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Intrasplenic steady-state dendritic cell precursors that are distinct from monocytes

Nature Immunology volume 7, pages 663–671 (2006)Cite this article

Abstract

Immediate precursors of the many subtypes of dendritic cells (DCs) remain obscure. Here we purified a splenic precursor population that produced all splenic CD8+ and CD8− conventional DCs (cDCs) but not plasmacytoid DCs or other lineages. This 'pre-cDC' population included cells 'precommitted' to form either CD8+ or CD8− cDCs. The pre-cDCs, which comprised 0.05% of splenocytes, expressed a CD11cintCD45RAloCD43intSIRP-αintCD4−CD8− major histocompatibility complex class II–negative surface phenotype. The pre-cDCs were not monocytes. Monocytes generated few cDCs in steady-state recipient mice. However, when transferred into mice with an inflammatory milieu dependent on granulocyte-macrophage colony-stimulating factor, monocytes produced a distinct type of splenic DC. Thus, the inflammatory status of the host influences the developmental origin and type of DC present in lymphoid tissues.

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Figure 1: In vivo assay for splenic cDC precursor activity.
Figure 2: Purification of cDC precursors from spleen.
Figure 3: Characterization of pre-cDCs and their progeny.
Figure 4: CD24 expression on pre-cDCs segregates precursors of CD8+ and CD8− cDCs.
Figure 5: Morphology and phagocytic capacity of pre-cDCs versus Ly6Chi bone marrow monocytes.
Figure 6: Monocytes produce splenic DCs during inflammation.

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References

  1. Steinman, R.M. Some interfaces of dendritic cell biology. APMIS 111, 675–697 (2003).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  3. 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  Google Scholar 

  4. Henri, S. et al. The dendritic cell populations of mouse lymph nodes. J. Immunol. 167, 741–748 (2001).

    Article  CAS  Google Scholar 

  5. Villadangos, J.A. & Heath, W.R. Life cycle, migration and antigen presenting functions of spleen and lymph node dendritic cells: Limitations of the Langerhans cells paradigm. Semin. Immunol. 17, 261–272 (2005).

    Article  Google Scholar 

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

    Article  CAS  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  Google Scholar 

  8. 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  Google Scholar 

  9. Schiavoni, G. et al. ICSBP is essential for the development of mouse type I interferon-producing cells and for the generation and activation of CD8α+ dendritic cells. J. Exp. Med. 196, 1415–1425 (2002).

    Article  CAS  Google Scholar 

  10. 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  Google Scholar 

  11. Spits, H., Couwenberg, F., Bakker, A.Q., Weijer, K. & Uittenbogaart, C.H. Id2 and Id3 inhibit development of CD34+ stem cells into predendritic cell (pre-DC)2 but not into pre-DC1. Evidence for a lymphoid origin of pre-DC2. J. Exp. Med. 192, 1775–1784 (2000).

    Article  CAS  Google Scholar 

  12. Hacker, C. et al. Transcriptional profiling identifies Id2 function in dendritic cell development. Nat. Immunol. 4, 380–386 (2003).

    Article  CAS  Google Scholar 

  13. Zhang, M. et al. Splenic stroma drives mature dendritic cells to differentiate into regulatory dendritic cells. Nat. Immunol. 5, 1124–1133 (2004).

    Article  CAS  Google Scholar 

  14. Shortman, K. & Wu, L. Are dendritic cells end cells? Nat. Immunol. 5, 1105–1106 (2004).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  16. 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  Google Scholar 

  17. 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  Google Scholar 

  18. 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  Google Scholar 

  19. Leon, B. et al. Dendritic cell differentiation potential of mouse monocytes: monocytes represent immediate precursors of CD8− and CD8+ splenic dendritic cells. Blood 103, 2668–2676 (2004).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  21. 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  Google Scholar 

  22. 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 

  23. Walzer, T., Brawand, P., Swart, D., Tocker, J. & De Smedt, T. No defect in T-cell priming, secondary response, or tolerance induction in response to inhaled antigens in Fms-like tyrosine kinase 3 ligand-deficient mice. J. Allergy Clin. Immunol. 115, 192–199 (2005).

    Article  CAS  Google Scholar 

  24. 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  Google Scholar 

  25. 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  Google Scholar 

  26. 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 

  27. 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  Google Scholar 

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

    Article  Google Scholar 

  29. Del Hoyo, G.M. et al. Corrigendum: Characterization of a common precursor population for dendritic cells. Nature 429, 205 (2004).

    Article  Google Scholar 

  30. Wang, Y. et al. Identification of CD8alpha+CD11c− lineage phenotype-negative cells in the spleen as committed precursor of CD8α+ dendritic cells. Blood 100, 569–577 (2002).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  32. 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  Google Scholar 

  33. 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  Google Scholar 

  34. Crowley, M., Inaba, K., Witmer-Pack, M. & Steinman, R.M. The cell surface of mouse dendritic cells: FACS analyses of dendritic cells from different tissues including thymus. Cell. Immunol. 118, 108–125 (1989).

    Article  CAS  Google Scholar 

  35. Cook, A.D., Braine, E.L. & Hamilton, J.A. Stimulus-dependent requirement for granulocyte-macrophage colony-stimulating factor in inflammation. J. Immunol. 173, 4643–4651 (2004).

    Article  CAS  Google Scholar 

  36. Sunderkotter, C. et al. Subpopulations of mouse blood monocytes differ in maturation stage and inflammatory response. J. Immunol. 172, 4410–4417 (2004).

    Article  Google Scholar 

  37. O'Neill, H.C. et al. Dendritic cell development in long-term spleen stromal cultures. Stem Cells 22, 475–486 (2004).

    Article  Google Scholar 

  38. Berthier, R., Martinon-Ego, C., Laharie, A.M. & Marche, P.N. A two-step culture method starting with early growth factors permits enhanced production of functional dendritic cells from murine splenocytes. J. Immunol. Methods 239, 95–107 (2000).

    Article  CAS  Google Scholar 

  39. Winzler, C. et al. Maturation stages of mouse dendritic cells in growth factor-dependent long-term cultures. J. Exp. Med. 185, 317–328 (1997).

    Article  CAS  Google Scholar 

  40. 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  Google Scholar 

  41. Merad, M. et al. Langerhans cells renew in the skin throughout life under steady-state conditions. Nat. Immunol. 3, 1135–1141 (2002).

    Article  CAS  Google Scholar 

  42. Randolph, G.J., Beaulieu, S., Lebecque, S., Steinman, R.M. & Muller, W.A. Differentiation of monocytes into dendritic cells in a model of transendothelial trafficking. Science 282, 480–483 (1998).

    Article  CAS  Google Scholar 

  43. 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  Google Scholar 

  44. Leung, B.P. et al. A novel dendritic cell-induced model of erosive inflammatory arthritis: distinct roles for dendritic cells in T cell activation and induction of local inflammation. J. Immunol. 169, 7071–7077 (2002).

    Article  CAS  Google Scholar 

  45. Eriksson, U. et al. Dendritic cell-induced autoimmune heart failure requires cooperation between adaptive and innate immunity. Nat. Med. 9, 1484–1490 (2003).

    Article  CAS  Google Scholar 

  46. Powell, T.J., Jenkins, C.D., Hattori, R. & MacPherson, G.G. Rat bone marrow-derived dendritic cells, but not ex vivo dendritic cells, secrete nitric oxide and can inhibit T-cell proliferation. Immunology 109, 197–208 (2003).

    Article  CAS  Google Scholar 

  47. Lu, L. et al. Induction of nitric oxide synthase in mouse dendritic cells by IFN-γ, endotoxin, and interaction with allogeneic T cells: nitric oxide production is associated with dendritic cell apoptosis. J. Immunol. 157, 3577–3586 (1996).

    CAS  PubMed  Google Scholar 

  48. 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  Google Scholar 

  49. 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  Google Scholar 

  50. O'Keeffe, M. et al. Dendritic cell precursor populations of mouse blood: identification of the murine homologues of human blood plasmacytoid pre-DC2 and CD11c+ DC1 precursors. Blood 101, 1453–1459 (2003).

    Article  CAS  Google Scholar 

  51. Grouard, G. et al. The enigmatic plasmacytoid T cells develop into dendritic cells with interleukin (IL)-3 and CD40-ligand. J. Exp. Med. 185, 1101–1111 (1997).

    Article  CAS  Google Scholar 

  52. Naik, S.H., Corcoran, L.M. & Wu, L. Development of murine plasmacytoid dendritic cell subsets. Immunol. Cell Biol. 83, 563–570 (2005).

    Article  CAS  Google Scholar 

  53. O'Keeffe, M. et al. Mouse plasmacytoid cells: long-lived cells, heterogeneous in surface phenotype and function, that differentiate into CD8+ dendritic cells only after microbial stimulus. J. Exp. Med. 196, 1307–1319 (2002).

    Article  CAS  Google Scholar 

  54. Zuniga, E.I., McGavern, D.B., Pruneda-Paz, J.L., Teng, C. & Oldstone, M.B. Bone marrow plasmacytoid dendritic cells can differentiate into myeloid dendritic cells upon virus infection. Nat. Immunol. 5, 1227–1234 (2004).

    Article  CAS  Google Scholar 

  55. Randolph, G.J., Sanchez-Schmitz, G., Liebman, R.M. & Schakel, K. The CD16+ (FcγRIII+) subset of human monocytes preferentially becomes migratory dendritic cells in a model tissue setting. J. Exp. Med. 196, 517–527 (2002).

    Article  CAS  Google Scholar 

  56. Krutzik, S.R. et al. TLR activation triggers the rapid differentiation of monocytes into macrophages and dendritic cells. Nat. Med. 11, 653–660 (2005).

    Article  CAS  Google Scholar 

  57. Vremec, D. & Shortman, K. Dendritic cell subtypes in mouse lymphoid organs: cross-correlation of surface markers, changes with incubation, and differences among thymus, spleen, and lymph nodes. J. Immunol. 159, 565–573 (1997).

    CAS  PubMed  Google Scholar 

  58. Martinez del Hoyo, G., Martin, P., Arias, C.F., Marin, A.R. & Ardavin, C. CD8α+ dendritic cells originate from the CD8α− dendritic cell subset by a maturation process involving CD8α, DEC-205, and CD24 up-regulation. Blood 99, 999–1004 (2002).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank K. Gray for animal husbandry; C. Young, C. Tarlinton, V. Milovac and J. Garbe for flow cytometry; S. Mifsud, L. Di Rago, B. Croker and M. Bradtke for technical assistance; and A. Roberts for discussions. Supported by the Cooperative Research Centre for Vaccine Technology (S.H.N.), the Australian Government (S.H.N.), Melbourne University (S.H.N.) and the Australian National Health and Medical Research Council (215203 to K.S.).

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  1. Meredith O'Keeffe

    Present address: Bavarian Nordic, Munich, 82152, Germany

Authors and Affiliations

  1. The Walter and Eliza Hall Institute of Medical Research and the Cooperative Research Centre for Vaccine Technology, Parkville, 3050, Victoria, Australia

    Shalin H Naik, Donald Metcalf, Annemarie van Nieuwenhuijze, Ian Wicks, Li Wu, Meredith O'Keeffe & Ken Shortman

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

    Shalin H Naik

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Supplementary information

Supplementary Fig. 1

In vivo assays for DC precursor positivity. (PDF 278 kb)

Supplementary Fig. 2

Protocol for isolation of pre-cDCs. (PDF 341 kb)

Supplementary Fig. 3

A model of splenic DC development from different precursors. (PDF 186 kb)

Supplementary Fig. 4

M-CSF responsiveness of pre-cDC and monocytes. (PDF 133 kb)

Supplementary Fig. 5

Monocyte isolation. (PDF 312 kb)

Supplementary Fig. 6

Monocyte recruitment during inflammation. (PDF 118 kb)

Supplementary Table 1

Surface phenotype of pre-cDC, cDC and pDC. (PDF 74 kb)

Supplementary Table 2

Lineage potential of pre-cDC and monocytes. (PDF 60 kb)

Supplementary Table 3

cDC precursor activity of BM monocytes and non-monocytes assayed day 10 after transfer. (PDF 49 kb)

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Naik, S., Metcalf, D., van Nieuwenhuijze, A. et al. Intrasplenic steady-state dendritic cell precursors that are distinct from monocytes. Nat Immunol 7, 663–671 (2006). https://doi.org/10.1038/ni1340

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