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

Nature volume 407, pages 383386 (21 September 2000) | Download Citation

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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.

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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.

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

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https://doi.org/10.1038/35030112

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