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Identification of clonogenic common Flt3+M-CSFR+ plasmacytoid and conventional dendritic cell progenitors in mouse bone marrow

Nature Immunology volume 8, pages 1207–1216 (2007)Cite this article

Abstract

Lymphoid tissue plasmacytoid and conventional dendritic cells (DCs) are continuously regenerated from hematopoietic stem cells. The cytokine dependence and biology of plasmacytoid and conventional DCs suggest that regeneration might proceed through common DC-restricted developmental intermediates. By selecting for cytokine receptor expression relevant to DC development, we identify here highly cycling Lin−c-KitintFlt3+M-CSFR+ cells with a distinct gene-expression profile in mouse bone marrow that, on a clonal level in vitro and as a population both in vitro and in vivo, efficiently generated plasmacytoid and conventional DCs but no other lineages, which increased in number after in vivo injection of the cytokine Flt3 ligand. These clonogenic common DC progenitors thus define a cytokine-regulated DC developmental pathway that ensures the supply of various DC populations.

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Figure 1: Identification of Lin−c-KitintFlt3+M-CSFR+ progenitor cells in mouse bone marrow.
Figure 2: Lin−c-KitintFlt3+M-CSFR+ progenitors generate pDCs and cDCs in vitro.
Figure 3: Single Lin−c-KitintFlt3+M-CSFR+ cells generate both pDCs and cDCs.
Figure 4: M-CSF acts together with Flt3L in the expansion of pDC populations from Lin−c-KitintFlt3+M-CSFR+ cells.
Figure 5: Lin−c-KitintFlt3+M-CSFR+ cells differentiate into pDCs and cDCs in lethally irradiated mice in vivo.
Figure 6: Lin−c-KitintFlt3+M-CSFR+ cells develop into functional pDCs and cDCs in vivo.
Figure 7: Expression profiles of lineage- and differentiation-affiliated genes.

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References

  1. Banchereau, J. & Steinman, R.M. Dendritic cells and the control of immunity. Nature 392, 245–252 (1998).

    Article  CAS  PubMed  Google Scholar 

  2. Steinman, R.M., Hawiger, D. & Nussenzweig, M.C. Tolerogenic dendritic cells. Annu. Rev. Immunol. 21, 685–711 (2003).

    Article  CAS  PubMed  Google Scholar 

  3. Shortman, K. & Liu, Y.J. Mouse and human dendritic cell subtypes. Nat. Rev. Immunol. 2, 151–161 (2002).

    Article  CAS  PubMed  Google Scholar 

  4. Kamath, A.T. et al. The development, maturation, and turnover rate of mouse spleen dendritic cell populations. J. Immunol. 165, 6762–6770 (2000).

    Article  CAS  PubMed  Google Scholar 

  5. Kabashima, K. et al. Intrinsic lymphotoxin-β receptor requirement for homeostasis of lymphoid tissue dendritic cells. Immunity 22, 439–450 (2005).

    Article  CAS  PubMed  Google Scholar 

  6. Liu, K. et al. Origin of dendritic cells in peripheral lymphoid organs of mice. Nat. Immunol. 8, 578–583 (2007).

    Article  CAS  PubMed  Google Scholar 

  7. Manz, M.G., Traver, D., Miyamoto, T., Weissman, I.L. & Akashi, K. Dendritic cell potentials of early lymphoid and myeloid progenitors. Blood 97, 3333–3341 (2001).

    Article  CAS  PubMed  Google Scholar 

  8. Traver, D. et al. Development of CD8α+ dendritic cells from a common myeloid progenitor. Science 290, 2152–2154 (2000).

    Article  CAS  PubMed  Google Scholar 

  9. Akashi, K., Traver, D., Miyamoto, T. & Weissman, I.L. A clonogenic common myeloid progenitor that gives rise to all myeloid lineages. Nature 404, 193–197 (2000).

    Article  CAS  PubMed  Google Scholar 

  10. Kondo, M. et al. Biology of hematopoietic stem cells and progenitors: implications for clinical application. Annu. Rev. Immunol. 21, 759–806 (2003).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  12. Galy, A., Travis, M., Cen, D. & Chen, B. Human, T, B, natural killer, and dendritic cells arise from a common bone marrow progenitor cell subset. Immunity 3, 459–473 (1995).

    Article  CAS  PubMed  Google Scholar 

  13. Manz, M.G., Miyamoto, T., Akashi, K. & Weissman, I.L. Prospective isolation of human clonogenic common myeloid progenitors. Proc. Natl. Acad. Sci. USA 99, 11872–11877 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Chicha, L., Jarrossay, D. & Manz, M.G. Clonal type I interferon-producing and dendritic cell precursors are contained in both human lymphoid and myeloid progenitor populations. J. Exp. Med. 200, 1519–1524 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Shigematsu, H. et al. Plasmacytoid dendritic cells activate lymphoid-specific genetic programs irrespective of their cellular origin. Immunity 21, 43–53 (2004).

    Article  CAS  PubMed  Google Scholar 

  16. D'Amico, A. & Wu, L. The early progenitors of mouse dendritic cells and plasmacytoid predendritic cells are within the bone marrow hemopoietic precursors expressing Flt3. J. Exp. Med. 198, 293–303 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Karsunky, H., Merad, M., Cozzio, A., Weissman, I.L. & Manz, M.G. Flt3 ligand regulates dendritic cell development from Flt3+ lymphoid and myeloid-committed progenitors to Flt3+ dendritic cells in vivo. J. Exp. Med. 198, 305–313 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Mende, I., Karsunky, H., Weissman, I.L., Engleman, E.G. & Merad, M. Flk2+ myeloid progenitors are the main source of Langerhans cells. Blood 107, 1383–1390 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Lyman, S.D. & Jacobsen, S.E. c-kit ligand and Flt3 ligand: stem/progenitor cell factors with overlapping yet distinct activities. Blood 91, 1101–1134 (1998).

    CAS  PubMed  Google Scholar 

  20. Gilliet, M. et al. The development of murine plasmacytoid dendritic cell precursors is differentially regulated by FLT3-ligand and granulocyte/macrophage colony-stimulating factor. J. Exp. Med. 195, 953–958 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. McKenna, H.J. et al. Mice lacking Flt3 ligand have deficient hematopoiesis affecting hematopoietic progenitor cells, dendritic cells, and natural killer cells. Blood 95, 3489–3497 (2000).

    CAS  PubMed  Google Scholar 

  22. Laouar, Y., Welte, T., Fu, X.Y. & Flavell, R.A. STAT3 is required for Flt3L-dependent dendritic cell differentiation. Immunity 19, 903–912 (2003).

    Article  CAS  PubMed  Google Scholar 

  23. Tussiwand, R., Onai, N., Mazzucchelli, L. & Manz, M.G. Inhibition of natural type I IFN-producing and dendritic cell development by a small molecule receptor tyrosine kinase inhibitor with Flt3 affinity. J. Immunol. 175, 3674–3680 (2005).

    Article  CAS  PubMed  Google Scholar 

  24. Maraskovsky, E. et al. Dramatic increase in the numbers of functionally mature dendritic cells in Flt3 ligand-treated mice: multiple dendritic cell subpopulations identified. J. Exp. Med. 184, 1953–1962 (1996).

    Article  CAS  PubMed  Google Scholar 

  25. Miller, G., Pillarisetty, V.G., Shah, A.B., Lahrs, S. & DeMatteo, R.P. Murine Flt3 ligand expands distinct dendritic cells with both tolerogenic and immunogenic properties. J. Immunol. 170, 3554–3564 (2003).

    Article  CAS  PubMed  Google Scholar 

  26. Onai, N., Obata-Onai, A., Tussiwand, R., Lanzavecchia, A. & Manz, M.G. Activation of the Flt3 signal transduction cascade rescues and enhances type I interferon-producing and dendritic cell development. J. Exp. Med. 203, 227–238 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Caux, C. et al. CD34+ hematopoietic progenitors from human cord blood differentiate along two independent dendritic cell pathways in response to GM-CSF+TNFα. J. Exp. Med. 184, 695–706 (1996).

    Article  CAS  PubMed  Google Scholar 

  28. Inaba, K. et al. Generation of large numbers of dendritic cells from mouse bone marrow cultures supplemented with granulocyte/macrophage colony-stimulating factor. J. Exp. Med. 176, 1693–1702 (1992).

    Article  CAS  PubMed  Google Scholar 

  29. Sallusto, F. & Lanzavecchia, A. Efficient presentation of soluble antigen by cultured human dendritic cells is maintained by granulocyte/macrophage colony-stimulating factor plus interleukin 4 and downregulated by tumor necrosis factor α. J. Exp. Med. 179, 1109–1118 (1994).

    Article  CAS  PubMed  Google Scholar 

  30. Vremec, D. et al. The influence of granulocyte/macrophage colony-stimulating factor on dendritic cell levels in mouse lymphoid organs. Eur. J. Immunol. 27, 40–44 (1997).

    Article  CAS  PubMed  Google Scholar 

  31. Witmer-Pack, M.D. et al. Identification of macrophages and dendritic cells in the osteopetrotic (op/op) mouse. J. Cell. Sci. 104, 1021–1029 (1993).

    PubMed  Google Scholar 

  32. Dai, X.M. et al. Targeted disruption of the mouse colony-stimulating factor 1 receptor gene results in osteopetrosis, mononuclear phagocyte deficiency, increased primitive progenitor cell frequencies, and reproductive defects. Blood 99, 111–120 (2002).

    Article  CAS  PubMed  Google Scholar 

  33. Ginhoux, F. et al. Langerhans cells arise from monocytes in vivo. Nat. Immunol. 7, 265–273 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. MacDonald, K.P. et al. The colony-stimulating factor 1 receptor is expressed on dendritic cells during differentiation and regulates their expansion. J. Immunol. 175, 1399–1405 (2005).

    Article  CAS  PubMed  Google Scholar 

  35. Olweus, J. et al. Dendritic cell ontogeny: a human dendritic cell lineage of myeloid origin. Proc. Natl. Acad. Sci. USA 94, 12551–12556 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Bruno, L., Seidl, T. & Lanzavecchia, A. Mouse pre-immunocytes as non-proliferating multipotent precursors of macrophages, interferon-producing cells, CD8α+ and CD8α− dendritic cells. Eur. J. Immunol. 31, 3403–3412 (2001).

    Article  CAS  PubMed  Google Scholar 

  37. del Hoyo, G.M. et al. Characterization of a common precursor population for dendritic cells. Nature 415, 1043–1047 (2002).

    Article  PubMed  Google Scholar 

  38. Fogg, D.K. et al. A clonogenic bone marrow progenitor specific for macrophages and dendritic cells. Science 311, 83–87 (2006).

    Article  CAS  PubMed  Google Scholar 

  39. Naik, S.H. et al. Intrasplenic steady-state dendritic cell precursors that are distinct from monocytes. Nat. Immunol. 7, 663–671 (2006).

    Article  CAS  PubMed  Google Scholar 

  40. Christensen, J.L. & Weissman, I.L. Flk-2 is a marker in hematopoietic stem cell differentiation: a simple method to isolate long-term stem cells. Proc. Natl. Acad. Sci. USA 98, 14541–14546 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Adolfsson, J. et al. Upregulation of Flt3 expression within the bone marrow Lin−Sca1+c-Kit+ stem cell compartment is accompanied by loss of self-renewal capacity. Immunity 15, 659–669 (2001).

    Article  CAS  PubMed  Google Scholar 

  42. Chklovskaia, E. et al. Reconstitution of dendritic and natural killer-cell subsets after allogeneic stem cell transplantation: effects of endogenous Flt3 ligand. Blood 103, 3860–3868 (2004).

    Article  CAS  PubMed  Google Scholar 

  43. Schotte, R., Nagasawa, M., Weijer, K., Spits, H. & Blom, B. The ETS transcription factor Spi-B is required for human plasmacytoid dendritic cell development. J. Exp. Med. 200, 1503–1509 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Zenke, M. & Hieronymus, T. Towards an understanding of the transcription factor network of dendritic cell development. Trends Immunol. 27, 140–145 (2006).

    Article  CAS  PubMed  Google Scholar 

  45. Kanno, Y., Levi, B.Z., Tamura, T. & Ozato, K. Immune cell-specific amplification of interferon signaling by the IRF-4/8-PU.1 complex. J. Interferon Cytokine Res. 25, 770–779 (2005).

    Article  CAS  PubMed  Google Scholar 

  46. Jung, S. et al. Analysis of fractalkine receptor CX3CR1 function by targeted deletion and green fluorescent protein reporter gene insertion. Mol. Cell. Biol. 20, 4106–4114 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Cook, D.N. et al. Generation and analysis of mice lacking the chemokine fractalkine. Mol. Cell. Biol. 21, 3159–3165 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Wallny, H.J., Sollami, G. & Karjalainen, K. Soluble mouse major histocompatibility complex class II molecules produced in Drosophila cells. Eur. J. Immunol. 25, 1262–1266 (1995).

    Article  CAS  PubMed  Google Scholar 

  49. Marie, I., Durbin, J.E. & Levy, D.E. Differential viral induction of distinct interferon-α genes by positive feedback through interferon regulatory factor-7. EMBO J. 17, 6660–6669 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

Supported by the Swiss National Science Foundation (310000-116637), the Deutsche Forschungsgemeinschaft (MA 2159/2-1) and the European Commission FP6 Network of Excellence initiative (LSHB-CT-2004-512074 DC-THERA).

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Author notes

  1. Nobuyuki Onai and Aya Obata-Onai: These authors contributed equally to this work.

Authors and Affiliations

  1. Institute for Research in Biomedicine, Bellinzona, CH-6500, Switzerland

    Nobuyuki Onai, Aya Obata-Onai, Michael A Schmid, David Jarrossay & Markus G Manz

  2. Department of Immunology, Akita University Graduate School of Medicine, Akita, 010-8543, Japan

    Nobuyuki Onai, Aya Obata-Onai & Toshiaki Ohteki

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  1. Nobuyuki Onai
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Contributions

N.O., A.O.-O. and M.A.S. designed experiments, did experiments, collected data and contributed to the writing of the manuscript; T.O. provided advice; D.J. did cell sorting; and M.G.M. directed the study and wrote the manuscript.

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Correspondence to Markus G Manz.

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Onai, N., Obata-Onai, A., Schmid, M. et al. Identification of clonogenic common Flt3+M-CSFR+ plasmacytoid and conventional dendritic cell progenitors in mouse bone marrow. Nat Immunol 8, 1207–1216 (2007). https://doi.org/10.1038/ni1518

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