Skip to main content
PMC home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1996 Aug 1;184(2):695–706. doi: 10.1084/jem.184.2.695

CD34+ hematopoietic progenitors from human cord blood differentiate along two independent dendritic cell pathways in response to GM-CSF+TNF alpha

PMCID: PMC2192705  PMID: 8760823

Abstract

Human dendritic cells (DC) can now be generated in vitro in large numbers by culturing CD34+ hematopoietic progenitors in presence of GM- CSF+TNF alpha for 12 d. The present study demonstrates that cord blood CD34+ HPC indeed differentiate along two independent DC pathways. At early time points (day 5-7) during the culture, two subsets of DC precursors identified by the exclusive expression of CD1a and CD14 emerge independently. Both precursor subsets mature at day 12-14 into DC with typical morphology and phenotype (CD80, CD83, CD86, CD58, high HLA class II). CD1a+ precursors give rise to cells characterized by the expression of Birbeck granules, the Lag antigen and E-cadherin, three markers specifically expressed on Langerhans cells in the epidermis. In contrast, the CD14+ progenitors mature into CD1a+ DC lacking Birbeck granules, E-cadherin, and Lag antigen but expressing CD2, CD9, CD68, and the coagulation factor XIIIa described in dermal dendritic cells. The two mature DC were equally potent in stimulating allogeneic CD45RA+ naive T cells. Interestingly, the CD14+ precursors, but not the CD1a+ precursors, represent bipotent cells that can be induced to differentiate, in response to M-CSF, into macrophage-like cells, lacking accessory function for T cells. Altogether, these results demonstrate that different pathways of DC development exist: the Langerhans cells and the CD14(+)-derived DC related to dermal DC or circulating blood DC. The physiological relevance of these two pathways of DC development is discussed with regard to their potential in vivo counterparts.

Full Text

The Full Text of this article is available as a PDF (5.0 MB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Agger R., Witmer-Pack M., Romani N., Stossel H., Swiggard W. J., Metlay J. P., Storozynsky E., Freimuth P., Steinman R. M. Two populations of splenic dendritic cells detected with M342, a new monoclonal to an intracellular antigen of interdigitating dendritic cells and some B lymphocytes. J Leukoc Biol. 1992 Jul;52(1):34–42. doi: 10.1002/jlb.52.1.34. [DOI] [PubMed] [Google Scholar]
  2. Ardavin C., Wu L., Li C. L., Shortman K. Thymic dendritic cells and T cells develop simultaneously in the thymus from a common precursor population. Nature. 1993 Apr 22;362(6422):761–763. doi: 10.1038/362761a0. [DOI] [PubMed] [Google Scholar]
  3. Blauvelt A., Katz S. I., Udey M. C. Human Langerhans cells express E-cadherin. J Invest Dermatol. 1995 Feb;104(2):293–296. doi: 10.1111/1523-1747.ep12612830. [DOI] [PubMed] [Google Scholar]
  4. Burkly L., Hession C., Ogata L., Reilly C., Marconi L. A., Olson D., Tizard R., Cate R., Lo D. Expression of relB is required for the development of thymic medulla and dendritic cells. Nature. 1995 Feb 9;373(6514):531–536. doi: 10.1038/373531a0. [DOI] [PubMed] [Google Scholar]
  5. Caux C., Dezutter-Dambuyant C., Schmitt D., Banchereau J. GM-CSF and TNF-alpha cooperate in the generation of dendritic Langerhans cells. Nature. 1992 Nov 19;360(6401):258–261. doi: 10.1038/360258a0. [DOI] [PubMed] [Google Scholar]
  6. Caux C., Durand I., Moreau I., Duvert V., Saeland S., Banchereau J. Tumor necrosis factor alpha cooperates with interleukin 3 in the recruitment of a primitive subset of human CD34+ progenitors. J Exp Med. 1993 Jun 1;177(6):1815–1820. doi: 10.1084/jem.177.6.1815. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Caux C., Favre C., Saeland S., Duvert V., Durand I., Mannoni P., Banchereau J. Potentiation of early hematopoiesis by tumor necrosis factor-alpha is followed by inhibition of granulopoietic differentiation and proliferation. Blood. 1991 Aug 1;78(3):635–644. [PubMed] [Google Scholar]
  8. Caux C., Saeland S., Favre C., Duvert V., Mannoni P., Banchereau J. Tumor necrosis factor-alpha strongly potentiates interleukin-3 and granulocyte-macrophage colony-stimulating factor-induced proliferation of human CD34+ hematopoietic progenitor cells. Blood. 1990 Jun 15;75(12):2292–2298. [PubMed] [Google Scholar]
  9. 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. 1995 Oct;3(4):459–473. doi: 10.1016/1074-7613(95)90175-2. [DOI] [PubMed] [Google Scholar]
  10. Inaba K., Inaba M., Deguchi M., Hagi K., Yasumizu R., Ikehara S., Muramatsu S., Steinman R. M. Granulocytes, macrophages, and dendritic cells arise from a common major histocompatibility complex class II-negative progenitor in mouse bone marrow. Proc Natl Acad Sci U S A. 1993 Apr 1;90(7):3038–3042. doi: 10.1073/pnas.90.7.3038. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Inaba K., Inaba M., Romani N., Aya H., Deguchi M., Ikehara S., Muramatsu S., Steinman R. M. Generation of large numbers of dendritic cells from mouse bone marrow cultures supplemented with granulocyte/macrophage colony-stimulating factor. J Exp Med. 1992 Dec 1;176(6):1693–1702. doi: 10.1084/jem.176.6.1693. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Inaba K., Steinman R. M., Pack M. W., Aya H., Inaba M., Sudo T., Wolpe S., Schuler G. Identification of proliferating dendritic cell precursors in mouse blood. J Exp Med. 1992 May 1;175(5):1157–1167. doi: 10.1084/jem.175.5.1157. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Kashihara M., Ueda M., Horiguchi Y., Furukawa F., Hanaoka M., Imamura S. A monoclonal antibody specifically reactive to human Langerhans cells. J Invest Dermatol. 1986 Nov;87(5):602–607. doi: 10.1111/1523-1747.ep12455849. [DOI] [PubMed] [Google Scholar]
  14. Kelsall B. L., Strober W. Distinct populations of dendritic cells are present in the subepithelial dome and T cell regions of the murine Peyer's patch. J Exp Med. 1996 Jan 1;183(1):237–247. doi: 10.1084/jem.183.1.237. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Lenz A., Heine M., Schuler G., Romani N. Human and murine dermis contain dendritic cells. Isolation by means of a novel method and phenotypical and functional characterization. J Clin Invest. 1993 Dec;92(6):2587–2596. doi: 10.1172/JCI116873. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Miltenyi S., Müller W., Weichel W., Radbruch A. High gradient magnetic cell separation with MACS. Cytometry. 1990;11(2):231–238. doi: 10.1002/cyto.990110203. [DOI] [PubMed] [Google Scholar]
  17. Nestle F. O., Zheng X. G., Thompson C. B., Turka L. A., Nickoloff B. J. Characterization of dermal dendritic cells obtained from normal human skin reveals phenotypic and functionally distinctive subsets. J Immunol. 1993 Dec 1;151(11):6535–6545. [PubMed] [Google Scholar]
  18. O'Doherty U., Peng M., Gezelter S., Swiggard W. J., Betjes M., Bhardwaj N., Steinman R. M. Human blood contains two subsets of dendritic cells, one immunologically mature and the other immature. Immunology. 1994 Jul;82(3):487–493. [PMC free article] [PubMed] [Google Scholar]
  19. O'Doherty U., Steinman R. M., Peng M., Cameron P. U., Gezelter S., Kopeloff I., Swiggard W. J., Pope M., Bhardwaj N. Dendritic cells freshly isolated from human blood express CD4 and mature into typical immunostimulatory dendritic cells after culture in monocyte-conditioned medium. J Exp Med. 1993 Sep 1;178(3):1067–1076. doi: 10.1084/jem.178.3.1067. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Reid C. D., Stackpoole A., Meager A., Tikerpae J. Interactions of tumor necrosis factor with granulocyte-macrophage colony-stimulating factor and other cytokines in the regulation of dendritic cell growth in vitro from early bipotent CD34+ progenitors in human bone marrow. J Immunol. 1992 Oct 15;149(8):2681–2688. [PubMed] [Google Scholar]
  21. Rosenzwajg M., Canque B., Gluckman J. C. Human dendritic cell differentiation pathway from CD34+ hematopoietic precursor cells. Blood. 1996 Jan 15;87(2):535–544. [PubMed] [Google Scholar]
  22. Sallusto F., Cella M., Danieli C., Lanzavecchia A. Dendritic cells use macropinocytosis and the mannose receptor to concentrate macromolecules in the major histocompatibility complex class II compartment: downregulation by cytokines and bacterial products. J Exp Med. 1995 Aug 1;182(2):389–400. doi: 10.1084/jem.182.2.389. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. 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. 1994 Apr 1;179(4):1109–1118. doi: 10.1084/jem.179.4.1109. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Santiago-Schwarz F., Belilos E., Diamond B., Carsons S. E. TNF in combination with GM-CSF enhances the differentiation of neonatal cord blood stem cells into dendritic cells and macrophages. J Leukoc Biol. 1992 Sep;52(3):274–281. [PubMed] [Google Scholar]
  25. Steinman R. M. The dendritic cell system and its role in immunogenicity. Annu Rev Immunol. 1991;9:271–296. doi: 10.1146/annurev.iy.09.040191.001415. [DOI] [PubMed] [Google Scholar]
  26. Szabolcs P., Avigan D., Gezelter S., Ciocon D. H., Moore M. A., Steinman R. M., Young J. W. Dendritic cells and macrophages can mature independently from a human bone marrow-derived, post-colony-forming unit intermediate. Blood. 1996 Jun 1;87(11):4520–4530. [PubMed] [Google Scholar]
  27. Szabolcs P., Moore M. A., Young J. W. Expansion of immunostimulatory dendritic cells among the myeloid progeny of human CD34+ bone marrow precursors cultured with c-kit ligand, granulocyte-macrophage colony-stimulating factor, and TNF-alpha. J Immunol. 1995 Jun 1;154(11):5851–5861. [PubMed] [Google Scholar]
  28. Tang A., Amagai M., Granger L. G., Stanley J. R., Udey M. C. Adhesion of epidermal Langerhans cells to keratinocytes mediated by E-cadherin. Nature. 1993 Jan 7;361(6407):82–85. doi: 10.1038/361082a0. [DOI] [PubMed] [Google Scholar]
  29. Thomas R., Davis L. S., Lipsky P. E. Isolation and characterization of human peripheral blood dendritic cells. J Immunol. 1993 Feb 1;150(3):821–834. [PubMed] [Google Scholar]
  30. Thomas R., Lipsky P. E. Human peripheral blood dendritic cell subsets. Isolation and characterization of precursor and mature antigen-presenting cells. J Immunol. 1994 Nov 1;153(9):4016–4028. [PubMed] [Google Scholar]
  31. Vallé A., Zuber C. E., Defrance T., Djossou O., De Rie M., Banchereau J. Activation of human B lymphocytes through CD40 and interleukin 4. Eur J Immunol. 1989 Aug;19(8):1463–1467. doi: 10.1002/eji.1830190818. [DOI] [PubMed] [Google Scholar]
  32. Weih F., Carrasco D., Durham S. K., Barton D. S., Rizzo C. A., Ryseck R. P., Lira S. A., Bravo R. Multiorgan inflammation and hematopoietic abnormalities in mice with a targeted disruption of RelB, a member of the NF-kappa B/Rel family. Cell. 1995 Jan 27;80(2):331–340. doi: 10.1016/0092-8674(95)90416-6. [DOI] [PubMed] [Google Scholar]
  33. Weissman D., Li Y., Ananworanich J., Zhou L. J., Adelsberger J., Tedder T. F., Baseler M., Fauci A. S. Three populations of cells with dendritic morphology exist in peripheral blood, only one of which is infectable with human immunodeficiency virus type 1. Proc Natl Acad Sci U S A. 1995 Jan 31;92(3):826–830. doi: 10.1073/pnas.92.3.826. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Wu L., Vremec D., Ardavin C., Winkel K., Süss G., Georgiou H., Maraskovsky E., Cook W., Shortman K. Mouse thymus dendritic cells: kinetics of development and changes in surface markers during maturation. Eur J Immunol. 1995 Feb;25(2):418–425. doi: 10.1002/eji.1830250217. [DOI] [PubMed] [Google Scholar]
  35. Young D. A., Lowe L. D., Clark S. C. Comparison of the effects of IL-3, granulocyte-macrophage colony-stimulating factor, and macrophage colony-stimulating factor in supporting monocyte differentiation in culture. Analysis of macrophage antibody-dependent cellular cytotoxicity. J Immunol. 1990 Jul 15;145(2):607–615. [PubMed] [Google Scholar]
  36. Young J. W., Szabolcs P., Moore M. A. Identification of dendritic cell colony-forming units among normal human CD34+ bone marrow progenitors that are expanded by c-kit-ligand and yield pure dendritic cell colonies in the presence of granulocyte/macrophage colony-stimulating factor and tumor necrosis factor alpha. J Exp Med. 1995 Oct 1;182(4):1111–1119. doi: 10.1084/jem.182.4.1111. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Zhou L. J., Tedder T. F. Human blood dendritic cells selectively express CD83, a member of the immunoglobulin superfamily. J Immunol. 1995 Apr 15;154(8):3821–3835. [PubMed] [Google Scholar]

Articles from The Journal of Experimental Medicine are provided here courtesy of The Rockefeller University Press

RESOURCES