precursor and short-lived effector CD8+ T cell fates via the graded expression of T-bet transcription factor. Immunity 27, 281–295 (2007).

    Article  CAS  Google Scholar 

  29. Zhang, M. et al. Differential survival of cytotoxic T cells and memory cell precursors. J. Immunol. 178, 3483–3491 (2007).

    Article  CAS  Google Scholar 

  30. Marrack, P. et al. Homeostasis of αβ TCR+ T cells. Nat. Immunol. 1, 107–111 (2000).

    Article  CAS  Google Scholar 

  31. Goldrath, A.W., Luckey, C.J., Park, R., Benoist, C. & Mathis, D. The molecular program induced in T cells undergoing homeostatic proliferation. Proc. Natl. Acad. Sci. USA 101, 16885–16890 (2004).

    Article  CAS  Google Scholar 

  32. Masopust, D., Vezys, V., Marzo, A.L. & Lefrancois, L. Preferential localization of effector memory cells in nonlymphoid tissue. Science 291, 2413–2417 (2001).

    Article  CAS  Google Scholar 

  33. Warnock, R.A., Askari, S., Butcher, E.C. & von Andrian, U.H. Molecular mechanisms of lymphocyte homing to peripheral lymph nodes. J. Exp. Med. 187, 205–216 (1998).

    Article  CAS  Google Scholar 

  34. 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 

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

    Article  CAS  Google Scholar 

  36. 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 

  37. Sprent, J., Cho, J.H., Boyman, O. & Surh, C.D. T cell homeostasis. Immunol. Cell Biol. 86, 312–319 (2008).

    Article  CAS  Google Scholar 

  38. Surh, C.D. & Sprent, J. Homeostatic T cell proliferation: how far can T cells be activated to self-ligands? J. Exp. Med. 192, F9–F14 (2000).

    Article  CAS  Google Scholar 

  39. Kerdiles, Y.M. et al. Foxo1 links homing and survival of naive T cells by regulating L-selectin, CCR7 and interleukin 7 receptor. Nat. Immunol. 10, 176–184 (2009).

    Article  CAS  Google Scholar 

  40. Lacombe, M.H., Hardy, M.P., Rooney, J. & Labrecque, N. IL-7 receptor expression levels do not identify CD8+ memory T lymphocyte precursors following peptide immunization. J. Immunol. 175, 4400–4407 (2005).

    Article  CAS  Google Scholar 

  41. Badovinac, V.P., Messingham, K.A., Jabbari, A., Haring, J.S. & Harty, J.T. Accelerated CD8+ T-cell memory and prime-boost response after dendritic-cell vaccination. Nat. Med. 11, 748–756 (2005).

    Article  CAS  Google Scholar 

  42. Rowland, B.D. & Peeper, D.S. KLF4, p21 and context-dependent opposing forces in cancer. Nat. Rev. Cancer 6, 11–23 (2006).

    Article  CAS  Google Scholar 

  43. Mahatan, C.S., Kaestner, K.H., Geiman, D.E. & Yang, V.W. Characterization of the structure and regulation of the murine gene encoding gut-enriched Kruppel-like factor (Kruppel-like factor 4). Nucleic Acids Res. 27, 4562–4569 (1999).

    Article  CAS  Google Scholar 

  44. Yao, J.J. et al. Tumor promoting properties of the ETS protein MEF in ovarian cancer. Oncogene 26, 4032–4037 (2007).

    Article  CAS  Google Scholar 

  45. Sandberg, M.L. et al. c-Myb and p300 regulate hematopoietic stem cell proliferation and differentiation. Dev. Cell 8, 153–166 (2005).

    Article  CAS  Google Scholar 

  46. Veiga-Fernandes, H. & Rocha, B. High expression of active CDK6 in the cytoplasm of CD8 memory cells favors rapid division. Nat. Immunol. 5, 31–37 (2004).

    Article  CAS  Google Scholar 

  47. Yusuf, I. et al. KLF4 is a FOXO target gene that suppresses B cell proliferation. Int. Immunol. 20, 671–681 (2008).

    Article  CAS  Google Scholar 

  48. Hogquist, K.A., Weinreich, M.A. & Jameson, S.C. T-cell migration: T-cell migration Kruppeled T cells move again. Immunol. Cell Biol. 86, 297–298 (2008).

    Article  CAS  Google Scholar 

  49. Vezys, V. et al. Memory CD8 T-cell compartment grows in size with immunological experience. Nature 457, 196–199 (2009).

    Article  CAS  Google Scholar 

  50. Ginaldi, L. et al. Changes in the expression of surface receptors on lymphocyte subsets in the elderly: quantitative flow cytometric analysis. Am. J. Hematol. 67, 63–72 (2001).

    Article  CAS  Google Scholar 

  51. Katz, J.P. et al. The zinc-finger transcription factor Klf4 is required for terminal differentiation of goblet cells in the colon. Development 129, 2619–2628 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Krieg, C., Boyman, O., Fu, Y.X. & Kaye, J. B and T lymphocyte attenuator regulates CD8+ T cell-intrinsic homeostasis and memory cell generation. Nat. Immunol. 8, 162–171 (2007).

    Article  CAS  Google Scholar 

  53. Galan-Caridad, J.M. et al. Zfx controls the self-renewal of embryonic and hematopoietic stem cells. Cell 129, 345–357 (2007).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank M. Finegold for support; T. Matano for support from the Japanese Foundation for AIDS prevention (to T.Y.); S. Nimer (Memorial Sloan-Kettering Cancer Center) for Elf4−/− and Vav-ELF4 mice; T. Tan (Baylor College of Medicine) for CD4-Cre mice. K. Kaestner (University of Pennsylvania) for mice with loxP-flanked Klf4; M. Puppi and L. Bae for assistance; M. Cubbage, C. Threeton and T. Goltsova for cell sorting; the Gulf Coast Digestive Disease Morphology Core and T.-A. Mistretta for microarray analysis; and C. Rooney for critical review of the manuscript. Supported by the National Cancer Institute of the US National Institutes of Health (KO1 CA099156-01 to H.D.L.), the Dan Duncan Cancer Center at Baylor College of Medicine (H.D.L.), the Curtis Hankamer Basic Research Fund (H.D.L.) and the US National Institute of Allergy and Infectious Diseases (1RO1AI077536-01 to H.D.L.).

Author information

Authors and Affiliations

  1. Department of Pathology, Baylor College of Medicine, Texas Children's Hospital, Houston, Texas

    Takeshi Yamada, Chun Shik Park & H Daniel Lacorazza

  2. Department of Immunology, Baylor College of Medicine, Texas Children's Hospital, Houston, Texas

    Maksim Mamonkin & H Daniel Lacorazza

Authors
  1. Takeshi Yamada
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chun Shik Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Maksim Mamonkin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. H Daniel Lacorazza
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

T.Y. designed and did most experiments, analyzed data and assisted in writing the manuscript; C.S.P. contributed to promoter assays, deletion of Klf4 and reviewed manuscript; M.M. contributed to promoter assays, detected CCR7 in CD4+ and CD8+ T cells by flow cytometry and reviewed manuscript; and H.D.L. conceived the research, designed experiments, directed the project as principal investigator, wrote the manuscript and funded the research.

Corresponding author

Correspondence to H Daniel Lacorazza.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–9 (PDF 535 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yamada, T., Park, C., Mamonkin, M. et al. Transcription factor ELF4 controls the proliferation and homing of CD8+ T cells via the Krüppel-like factors KLF4 and KLF2. Nat Immunol 10, 618–626 (2009). https://doi.org/10.1038/ni.1730

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ni.1730

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