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The basic leucine zipper transcription factor E4BP4 is essential for natural killer cell development

An Erratum to this article was published on 01 June 2010

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Abstract

Natural killer (NK) cells are a subset of lymphocytes crucial for innate immunity and modification of adaptive immune responses. In contrast to commitment to the T cell or B cell lineage, little is known about NK cell lineage commitment. Here we show that the basic leucine zipper (bZIP) transcription factor E4BP4 (also called NFIL3) is essential for generation of the NK cell lineage. E4BP4-deficient mice (Nfil3−/–; called 'E4bp4−/–' here) had B cells, T cells and NKT cells but specifically lack NK cells and showed severely impaired NK cell–mediated cytotoxicity. Overexpression of E4bp4 was sufficient to increase NK cell production from hematopoietic progenitor cells. E4BP4 acted in a cell-intrinsic manner 'downstream' of the interleukin 15 receptor (IL-15R) and through the transcription factor Id2. E4bp4−/− mice may provide a model for definitive analysis of the contribution of NK cells to immune responses and pathologies.

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Figure 1: Expression of E4bp4 in mouse lymphoid populations.
Figure 2: Loss of peripheral NK cells and NK activity in E4bp4−/− mice.
Figure 3: A block in early bone marrow NK development in E4bp4−/− mice.
Figure 4: E4bp4 is a cell-instrinsic requirement for NK cell development.
Figure 5: IL-15-dependent NK cell production from E4bp4−/− bone marrow is impaired.
Figure 6: Ectopic E4bp4 expression restores E4bp4−/− NK cell development and substantially increases wild-type NK cell development.
Figure 7: E4bp4 and Id2 are in the genetic pathway regulating NK cell development.

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  • 05 October 2009

    NOTE: In the version of this article initially published, the equal contribution of Duncan M. Gascoyne and Elaine Long is not noted. The error has been corrected in the HTML and PDF versions of the article.

References

  1. Di Santo, J.P. Natural killer cell developmental pathways: a question of balance. Annu. Rev. Immunol. 24, 257–286 (2006).

    Article  CAS  Google Scholar 

  2. Vivier, E., Tomasello, E., Baratin, M., Walzer, T. & Ugolini, S. Functions of natural killer cells. Nat. Immunol. 9, 503–510 (2008).

    Article  CAS  Google Scholar 

  3. Wu, J. & Lanier, L.L. Natural killer cells and cancer. Adv. Cancer Res. 90, 127–156 (2003).

    Article  CAS  Google Scholar 

  4. Lodoen, M.B. & Lanier, L.L. Natural killer cells as an initial defense against pathogens. Curr. Opin. Immunol. 18, 391–398 (2006).

    Article  CAS  Google Scholar 

  5. Yokoyama, W.M., Kim, S. & French, A.R. The dynamic life of natural killer cells. Annu. Rev. Immunol. 22, 405–429 (2004).

    Article  CAS  Google Scholar 

  6. Di Santo, J.P. Natural killer cells: diversity in search of a niche. Nat. Immunol. 9, 473–475 (2008).

    Article  CAS  Google Scholar 

  7. Huntington, N.D., Vosshenrich, C.A. & Di Santo, J.P. Developmental pathways that generate natural-killer-cell diversity in mice and humans. Nat. Rev. Immunol. 7, 703–714 (2007).

    Article  CAS  Google Scholar 

  8. Kennedy, M.K. et al. Reversible defects in natural killer and memory CD8 T cell lineages in interleukin 15-deficient mice. J. Exp. Med. 191, 771–780 (2000).

    Article  CAS  Google Scholar 

  9. Suzuki, H., Duncan, G.S., Takimoto, H. & Mak, T.W. Abnormal development of intestinal intraepithelial lymphocytes and peripheral natural killer cells in mice lacking the IL-2 receptor beta chain. J. Exp. Med. 185, 499–505 (1997).

    Article  CAS  Google Scholar 

  10. Orkin, S.H. & Zon, L.I. Hematopoiesis: an evolving paradigm for stem cell biology. Cell 132, 631–644 (2008).

    Article  CAS  Google Scholar 

  11. Barton, K. et al. The Ets-1 transcription factor is required for the development of natural killer cells in mice. Immunity 9, 555–563 (1998).

    Article  CAS  Google Scholar 

  12. Boos, M.D., Yokota, Y., Eberl, G. & Kee, B.L. Mature natural killer cell and lymphoid tissue-inducing cell development requires Id2-mediated suppression of E protein activity. J. Exp. Med. 204, 1119–1130 (2007).

    Article  CAS  Google Scholar 

  13. Samson, S.I. et al. GATA-3 promotes maturation, IFN-γ production, and liver-specific homing of NK cells. Immunity 19, 701–711 (2003).

    Article  CAS  Google Scholar 

  14. Colucci, F. et al. Differential requirement for the transcription factor PU.1 in the generation of natural killer cells versus B and T cells. Blood 97, 2625–2632 (2001).

    Article  CAS  Google Scholar 

  15. 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 

  16. Townsend, M.J. et al. T-bet regulates the terminal maturation and homeostasis of NK and Vα14i NKT cells. Immunity 20, 477–494 (2004).

    Article  CAS  Google Scholar 

  17. Taki, S., Nakajima, S., Ichikawa, E., Saito, T. & Hida, S. IFN regulatory factor-2 deficiency revealed a novel checkpoint critical for the generation of peripheral NK cells. J. Immunol. 174, 6005–6012 (2005).

    Article  CAS  Google Scholar 

  18. Cowell, I.G. E4BP4/NFIL3, a PAR-related bZIP factor with many roles. Bioessays 24, 1023–1029 (2002).

    Article  CAS  Google Scholar 

  19. Cowell, I.G., Skinner, A. & Hurst, H.C. Transcriptional repression by a novel member of the bZIP family of transcription factors. Mol. Cell. Biol. 12, 3070–3077 (1992).

    Article  CAS  Google Scholar 

  20. Zhang, W. et al. Molecular cloning and characterization of NF-IL3A, a transcriptional activator of the human interleukin-3 promoter. Mol. Cell. Biol. 15, 6055–6063 (1995).

    Article  CAS  Google Scholar 

  21. Ikushima, S. et al. Pivotal role for the NFIL3/E4BP4 transcription factor in interleukin 3-mediated survival of pro-B lymphocytes. Proc. Natl. Acad. Sci. USA 94, 2609–2614 (1997).

    Article  CAS  Google Scholar 

  22. Mitsui, S., Yamaguchi, S., Matsuo, T., Ishida, Y. & Okamura, H. Antagonistic role of E4BP4 and PAR proteins in the circadian oscillatory mechanism. Genes Dev. 15, 995–1006 (2001).

    Article  CAS  Google Scholar 

  23. Doi, M., Okano, T., Yujnovsky, I., Sassone-Corsi, P. & Fukada, Y. Negative control of circadian clock regulator E4BP4 by casein kinase Iepsilon-mediated phosphorylation. Curr. Biol. 14, 975–980 (2004).

    Article  CAS  Google Scholar 

  24. Doi, M., Nakajima, Y., Okano, T. & Fukada, Y. Light-induced phase-delay of the chicken pineal circadian clock is associated with the induction of cE4bp4, a potential transcriptional repressor of cPer2 gene. Proc. Natl. Acad. Sci. USA 98, 8089–8094 (2001).

    Article  CAS  Google Scholar 

  25. Junghans, D. et al. The CES-2-related transcription factor E4BP4 is an intrinsic regulator of motoneuron growth and survival. Development 131, 4425–4434 (2004).

    Article  CAS  Google Scholar 

  26. Hough, C. et al. Cell type-specific regulation of von Willebrand factor expression by the E4BP4 transcriptional repressor. Blood 105, 1531–1539 (2005).

    Article  CAS  Google Scholar 

  27. Silvestris, F. et al. Negative regulation of the osteoblast function in multiple myeloma through the repressor gene E4BP4 activated by malignant plasma cells. Clin. Cancer Res. 14, 6081–6091 (2008).

    Article  CAS  Google Scholar 

  28. Priceman, S.J. et al. Calcium-dependent upregulation of E4BP4 expression correlates with glucocorticoid-evoked apoptosis of human leukemic CEM cells. Biochem. Biophys. Res. Commun. 344, 491–499 (2006).

    Article  CAS  Google Scholar 

  29. Kärre, K., Ljunggren, H.G., Piontek, G. & Kiessling, R. Selective rejection of H-2-deficient lymphoma variants suggests alternative immune defence strategy. Nature 319, 675–678 (1986).

    Article  Google Scholar 

  30. Kim, S. et al. In vivo developmental stages in murine natural killer cell maturation. Nat. Immunol. 3, 523–528 (2002).

    Article  Google Scholar 

  31. Williams, N.S. et al. Differentiation of NK1.1+, Ly49+ NK cells from flt3+ multipotent marrow progenitor cells. J. Immunol. 163, 2648–2656 (1999).

    CAS  PubMed  Google Scholar 

  32. Vieira, P. & Cumano, A. Differentiation of B lymphocytes from hematopoietic stem cells. Methods Mol. Biol. 271, 67–76 (2004).

    CAS  PubMed  Google Scholar 

  33. Huntington, N.D. et al. Interleukin 15-mediated survival of natural killer cells is determined by interactions among Bim, Noxa and Mcl-1. Nat. Immunol. 8, 856–863 (2007).

    Article  CAS  Google Scholar 

  34. Boos, M.D., Ramirez, K. & Kee, B.L. Extrinsic and intrinsic regulation of early natural killer cell development. Immunol. Res. 40, 193–207 (2008).

    Article  CAS  Google Scholar 

  35. Vosshenrich, C.A. et al. Roles for common cytokine receptor γ-chain-dependent cytokines in the generation, differentiation, and maturation of NK cell precursors and peripheral NK cells in vivo. J. Immunol. 174, 1213–1221 (2005).

    Article  CAS  Google Scholar 

  36. Rosmaraki, E.E. et al. Identification of committed NK cell progenitors in adult murine bone marrow. Eur. J. Immunol. 31, 1900–1909 (2001).

    Article  CAS  Google Scholar 

  37. Terme, M., Ullrich, E., Delahaye, N.F., Chaput, N. & Zitvogel, L. Natural killer cell-directed therapies: moving from unexpected results to successful strategies. Nat. Immunol. 9, 486–494 (2008).

    Article  CAS  Google Scholar 

  38. Fernandes, G., Carandente, F., Halberg, E., Halberg, F. & Good, R.A. Circadian rhythm in activity of lympholytic natural killer cells from spleens of Fischer rats. J. Immunol. 123, 622–625 (1979).

    CAS  PubMed  Google Scholar 

  39. Arjona, A. & Sarkar, D.K. Circadian oscillations of clock genes, cytolytic factors, and cytokines in rat NK cells. J. Immunol. 174, 7618–7624 (2005).

    Article  CAS  Google Scholar 

  40. Westerhuis, G., Maas, W.G., Willemze, R., Toes, R.E. & Fibbe, W.E. Long-term mixed chimerism after immunologic conditioning and MHC-mismatched stem-cell transplantation is dependent on NK-cell tolerance. Blood 106, 2215–2220 (2005).

    Article  CAS  Google Scholar 

  41. Morrow, M., Horton, S., Kioussis, D., Brady, H.J.M. & Williams, O. TEL-AML1 promotes development of specific hematopoietic lineages consistent with preleukemic activity. Blood 103, 3890–3896 (2004).

    Article  CAS  Google Scholar 

  42. Stegmeier, F., Hu, G., Rickles, R.J., Hannon, G.J. & Elledge, S.J. Lentiviral microRNA-based system for single-copy polymerase II-regulated RNA interference in mammalian cells. Proc. Natl. Acad. Sci. USA 102, 13212–13217 (2005).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank J. Zhuang (University of Liverpool) for pMSCV-Mcl-1; M. Woodward (King's College London) for pMSCV-E4bp4; A. O'Garra (Medical Research Council, National Institute for Medical Research) and A. Potocnik (Medical Research Council, National Institute for Medical Research) for additional reagents; and A. Eddaoudi for help with cell sorting. Supported by Children with Leukaemia (H.J.M.B.) and the Leukaemia Research Fund.

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D.M.G., E.L., H.V.-F., J.d.B., O.W. and B.S. did experiments; D.M.G., O.W., M.C., D.K. and H.J.M.B. designed experiments; D.M.G. and H.J.M.B. wrote the manuscript; and H.J.M.B. directed the research.

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Correspondence to Hugh J M Brady.

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Gascoyne, D., Long, E., Veiga-Fernandes, H. et al. The basic leucine zipper transcription factor E4BP4 is essential for natural killer cell development. Nat Immunol 10, 1118–1124 (2009). https://doi.org/10.1038/ni.1787

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