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. 1994 Jul 1;180(1):83–93. doi: 10.1084/jem.180.1.83

Proliferating dendritic cell progenitors in human blood

PMCID: PMC2191538  PMID: 8006603

Abstract

CD34+ cells in human cord blood and marrow are known to give rise to dendritic cells (DC), as well as to other myeloid lineages. CD34+ cells are rare in adult blood, however, making it difficult to use CD34+ cells to ascertain if DC progenitors are present in the circulation and if blood can be a starting point to obtain large numbers of these immunostimulatory antigen-presenting cells for clinical studies. A systematic search for DC progenitors was therefore carried out in several contexts. In each case, we looked initially for the distinctive proliferating aggregates that were described previously in mice. In cord blood, it was only necessary to deplete erythroid progenitors, and add granulocyte/macrophage colony-stimulating factor (GM-CSF) together with tumor necrosis factor (TNF), to observe many aggregates and the production of typical DC progeny. In adult blood from patients receiving CSFs after chemotherapy for malignancy, GM-CSF and TNF likewise generated characteristic DCs from HLA-DR negative precursors. However, in adult blood from healthy donors, the above approaches only generated small DC aggregates which then seemed to become monocytes. When interleukin 4 was used to suppress monocyte development (Jansen, J. H., G.-J. H. M. Wientjens, W. E. Fibbe, R. Willemze, and H. C. Kluin- Nelemans. 1989. J. Exp. Med. 170:577.), the addition of GM-CSF led to the formation of large proliferating DC aggregates and within 5-7 d, many nonproliferating progeny, about 3-8 million cells per 40 ml of blood. The progeny had a characteristic morphology and surface composition (e.g., abundant HLA-DR and accessory molecules for cell- mediated immunity) and were potent stimulators of quiescent T cells. Therefore, large numbers of DCs can be mobilized by specific cytokines from progenitors in the blood stream. These relatively large numbers of DC progeny should facilitate future studies of their Fc epsilon RI and CD4 receptors, and their use in stimulating T cell-mediated resistance to viruses and tumors.

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Selected References

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  1. Barclay A. N., Mayrhofer G. Bone marrow origin of Ia-positive cells in the medulla rat thymus. J Exp Med. 1981 Jun 1;153(6):1666–1671. doi: 10.1084/jem.153.6.1666. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bieber T., de la Salle H., Wollenberg A., Hakimi J., Chizzonite R., Ring J., Hanau D., de la Salle C. Human epidermal Langerhans cells express the high affinity receptor for immunoglobulin E (Fc epsilon RI). J Exp Med. 1992 May 1;175(5):1285–1290. doi: 10.1084/jem.175.5.1285. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. 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]
  4. 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]
  5. Eaves C. J. Peripheral blood stem cells reach new heights. Blood. 1993 Oct 1;82(7):1957–1959. [PubMed] [Google Scholar]
  6. Ema H., Suda T., Miura Y., Nakauchi H. Colony formation of clone-sorted human hematopoietic progenitors. Blood. 1990 May 15;75(10):1941–1946. [PubMed] [Google Scholar]
  7. Freudenthal P. S., Steinman R. M. The distinct surface of human blood dendritic cells, as observed after an improved isolation method. Proc Natl Acad Sci U S A. 1990 Oct;87(19):7698–7702. doi: 10.1073/pnas.87.19.7698. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Gerdes J., Lemke H., Baisch H., Wacker H. H., Schwab U., Stein H. Cell cycle analysis of a cell proliferation-associated human nuclear antigen defined by the monoclonal antibody Ki-67. J Immunol. 1984 Oct;133(4):1710–1715. [PubMed] [Google Scholar]
  9. Havenith C. E., Breedijk A. J., Betjes M. G., Calame W., Beelen R. H., Hoefsmit E. C. T cell priming in situ by intratracheally instilled antigen-pulsed dendritic cells. Am J Respir Cell Mol Biol. 1993 Mar;8(3):319–324. doi: 10.1165/ajrcmb/8.3.319. [DOI] [PubMed] [Google Scholar]
  10. Heufler C., Koch F., Schuler G. Granulocyte/macrophage colony-stimulating factor and interleukin 1 mediate the maturation of murine epidermal Langerhans cells into potent immunostimulatory dendritic cells. J Exp Med. 1988 Feb 1;167(2):700–705. doi: 10.1084/jem.167.2.700. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. 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]
  12. Inaba K., Inaba M., Naito M., Steinman R. M. Dendritic cell progenitors phagocytose particulates, including bacillus Calmette-Guerin organisms, and sensitize mice to mycobacterial antigens in vivo. J Exp Med. 1993 Aug 1;178(2):479–488. doi: 10.1084/jem.178.2.479. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. 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]
  14. Inaba K., Metlay J. P., Crowley M. T., Steinman R. M. Dendritic cells pulsed with protein antigens in vitro can prime antigen-specific, MHC-restricted T cells in situ. J Exp Med. 1990 Aug 1;172(2):631–640. doi: 10.1084/jem.172.2.631. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. 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]
  16. Jansen J. H., Wientjens G. J., Fibbe W. E., Willemze R., Kluin-Nelemans H. C. Inhibition of human macrophage colony formation by interleukin 4. J Exp Med. 1989 Aug 1;170(2):577–582. doi: 10.1084/jem.170.2.577. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Kaplan G., Walsh G., Guido L. S., Meyn P., Burkhardt R. A., Abalos R. M., Barker J., Frindt P. A., Fajardo T. T., Celona R. Novel responses of human skin to intradermal recombinant granulocyte/macrophage-colony-stimulating factor: Langerhans cell recruitment, keratinocyte growth, and enhanced wound healing. J Exp Med. 1992 Jun 1;175(6):1717–1728. doi: 10.1084/jem.175.6.1717. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. 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]
  19. Katz S. I., Tamaki K., Sachs D. H. Epidermal Langerhans cells are derived from cells originating in bone marrow. Nature. 1979 Nov 15;282(5736):324–326. doi: 10.1038/282324a0. [DOI] [PubMed] [Google Scholar]
  20. Koch F., Heufler C., Kämpgen E., Schneeweiss D., Böck G., Schuler G. Tumor necrosis factor alpha maintains the viability of murine epidermal Langerhans cells in culture, but in contrast to granulocyte/macrophage colony-stimulating factor, without inducing their functional maturation. J Exp Med. 1990 Jan 1;171(1):159–171. doi: 10.1084/jem.171.1.159. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Koide S. L., Inaba K., Steinman R. M. Interleukin 1 enhances T-dependent immune responses by amplifying the function of dendritic cells. J Exp Med. 1987 Feb 1;165(2):515–530. doi: 10.1084/jem.165.2.515. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. 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]
  23. Liu L. M., MacPherson G. G. Antigen acquisition by dendritic cells: intestinal dendritic cells acquire antigen administered orally and can prime naive T cells in vivo. J Exp Med. 1993 May 1;177(5):1299–1307. doi: 10.1084/jem.177.5.1299. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. MacPherson G. G. Properties of lymph-borne (veiled) dendritic cells in culture. I. Modulation of phenotype, survival and function: partial dependence on GM-CSF. Immunology. 1989 Sep;68(1):102–107. [PMC free article] [PubMed] [Google Scholar]
  25. Mayani H., Dragowska W., Lansdorp P. M. Cytokine-induced selective expansion and maturation of erythroid versus myeloid progenitors from purified cord blood precursor cells. Blood. 1993 Jun 15;81(12):3252–3258. [PubMed] [Google Scholar]
  26. Naito K., Inaba K., Hirayama Y., Inaba-Miyama M., Sudo T., Muramatsu S. Macrophage factors which enhance the mixed leukocyte reaction initiated by dendritic cells. J Immunol. 1989 Mar 15;142(6):1834–1839. [PubMed] [Google Scholar]
  27. 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]
  28. Pettengell R., Morgenstern G. R., Woll P. J., Chang J., Rowlands M., Young R., Radford J. A., Scarffe J. H., Testa N. G., Crowther D. Peripheral blood progenitor cell transplantation in lymphoma and leukemia using a single apheresis. Blood. 1993 Dec 15;82(12):3770–3777. [PubMed] [Google Scholar]
  29. Pugh C. W., MacPherson G. G., Steer H. W. Characterization of nonlymphoid cells derived from rat peripheral lymph. J Exp Med. 1983 Jun 1;157(6):1758–1779. doi: 10.1084/jem.157.6.1758. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Reid C. D., Fryer P. R., Clifford C., Kirk A., Tikerpae J., Knight S. C. Identification of hematopoietic progenitors of macrophages and dendritic Langerhans cells (DL-CFU) in human bone marrow and peripheral blood. Blood. 1990 Sep 15;76(6):1139–1149. [PubMed] [Google Scholar]
  31. 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]
  32. Romani N., Lenz A., Glassel H., Stössel H., Stanzl U., Majdic O., Fritsch P., Schuler G. Cultured human Langerhans cells resemble lymphoid dendritic cells in phenotype and function. J Invest Dermatol. 1989 Nov;93(5):600–609. doi: 10.1111/1523-1747.ep12319727. [DOI] [PubMed] [Google Scholar]
  33. 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]
  34. Santiago-Schwarz F., Divaris N., Kay C., Carsons S. E. Mechanisms of tumor necrosis factor-granulocyte-macrophage colony-stimulating factor-induced dendritic cell development. Blood. 1993 Nov 15;82(10):3019–3028. [PubMed] [Google Scholar]
  35. Sattentau Q. J., Weiss R. A. The CD4 antigen: physiological ligand and HIV receptor. Cell. 1988 Mar 11;52(5):631–633. doi: 10.1016/0092-8674(88)90397-2. [DOI] [PubMed] [Google Scholar]
  36. Scheicher C., Mehlig M., Zecher R., Reske K. Dendritic cells from mouse bone marrow: in vitro differentiation using low doses of recombinant granulocyte-macrophage colony-stimulating factor. J Immunol Methods. 1992 Oct 2;154(2):253–264. doi: 10.1016/0022-1759(92)90199-4. [DOI] [PubMed] [Google Scholar]
  37. Sornasse T., Flamand V., De Becker G., Bazin H., Tielemans F., Thielemans K., Urbain J., Leo O., Moser M. Antigen-pulsed dendritic cells can efficiently induce an antibody response in vivo. J Exp Med. 1992 Jan 1;175(1):15–21. doi: 10.1084/jem.175.1.15. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. 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. 1974 Jun 1;139(6):1431–1445. doi: 10.1084/jem.139.6.1431. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. 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]
  40. Wang B., Rieger A., Kilgus O., Ochiai K., Maurer D., Födinger D., Kinet J. P., Stingl G. Epidermal Langerhans cells from normal human skin bind monomeric IgE via Fc epsilon RI. J Exp Med. 1992 May 1;175(5):1353–1365. doi: 10.1084/jem.175.5.1353. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Witmer-Pack M. D., Olivier W., Valinsky J., Schuler G., Steinman R. M. Granulocyte/macrophage colony-stimulating factor is essential for the viability and function of cultured murine epidermal Langerhans cells. J Exp Med. 1987 Nov 1;166(5):1484–1498. doi: 10.1084/jem.166.5.1484. [DOI] [PMC free article] [PubMed] [Google Scholar]

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