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Origin of dendritic cells in peripheral lymphoid organs of mice

Nature Immunology volume 8, pages 578–583 (2007)Cite this article

Abstract

Parabiosis experiments demonstrating that dendritic cells (DCs) do not equilibrate between mice even after prolonged joining by parabiosis have suggested that DCs are derived from self-renewing progenitors that divide in situ. However, here we found that unequal exchange of DCs between mice joined by parabiosis reflected uneven distribution of DC precursors in blood due to their short half-life in circulation. DCs underwent only a limited number of divisions in the spleen or lymph nodes over a 10- to 14-day period and were replenished from blood-borne precursors at a rate of nearly 4,300 cells per hour. Daughter DCs presented antigens captured by their progenitors, suggesting that DC division in peripheral lymphoid organs can prolong the duration of antigen presentation in vivo.

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Figure 1: Rapid turnover of dividing DCs in the spleen and lymph nodes.
Figure 2: Leukocyte exchange in parabiotic mice.
Figure 3: Blood DC precursor clearance and exchange in parabiotic mice.
Figure 4: DC chimerism in parabiotic mice after surgical separation.
Figure 5: Antigen retention by dividing DCs in the spleen.

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References

  1. Liu, Y.J. Dendritic cell subsets and lineages, and their functions in innate and adaptive immunity. Cell 106, 259–262 (2001).

    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. Steinman, R.M. et al. Dendritic cell function in vivo during the steady state: a role in peripheral tolerance. Ann. NY Acad. Sci. 987, 15–25 (2003).

    Article  CAS  Google Scholar 

  4. 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 

  5. Witmer, M.D. & Steinman, R.M. The anatomy of peripheral lymphoid organs with emphasis on accessory cells: light-microscopic immunocytochemical studies of mouse spleen, lymph node, and Peyer's patch. Am. J. Anat. 170, 465–481 (1984).

    Article  CAS  Google Scholar 

  6. Vremec, D. et al. The surface phenotype of dendritic cells purified from mouse thymus and spleen: investigation of the CD8 expression by a subpopulation of dendritic cells. J. Exp. Med. 176, 47–58 (1992).

    Article  CAS  Google Scholar 

  7. Dudziak, D. et al. Differential antigen processing by dendritic cell subsets in vivo. Science 315, 107–111 (2007).

    Article  CAS  Google Scholar 

  8. Manz, M.G. et al. Dendritic cell development from common myeloid progenitors. Ann. NY Acad. Sci. 938, 167–173 (2001).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  10. 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 

  11. Harman, B.C., Miller, J.P., Nikbakht, N., Gerstein, R. & Allman, D. Mouse plasmacytoid dendritic cells derive exclusively from estrogen-resistant myeloid progenitors. Blood 108, 878–885 (2006).

    Article  CAS  Google Scholar 

  12. Colonna, M., Trinchieri, G. & Liu, Y.J. Plasmacytoid dendritic cells in immunity. Nat. Immunol. 5, 1219–1226 (2004).

    Article  CAS  Google Scholar 

  13. 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 alpha. J. Exp. Med. 179, 1109–1118 (1994).

    Article  CAS  Google Scholar 

  14. Bender, A., Sapp, M., Schuler, G., Steinman, R.M. & Bhardwaj, N. Improved methods for the generation of dendritic cells from nonproliferating progenitors in human blood. J. Immunol. Methods 196, 121–135 (1996).

    Article  CAS  Google Scholar 

  15. 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 

  16. 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 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  20. 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 

  21. Varol, C. et al. Monocytes give rise to mucosal, but not splenic, conventional dendritic cells. J. Exp. Med. 204, 171–180 (2006).

    Article  Google Scholar 

  22. 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 

  23. Kamath, A.T., Henri, S., Battye, F., Tough, D.F. & Shortman, K. Developmental kinetics and lifespan of dendritic cells in mouse lymphoid organs. Blood 100, 1734–1741 (2002).

    CAS  PubMed  Google Scholar 

  24. Ruedl, C., Koebel, P., Bachmann, M., Hess, M. & Karjalainen, K. Anatomical origin of dendritic cells determines their life span in peripheral lymph nodes. J. Immunol. 165, 4910–4916 (2000).

    Article  CAS  Google Scholar 

  25. 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 

  26. 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 

  27. Bogunovic, M. et al. Identification of a radio-resistant and cycling dermal dendritic cell population in mice and men. J. Exp. Med. 203, 2627–2638 (2006).

    Article  CAS  Google Scholar 

  28. Wright, D.E., Wagers, A.J., Gulati, A.P., Johnson, F.L. & Weissman, I.L. Physiological migration of hematopoietic stem and progenitor cells. Science 294, 1933–1936 (2001).

    Article  CAS  Google Scholar 

  29. Abkowitz, J.L., Robinson, A.E., Kale, S., Long, M.W. & Chen, J. Mobilization of hematopoietic stem cells during homeostasis and after cytokine exposure. Blood 102, 1249–1253 (2003).

    Article  CAS  Google Scholar 

  30. Harris, R.B., Zhou, J., Weigle, D.S. & Kuijper, J.L. Recombinant leptin exchanges between parabiosed mice but does not reach equilibrium. Am. J. Physiol. 272, R1800–R1808 (1997).

    CAS  PubMed  Google Scholar 

  31. Nishizawa, Y. & Bray, G.A. Evidence for a circulating ergostatic factor: studies on parabiotic rats. Am. J. Physiol. 239, R344–R351 (1980).

    CAS  PubMed  Google Scholar 

  32. Lagasse, E. & Weissman, I.L. Bcl-2 inhibits apoptosis of neutrophils but not their engulfment by macrophages. J. Exp. Med. 179, 1047–1052 (1994).

    Article  CAS  Google Scholar 

  33. van Furth, R. & Cohn, Z.A. The origin and kinetics of mononuclear phagocytes. J. Exp. Med. 128, 415–435 (1968).

    Article  CAS  Google Scholar 

  34. Morrison, S.J. & Weissman, I.L. The long-term repopulating subset of hematopoietic stem cells is deterministic and isolatable by phenotype. Immunity 1, 661–673 (1994).

    Article  CAS  Google Scholar 

  35. Steinman, R.M., Lustig, D.S. & Cohn, Z.A. Identification of a novel cell type in peripheral lymphoid organs of mice. 3. Functional properties in vivo. J. Exp. Med. 139, 1431–1445 (1974).

    Article  CAS  Google Scholar 

  36. Steinman, R.M. & Nussenzweig, M.C. Dendritic cells: features and functions. Immunol. Rev. 53, 127–147 (1980).

    Article  CAS  Google Scholar 

  37. Pugh, C.W., MacPherson, G.G. & Steer, H.W. Characterization of nonlymphoid cells derived from rat peripheral lymph. J. Exp. Med. 157, 1758–1779 (1983).

    Article  CAS  Google Scholar 

  38. Hawiger, D. et al. Dendritic cells induce peripheral T cell unresponsiveness under steady state conditions in vivo. J. Exp. Med. 194, 769–779 (2001).

    Article  CAS  Google Scholar 

  39. Bonifaz, L.C. et al. In vivo targeting of antigens to maturing dendritic cells via the DEC-205 receptor improves T cell vaccination. J. Exp. Med. 199, 815–824 (2004).

    Article  CAS  Google Scholar 

  40. Rudensky, A., Rath, S., Preston-Hurlburt, P., Murphy, D.B. & Janeway, C.A., Jr. On the complexity of self. Nature 353, 660–662 (1991).

    Article  CAS  Google Scholar 

  41. 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  Google Scholar 

  42. Redmond, W.L., Hernandez, J. & Sherman, L.A. Deletion of naive CD8 T cells requires persistent antigen and is not programmed by an initial signal from the tolerogenic APC. J. Immunol. 171, 6349–6354 (2003).

    Article  CAS  Google Scholar 

  43. Zammit, D.J., Cauley, L.S., Pham, Q.M. & Lefrancois, L. Dendritic cells maximize the memory CD8 T cell response to infection. Immunity 22, 561–570 (2005).

    Article  CAS  Google Scholar 

  44. Bullock, T.N., Mullins, D.W. & Engelhard, V.H. Antigen density presented by dendritic cells in vivo differentially affects the number and avidity of primary, memory, and recall CD8+ T cells. J. Immunol. 170, 1822–1829 (2003).

    Article  CAS  Google Scholar 

  45. Catron, D.M., Rusch, L.K., Hataye, J., Itano, A.A. & Jenkins, M.K. CD4+ T cells that enter the draining lymph nodes after antigen injection participate in the primary response and become central-memory cells. J. Exp. Med. 203, 1045–1054 (2006).

    Article  CAS  Google Scholar 

  46. Kretschmer, K. et al. Inducing and expanding regulatory T cell populations by foreign antigen. Nat. Immunol. 6, 1219–1227 (2005).

    Article  CAS  Google Scholar 

  47. Ansel, K.M., Harris, R.B. & Cyster, J.G. CXCL13 is required for B1 cell homing, natural antibody production, and body cavity immunity. Immunity 16, 67–76 (2002).

    Article  CAS  Google Scholar 

  48. Gordon, S. & Taylor, P.R. Monocyte and macrophage heterogeneity. Nat. Rev. Immunol. 5, 953–964 (2005).

    Article  CAS  Google Scholar 

  49. Blasius, A. et al. A cell-surface molecule selectively expressed on murine natural interferon-producing cells that blocks secretion of interferon-α. Blood 103, 4201–4206 (2004).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank R. Steinman, K. Tarbell and E. Besmer for reading the manuscript. Supported by the National Institutes of Health (M.N. and J.H.), the Verto Institute (J.H.) and the Howard Hughes Medical Institute (M.N.).

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Authors and Affiliations

  1. Laboratory of Molecular Immunology, The Rockefeller University, New York, 10021, New York, USA

    Kang Liu, Claudia Waskow, Kaihui Yao & Michel Nussenzweig

  2. Department of Applied Mathematics, Yale University, New Haven, 06520, Connecticut, USA

    Xiangtao Liu

  3. Department of Epidemiology and Public Health, Yale University, New Haven, 06520, Connecticut, USA

    Josephine Hoh

  4. Howard Hughes Medical Institute, The Rockefeller University, New York, 10021, NY, USA

    Michel Nussenzweig

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  1. Kang Liu
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Correspondence to Michel Nussenzweig.

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Supplementary information

Supplementary Fig. 1

Not all blood leukocytes are equally exchanged in the parabiotic system despite shared circulation. (PDF 325 kb)

Supplementary Fig. 2

Dividing DCs in lymph nodes. (PDF 386 kb)

Supplementary Fig. 3

Blood T cell clearance and exchange in parabiotic mice. (PDF 610 kb)

Supplementary Methods (PDF 79 kb)

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Liu, K., Waskow, C., Liu, X. et al. Origin of dendritic cells in peripheral lymphoid organs of mice. Nat Immunol 8, 578–583 (2007). https://doi.org/10.1038/ni1462

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