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Development of plasmacytoid and conventional dendritic cell subtypes from single precursor cells derived in vitro and in vivo

Nature Immunology volume 8, pages 1217–1226 (2007)Cite this article

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Abstract

The development of functionally specialized subtypes of dendritic cells (DCs) can be modeled through the culture of bone marrow with the ligand for the cytokine receptor Flt3. Such cultures produce DCs resembling spleen plasmacytoid DCs (pDCs), CD8+ conventional DCs (cDCs) and CD8− cDCs. Here we isolated two sequential DC-committed precursor cells from such cultures: dividing 'pro-DCs', which gave rise to transitional 'pre-DCs' en route to differentiating into the three distinct DC subtypes (pDCs, CD8+ cDCs and CD8− cDCs). We also isolated an in vivo equivalent of the DC-committed pro-DC precursor cell, which also gave rise to the three DC subtypes. Clonal analysis of the progeny of individual pro-DC precursors demonstrated that some pro-DC precursors gave rise to all three DC subtypes, some produced cDCs but not pDCs, and some were fully committed to a single DC subtype. Thus, commitment to particular DC subtypes begins mainly at this pro-DC stage.

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Figure 1: DC precursors in cultures of bone marrow stimulated with Flt3L.
Figure 2: Development potential of CD11c− and CD11c+ DC precursors in vitro after reculture or in vivo after transfer to recipient mice.
Figure 3: Surface phenotype of pro-DCs derived from cultures.
Figure 4: Pro-DCs from in vitro culture versus precursor populations isolated from bone marrow.
Figure 5: Clones of DCs produced in culture from single pro-DC precursors.

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Change history

  • 19 October 2007

    In the version of this article initially published online, the outlined boxes in the flow cytometry plots in Figure 5d are incorrect. The error has been corrected for all versions of the article.

  • 25 October 2007

    In the HTML version of this paper published online, Figure 2 was missing and a duplicate copy of Figure 4 was included in its place. This error has been corrected in the HTML version of the paper.

References

  1. Shortman, K. & Naik, S.H. Steady-state and inflammatory dendritic-cell development. Nat. Rev. Immunol. 7, 19–30 (2007).

    Article  CAS  PubMed  Google Scholar 

  2. Vremec, D., Pooley, J., Hochrein, H., Wu, L. & Shortman, K. CD4 and CD8 expression by dendritic cell subtypes in mouse thymus and spleen. J. Immunol. 164, 2978–2986 (2000).

    Article  CAS  PubMed  Google Scholar 

  3. Geissmann, F., Jung, S. & Littman, D.R. Blood monocytes consist of two principal subsets with distinct migratory properties. Immunity 19, 71–82 (2003).

    Article  CAS  PubMed  Google Scholar 

  4. 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 

  5. Randolph, G.J., Inaba, K., Robbiani, D.F., Steinman, R.M. & Muller, W.A. Differentiation of phagocytic monocytes into lymph node dendritic cells in vivo. Immunity 11, 753–761 (1999).

    Article  CAS  PubMed  Google Scholar 

  6. Serbina, N.V., Salazar-Mather, T.P., Biron, C.A., Kuziel, W.A. & Pamer, E.G. TNF/iNOS-producing dendritic cells mediate innate immune defense against bacterial infection. Immunity 19, 59–70 (2003).

    Article  CAS  PubMed  Google Scholar 

  7. Wu, L. et al. Development of thymic and splenic dendritic cell populations from different hemopoietic precursors. Blood 98, 3376–3382 (2001).

    Article  CAS  PubMed  Google Scholar 

  8. 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 

  9. 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 

  10. 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 

  11. Diao, J., Winter, E., Chen, W., Cantin, C. & Cattral, M.S. Characterization of distinct conventional and plasmacytoid dendritic cell-committed precursors in murine bone marrow. J. Immunol. 173, 1826–1833 (2004).

    Article  CAS  PubMed  Google Scholar 

  12. 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 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Nikolic, T., de Bruijn, M.F., Lutz, M.B. & Leenen, P.J. Developmental stages of myeloid dendritic cells in mouse bone marrow. Int. Immunol. 15, 515–524 (2003).

    Article  CAS  PubMed  Google Scholar 

  15. 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 

  16. Brawand, P. et al. Murine plasmacytoid pre-dendritic cells generated from Flt3 ligand-supplemented bone marrow cultures are immature APCs. J. Immunol. 169, 6711–6719 (2002).

    Article  CAS  PubMed  Google Scholar 

  17. Brasel, K., De Smedt, T., Smith, J.L. & Maliszewski, C.R. Generation of murine dendritic cells from Flt3-ligand-supplemented bone marrow cultures. Blood 96, 3029–3039 (2000).

    CAS  PubMed  Google Scholar 

  18. 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 

  19. Naik, S.H. et al. Cutting edge: Generation of splenic CD8+ and CD8– dendritic cell equivalents in Fms-like tyrosine kinase 3 ligand bone marrow cultures. J. Immunol. 174, 6592–6597 (2005).

    Article  CAS  PubMed  Google Scholar 

  20. 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 

  21. 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 

  22. 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 

  23. Onai, N. et al. Identification of clonogenic common Flt3+M-CSFR+ plasmacytoid and dendritic cell progenitors in mouse bone marrow. Nat. Immunol. (in the press) (2007).

  24. 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 

  25. Suzuki, S. et al. Critical roles of interferon regulatory factor 4 in CD11bhighCD8α– dendritic cell development. Proc. Natl. Acad. Sci. USA 101, 8981–8986 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Janssen, E. et al. Efficient T cell activation via a Toll-interleukin 1 receptor-independent pathway. Immunity 24, 787–799 (2006).

    Article  CAS  PubMed  Google Scholar 

  27. Dettke, M. et al. Increased serum Flt3-ligand in healthy donors undergoing granulocyte colony-stimulating factor-induced peripheral stem cell mobilization. J. Hematother. Stem Cell Res. 10, 317–320 (2001).

    Article  CAS  PubMed  Google Scholar 

  28. Haidar, J.H. et al. Serum Flt3 ligand variation as a predictive indicator of hematopoietic stem cell mobilization. J. Hematother. Stem Cell Res. 11, 533–538 (2002).

    Article  CAS  PubMed  Google Scholar 

  29. Lyman, S.D. et al. Plasma/serum levels of Flt3 ligand are low in normal individuals and highly elevated in patients with Fanconi anemia and acquired aplastic anemia. Blood 86, 4091–4096 (1995).

    CAS  PubMed  Google Scholar 

  30. Franchini, M. et al. Dendritic cells from mice neonatally vaccinated with modified vaccinia virus Ankara transfer resistance against herpes simplex virus type I to naive one-week-old mice. J. Immunol. 172, 6304–6312 (2004).

    Article  CAS  PubMed  Google Scholar 

  31. Naik, S., Vremec, D., Wu, L., O'Keeffe, M. & Shortman, K. CD8α+ mouse spleen dendritic cells do not originate from the CD8α– dendritic cell subset. Blood 102, 601–604 (2003).

    Article  CAS  PubMed  Google Scholar 

  32. 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 

  33. Diao, J. et al. In situ replication of immediate dendritic cell (DC) precursors contributes to conventional DC homeostasis in lymphoid tissue. J. Immunol. 176, 7196–7206 (2006).

    Article  CAS  PubMed  Google Scholar 

  34. Hochrein, H. et al. Herpes simplex virus type-1 induces IFN-α production via Toll-like receptor 9-dependent and -independent pathways. Proc. Natl. Acad. Sci. USA 101, 11416–11421 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Metcalf, D., Di Rago, L. & Mifsud, S. Synergistic and inhibitory interactions in the in vitro control of murine megakaryocyte colony formation. Stem Cells 20, 552–560 (2002).

    Article  CAS  PubMed  Google Scholar 

  36. Carotta, S., Brady, J., Wu, L. & Nutt, S.L. Transient Notch signaling induces NK cell potential in Pax5-deficient pro-B cells. Eur. J. Immunol. 36, 3294–3304 (2006).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank K. Gray and T. Berketa for animal husbandry; L. Di Rago and S. Mifsud for technical assistance with colony assays; F. Battye, F. van Diepen and the flow cytometry facilities for cell sorting and analysis; A. Keller and R. Schotte for technical assistance; and K. McIntosh for assistance with the manuscript. The Chinese hamster ovary cell line producing recombinant mouse Flt3L was provided by N. Nicola (The Walter and Eliza Hall Institute). Supported by the National Health and Medical Research Council, Australia; the Marie Curie foundation (039477 to S.H.N.); and the Korean Science and Engineering Foundation through the Medical Research Centre for Cancer Molecular Therapy, Dong-A University (J.-Y.K. and H.-Y.P.).

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Author notes

  1. Hae-Young Park, Meredith O'Keeffe & Jong-Young Kwak

    Present address: Present addresses: Department of Biochemistry, College of Medicine and Medical Research for Cancer Molecular Therapy, Dong-A University, Busan 602-714, Korea (H.-Y.P. and J.-Y.K.) and Bavarian Nordic, Munich 82152, Germany (M.O.).,

Authors and Affiliations

  1. The Walter and Eliza Hall Institute, Parkville, 3050, Victoria, Australia

    Shalin H Naik, Priyanka Sathe, Hae-Young Park, Donald Metcalf, Anna I Proietto, Aleksander Dakic, Sebastian Carotta, Meredith O'Keeffe, Melanie Bahlo, Anthony Papenfuss, Jong-Young Kwak, Li Wu & Ken Shortman

  2. The Netherlands Cancer Institute, Amsterdam, 1066CX, The Netherlands

    Shalin H Naik

  3. Department of Medical Biology, The University of Melbourne, Parkville, 3010, Victoria, Australia

    Priyanka Sathe & Anna I Proietto

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Contributions

S.H.N. designed and did most experiments and wrote the manuscript; K.S. designed experiments and wrote the manuscript; P.S. and H.-Y.P. isolated bone marrow precursor cells and did clonal experiments; J.-Y.K., M.O.'K. and L.W. helped to design experiments; D.M. did and analyzed colony assays; A.I.P. and A.D. assisted with precursor characterization; S.C. did the OP9 B precursor assays; M.B. and A.P. designed and did the statistical analysis; and all authors discussed the results and helped to write the manuscript.

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Correspondence to Shalin H Naik or Ken Shortman.

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Naik, S., Sathe, P., Park, HY. et al. Development of plasmacytoid and conventional dendritic cell subtypes from single precursor cells derived in vitro and in vivo. Nat Immunol 8, 1217–1226 (2007). https://doi.org/10.1038/ni1522

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