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.

  • Letter
  • Published:

Cell-fate conversion of lymphoid-committed progenitors by instructive actions of cytokines

Nature volume 407, pages 383–386 (2000)Cite this article

Abstract

The primary role of cytokines in haemato-lymphopoiesis is thought to be the regulation of cell growth and survival1,2,3. But the instructive action of cytokines in haematopoiesis has not been well addressed4. Here we show that a clonogenic common lymphoid progenitor5, a bone marrow-resident cell that gives rise exclusively to lymphocytes (T, B and natural killer cells), can be redirected to the myeloid lineage by stimulation through exogenously expressed interleukin (IL)-2 and GM-CSF (granulocyte/macrophage colony-stimulating factor) receptors. Analysis of mutants of the β-chain of the IL-2 receptor revealed that the granulocyte- and monocyte-differentiation signals are triggered by different cytoplasmic domains, showing that the signalling pathway(s) responsible for these unique developmental outcomes are separable. Finally, we show that the endogenous myelo-monocytic cytokine receptors for GM-CSF and macrophage colony-stimulating factor (M-CSF) are expressed at low to moderate levels on the more primitive haematopoietic stem cells, are absent on common lymphoid progenitors, and are upregulated after myeloid lineage induction by IL-2. We conclude that cytokine signalling can regulate cell-fate decisions and propose that a critical step in lymphoid commitment is downregulation of cytokine receptors that drive myeloid cell development.

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: Granulocyte/macrophage differentiation from CLPs of IL-2Rβ transgenic mice.
Figure 2: Clonogenic trans-differentiation activity of CLPs from IL-2Rβ transgenic mice.
Figure 3: Induction of myeloid cells from CLPs of wild-type mice.
Figure 4: Granulocyte/macrophage induction in CLPs is initiated by stimulation with GM-CSF.

Similar content being viewed by others

References

  1. Fairbairn, L. J., Cowling, G. J., Reipert, B. M. & Dexter, T. M. Suppression of apoptosis allows differentiation and development of a multipotent hemopoietic cell line in the absence of added growth factors. Cell 74, 823–832 ( 1993).

    Article  CAS  Google Scholar 

  2. Ogawa, M. Differentiation and proliferation of hematopoietic stem cells. Blood 81, 2844–2853 ( 1993).

    CAS  PubMed  Google Scholar 

  3. Watowich, S. S. et al. Cytokine receptor signal transduction and the control of hematopoietic cell development. Annu. Rev. Cell Dev. Biol. 12, 91–128 (1996).

    Article  CAS  Google Scholar 

  4. Metcalf, D. Stem cells, pre-progenitor cells and lineage-committed cells: are our dogmas correct? Ann. NY Acad. Sci. 872, 289– 303 (1999); discussion 872, 303–304 (1999).

    Article  ADS  CAS  Google Scholar 

  5. Kondo, M., Weissman, I. L. & Akashi, K. Identification of clonogenic common lymphoid progenitors in mouse bone marrow. Cell 91, 661– 672 (1997).

    Article  CAS  Google Scholar 

  6. Ogasawara, K. et al. Requirement for IRF-1 in the microenvironment supporting development of natural killer cells. Nature 391, 700 –703 (1998); erratum 392, 843 (1998).

    Article  ADS  CAS  Google Scholar 

  7. Lodolce, J. P. et al. IL-15 receptor maintains lymphoid homeostasis by supporting lymphocyte homing and proliferation. Immunity 9, 669–676 (1998).

    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. Giri, J. G. et al. Utilization of the beta and gamma chains of the IL-2 receptor by the novel cytokine IL-15. EMBO J. 13, 2822–2830 (1994).

    Article  CAS  Google Scholar 

  10. Sugamura, K. et al. The interleukin-2 receptor gamma chain: its role in the multiple cytokine receptor complexes and T cell development in XSCID. Annu. Rev. Immunol. 14, 179–205 (1996).

    Article  CAS  Google Scholar 

  11. Kondo, M. et al. Sharing of the interleukin-2 (IL-2) receptor gamma chain between receptors for IL-2 and IL-4. Science 262, 1874–1877 (1993).

    Article  ADS  CAS  Google Scholar 

  12. Nemoto, T. et al. Differences in the interleukin-2 (IL-2) receptor system in human and mouse: alpha chain is required for formation of the functional mouse IL-2 receptor. Eur. J. Immunol. 25, 3001 –3005 (1995).

    Article  CAS  Google Scholar 

  13. Asano, M. et al. IL-2 can support growth of CD8+ T cells but not CD4+ T cells of human IL-2 receptor beta-chain transgenic mice. J. Immunol. 153, 5373–5381 ( 1994).

    CAS  PubMed  Google Scholar 

  14. Nakano, T., Kodama, H. & Honjo, T. Generation of lymphohematopoietic cells from embryonic stem cells in culture. Science 265, 1098 –1101 (1994).

    Article  ADS  CAS  Google Scholar 

  15. Domen, J., Gandy, K. L. & Weissman, I. L. Systemic overexpression of BCL-2 in the hematopoietic system protects transgenic mice from the consequences of lethal irradiation. Blood 91, 2272–2282 (1998).

    CAS  PubMed  Google Scholar 

  16. Henry, C., Marbrook, J., Vann, D. C., Kodlin, D. & Wofsy, C. in Selected Methods in Cellular Immunology (eds Mishell, B. B. & Shiigi, S. M.) 138– 152 (WH Freeman, San Francisco, 1981).

    Google Scholar 

  17. Schlissel, M. S. & Stanhope-Baker, P. Accessibility and the developmental regulation of V(D)J recombination. Semin. Immunol. 9, 161–170 ( 1997).

    Article  CAS  Google Scholar 

  18. Hatakeyama, M., Mori, H., Doi, T. & Taniguchi, T. A restricted cytoplasmic region of IL-2 receptor beta chain is essential for growth signal transduction but not for ligand binding and internalization. Cell 59, 837–845 ( 1989).

    Article  CAS  Google Scholar 

  19. Nelson, B. H. & Willerford, D. M. Biology of the interleukin-2 receptor. Adv. Immunol. 70, 1– 81 (1998).

    Article  CAS  Google Scholar 

  20. Constantinescu, S. N., Ghaffari, S. & Lodish, H. F. The erythropoietin receptor: structure, activation and intracellular signal transduction. Trends Endocrinol. Metab. 10, 18–23 ( 1999).

    Article  CAS  Google Scholar 

  21. Watanabe, S. et al. Reconstituted human granulocyte-macrophage colony-stimulating factor receptor transduces growth-promoting signals in mouse NIH 3T3 cells: comparison with signalling in BA/F3 pro-B cells. Mol. Cell. Biol. 13, 1440–1448 ( 1993).

    Article  CAS  Google Scholar 

  22. Ha, K., Minden, M., Hozumi, N. & Gelfand, E. W. Immunoglobulin gene rearrangement in acute myelogenous leukemia. Cancer Res. 44, 4658–4660 (1984).

    CAS  PubMed  Google Scholar 

  23. Palumbo, A., Minowada, J., Erikson, J., Croce, C. M. & Rovera, G. Lineage infidelity of a human myelogenous leukemia cell line. Blood 64, 1059– 1063 (1984).

    CAS  PubMed  Google Scholar 

  24. Cheng, G. Y., Minden, M. D., Toyonaga, B., Mak, T. W. & McCulloch, E. A. T cell receptor and immunoglobulin gene rearrangements in acute myeloblastic leukemia. J. Exp. Med. 163, 414–424 ( 1986).

    Article  CAS  Google Scholar 

  25. Godfrey, D. I., Kennedy, J., Mombaerts, P., Tonegawa, S. & Zlotnik, A. Onset of TCR-beta gene rearrangement and role of TCR-beta expression during CD3-CD4-CD8- thymocyte differentiation. J. Immunol. 152 , 4783–4792 (1994).

    CAS  PubMed  Google Scholar 

  26. Hardy, R. R., Carmack, C. E., Shinton, S. A., Kemp, J. D. & Hayakawa, K. Resolution and characterization of pro-B and pre-pro-B cell stages in normal mouse bone marrow. J. Exp. Med. 173, 1213–1225 (1991).

    Article  CAS  Google Scholar 

  27. Rolink, A. et al. A subpopulation of B220+ cells in murine bone marrow does not express CD19 and contains natural killer cell progenitors. J. Exp. Med. 183, 187–194 (1996).

    Article  CAS  Google Scholar 

  28. Ghaffari, S. et al. BCR-ABL and v-SRC tyrosine kinase oncoproteins support normal erythroid development in erythropoietin receptor-deficient progenitor cells. Proc. Natl Acad. Sci. USA 96, 13186– 13190 (1999).

    Article  ADS  CAS  Google Scholar 

Download references

Acknowledgements

We thank T. Honjo for IL-2Rβ transgenic mice; G. Nolan for the retroviral system; S. Watanabe for cDNAs for human GM-CSFRα and βc; G. Q. Daley for a retroviral expression vector for EpoR; S.-I. Nishikawa for OP9 cells and anti-IL-7Rα antibody; and L. Jerabek for laboratory management. This work was supported by USPHS grant to I.L.W, and a Jose Carreras International Leukemia Foundation Grant to K.A. M.K., D.C.S. and A.G.K. are supported by fellowships from the Irvington Institute for Immunology, American Cancer Society California Division, and USPHS Training Grant, respectively.

Author information

Authors and Affiliations

  1. Departments of Pathology and Developmental Biology, Stanford University School of Medicine, Stanford, 94305-5324, California, USA

    Motonari Kondo, David C. Scherer, Toshihiro Miyamoto, Angela G. King, Koichi Akashi & Irving L. Weissman

  2. Department of Microbiology and Immunology Tohoku University School of Medicine, Sendai, 980-8575, Japan

    Kazuo Sugamura

Authors
  1. Motonari Kondo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. David C. Scherer
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Toshihiro Miyamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Angela G. King
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Koichi Akashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kazuo Sugamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Irving L. Weissman
    View author publications

    You can also search for this author in PubMed Google Scholar

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kondo, M., Scherer, D., Miyamoto, T. et al. Cell-fate conversion of lymphoid-committed progenitors by instructive actions of cytokines. Nature 407, 383–386 (2000). https://doi.org/10.1038/35030112

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/35030112

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

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