Skip to main content
NCBI home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1994 Jun 1;179(6):1767–1776. doi: 10.1084/jem.179.6.1767

Understanding the dendritic cell lineage through a study of cytokine receptors

PMCID: PMC2191528  PMID: 8195707

Abstract

Dendritic cells form a system of antigen presenting cells that are specialized to stimulate T lymphocytes, including quiescent T cells. The lineage of dendritic cells is not fully characterized, although prior studies have shown that growth and differentiation are controlled by cytokines, particularly granulocyte/macrophage colony-stimulating factor (GM-CSF). To further elucidate the nature and control of the dendritic cell lineage, we have studied the expression of specific cytokine receptors. Sufficient numbers of dendritic cells were purified from spleen and skin to do quantitative binding studies with radiolabeled M-CSF, GM-CSF, and interleukin 1 (IL-1). To verify the nonlymphoid nature of dendritic cells, we made an initial search for rearrangements in T cell receptor and immunoglobulin genes and none were found. M-CSF binding sites, a property of mononuclear phagocytes, also were absent. In contrast, GM-CSF receptors were abundant on mature dendritic cells, with approximately 3,000 binding sites/cell with a single Kd of 500-1,000 pM. Substantial numbers of high affinity (< 100 pM) IL-1 binding sites were identified as well; cultured epidermal dendritic cells (i.e., epidermal Langerhans cells) had 500/cell and spleen dendritic cells approximately 70/cell. Cross-linking approaches showed the 80-kD species that is expected of high-affinity type 1 IL-1 receptor. Anti-type 1 IL-1 receptor (R) mAbs also visualized these receptors by flow cytometry on freshly isolated epidermal dendritic cells. These results provide new evidence that dendritic cells represent a differentiation pathway distinct from lymphocytes and monocytes. Together with recent findings on the effects of IL-1 and GM- CSF on epidermal dendritic cells in situ (see Results and Discussion), the data lead to a proposal whereby IL-1 signals IL-1R to upregulate GM- CSF receptors and thereby, the observed responsiveness of dendritic cells to GM-CSF for growth, viability, and function.

Full Text

The Full Text of this article is available as a PDF (1.3 MB).

Selected References

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

  1. 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]
  2. Arend W. P. Interleukin-1 receptor antagonist. Adv Immunol. 1993;54:167–227. doi: 10.1016/s0065-2776(08)60535-0. [DOI] [PubMed] [Google Scholar]
  3. Budel L. M., Hoogerbrugge H., Pouwels K., van Buitenen C., Delwel R., Löwenberg B., Touw I. P. Granulocyte-macrophage colony-stimulating factor receptors alter their binding characteristics during myeloid maturation through up-regulation of the affinity converting beta subunit (KH97). J Biol Chem. 1993 May 15;268(14):10154–10159. [PubMed] [Google Scholar]
  4. 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]
  5. Chen B. D., Lin H. S., Hsu S. Lipopolysaccharide inhibits the binding of colony-stimulating factor (CSF-1) to murine peritoneal exudate macrophages. J Immunol. 1983 May;130(5):2256–2260. [PubMed] [Google Scholar]
  6. Chien Y. H., Iwashima M., Wettstein D. A., Kaplan K. B., Elliott J. F., Born W., Davis M. M. T-cell receptor delta gene rearrangements in early thymocytes. Nature. 1987 Dec 24;330(6150):722–727. doi: 10.1038/330722a0. [DOI] [PubMed] [Google Scholar]
  7. Chizzonite R., Truitt T., Kilian P. L., Stern A. S., Nunes P., Parker K. P., Kaffka K. L., Chua A. O., Lugg D. K., Gubler U. Two high-affinity interleukin 1 receptors represent separate gene products. Proc Natl Acad Sci U S A. 1989 Oct;86(20):8029–8033. doi: 10.1073/pnas.86.20.8029. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. 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. 1989 Jan;118(1):108–125. doi: 10.1016/0008-8749(89)90361-4. [DOI] [PubMed] [Google Scholar]
  9. Deyerle K. L., Sims J. E., Dower S. K., Bothwell M. A. Pattern of IL-1 receptor gene expression suggests role in noninflammatory processes. J Immunol. 1992 Sep 1;149(5):1657–1665. [PubMed] [Google Scholar]
  10. Dower S. K., Kronheim S. R., March C. J., Conlon P. J., Hopp T. P., Gillis S., Urdal D. L. Detection and characterization of high affinity plasma membrane receptors for human interleukin 1. J Exp Med. 1985 Aug 1;162(2):501–515. doi: 10.1084/jem.162.2.501. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Enk A. H., Angeloni V. L., Udey M. C., Katz S. I. An essential role for Langerhans cell-derived IL-1 beta in the initiation of primary immune responses in skin. J Immunol. 1993 May 1;150(9):3698–3704. [PubMed] [Google Scholar]
  12. Enk A. H., Katz S. I. Early molecular events in the induction phase of contact sensitivity. Proc Natl Acad Sci U S A. 1992 Feb 15;89(4):1398–1402. doi: 10.1073/pnas.89.4.1398. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Feinberg A. P., Vogelstein B. A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity. Anal Biochem. 1983 Jul 1;132(1):6–13. doi: 10.1016/0003-2697(83)90418-9. [DOI] [PubMed] [Google Scholar]
  14. Gallis B., Prickett K. S., Jackson J., Slack J., Schooley K., Sims J. E., Dower S. K. IL-1 induces rapid phosphorylation of the IL-1 receptor. J Immunol. 1989 Nov 15;143(10):3235–3240. [PubMed] [Google Scholar]
  15. 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]
  16. Heufler C., Topar G., Koch F., Trockenbacher B., Kämpgen E., Romani N., Schuler G. Cytokine gene expression in murine epidermal cell suspensions: interleukin 1 beta and macrophage inflammatory protein 1 alpha are selectively expressed in Langerhans cells but are differentially regulated in culture. J Exp Med. 1992 Oct 1;176(4):1221–1226. doi: 10.1084/jem.176.4.1221. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Holt P. G., Oliver J., Bilyk N., McMenamin C., McMenamin P. G., Kraal G., Thepen T. Downregulation of the antigen presenting cell function(s) of pulmonary dendritic cells in vivo by resident alveolar macrophages. J Exp Med. 1993 Feb 1;177(2):397–407. doi: 10.1084/jem.177.2.397. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Holt P. G., Oliver J., McMenamin C., Schon-Hegrad M. A. Studies on the surface phenotype and functions of dendritic cells in parenchymal lung tissue of the rat. Immunology. 1992 Apr;75(4):582–587. [PMC free article] [PubMed] [Google Scholar]
  19. 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]
  20. 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]
  21. 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]
  22. Inaba K., Witmer-Pack M. D., Inaba M., Muramatsu S., Steinman R. M. The function of Ia+ dendritic cells and Ia- dendritic cell precursors in thymocyte mitogenesis to lectin and lectin plus interleukin 1. J Exp Med. 1988 Jan 1;167(1):149–162. doi: 10.1084/jem.167.1.149. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Kitamura T., Takaku F., Miyajima A. IL-1 up-regulates the expression of cytokine receptors on a factor-dependent human hemopoietic cell line, TF-1. Int Immunol. 1991 Jun;3(6):571–577. doi: 10.1093/intimm/3.6.571. [DOI] [PubMed] [Google Scholar]
  24. Knight S. C., Stagg A. J. Antigen-presenting cell types. Curr Opin Immunol. 1993 Jun;5(3):374–382. doi: 10.1016/0952-7915(93)90056-x. [DOI] [PubMed] [Google Scholar]
  25. 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]
  26. Koch F., Kämpgen E., Schuler G., Romani N. Effective enrichment of murine epidermal Langerhans cells by a modified(mismatched) panning technique. J Invest Dermatol. 1992 Dec;99(6):803–807. doi: 10.1111/1523-1747.ep12614764. [DOI] [PubMed] [Google Scholar]
  27. 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]
  28. Lang R. B., Stanton L. W., Marcu K. B. On immunoglobulin heavy chain gene switching: two gamma 2b genes are rearranged via switch sequences in MPC-11 cells but only one is expressed. Nucleic Acids Res. 1982 Jan 22;10(2):611–630. doi: 10.1093/nar/10.2.611. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Lundqvist E. N., Bäck O. Interleukin-1 decreases the number of Ia+ epidermal dendritic cells but increases their expression of Ia antigen. Acta Derm Venereol. 1990;70(5):391–394. [PubMed] [Google Scholar]
  30. MacPherson G. G., Fossum S., Harrison B. Properties of lymph-borne (veiled) dendritic cells in culture. II. Expression of the IL-2 receptor: role of GM-CSF. Immunology. 1989 Sep;68(1):108–113. [PMC free article] [PubMed] [Google Scholar]
  31. Matsue H., Cruz P. D., Jr, Bergstresser P. R., Takashima A. Langerhans cells are the major source of mRNA for IL-1 beta and MIP-1 alpha among unstimulated mouse epidermal cells. J Invest Dermatol. 1992 Nov;99(5):537–541. doi: 10.1111/1523-1747.ep12667296. [DOI] [PubMed] [Google Scholar]
  32. McMahan C. J., Slack J. L., Mosley B., Cosman D., Lupton S. D., Brunton L. L., Grubin C. E., Wignall J. M., Jenkins N. A., Brannan C. I. A novel IL-1 receptor, cloned from B cells by mammalian expression, is expressed in many cell types. EMBO J. 1991 Oct;10(10):2821–2832. doi: 10.1002/j.1460-2075.1991.tb07831.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Muñoz E., Zubiaga A. M., Sims J. E., Huber B. T. IL-1 signal transduction pathways. I. Two functional IL-1 receptors are expressed in T cells. J Immunol. 1991 Jan 1;146(1):136–143. [PubMed] [Google Scholar]
  34. 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]
  35. 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]
  36. Park L. S., Friend D., Gillis S., Urdal D. L. Characterization of the cell surface receptor for granulocyte-macrophage colony-stimulating factor. J Biol Chem. 1986 Mar 25;261(9):4177–4183. [PubMed] [Google Scholar]
  37. Park L. S., Martin U., Sorensen R., Luhr S., Morrissey P. J., Cosman D., Larsen A. Cloning of the low-affinity murine granulocyte-macrophage colony-stimulating factor receptor and reconstitution of a high-affinity receptor complex. Proc Natl Acad Sci U S A. 1992 May 15;89(10):4295–4299. doi: 10.1073/pnas.89.10.4295. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Reed K. C., Mann D. A. Rapid transfer of DNA from agarose gels to nylon membranes. Nucleic Acids Res. 1985 Oct 25;13(20):7207–7221. doi: 10.1093/nar/13.20.7207. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. 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]
  40. Romani N., Schuler G. The immunologic properties of epidermal Langerhans cells as a part of the dendritic cell system. Springer Semin Immunopathol. 1992;13(3-4):265–279. doi: 10.1007/BF00200527. [DOI] [PubMed] [Google Scholar]
  41. 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]
  42. Schuler G., Steinman R. M. Murine epidermal Langerhans cells mature into potent immunostimulatory dendritic cells in vitro. J Exp Med. 1985 Mar 1;161(3):526–546. doi: 10.1084/jem.161.3.526. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Stanley E. R., Guilbert L. J. Methods for the purification, assay, characterization and target cell binding of a colony stimulating factor (CSF-1). J Immunol Methods. 1981;42(3):253–284. doi: 10.1016/0022-1759(81)90156-3. [DOI] [PubMed] [Google Scholar]
  44. 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]
  45. Strominger J. L. Developmental biology of T cell receptors. Science. 1989 May 26;244(4907):943–950. doi: 10.1126/science.2658058. [DOI] [PubMed] [Google Scholar]
  46. Takahashi K., Naito M., Shultz L. D., Hayashi S., Nishikawa S. Differentiation of dendritic cell populations in macrophage colony-stimulating factor-deficient mice homozygous for the osteopetrosis (op) mutation. J Leukoc Biol. 1993 Jan;53(1):19–28. doi: 10.1002/jlb.53.1.19. [DOI] [PubMed] [Google Scholar]
  47. Traunecker A., Oliveri F., Allen N., Karjalainen K. Normal T cell development is possible without 'functional' gamma chain genes. EMBO J. 1986 Jul;5(7):1589–1593. doi: 10.1002/j.1460-2075.1986.tb04400.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Walker F., Burgess A. W. Specific binding of radioiodinated granulocyte-macrophage colony-stimulating factor to hemopoietic cells. EMBO J. 1985 Apr;4(4):933–939. doi: 10.1002/j.1460-2075.1985.tb03721.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Watanabe Y., Kitamura T., Hayashida K., Miyajima A. Monoclonal antibody against the common beta subunit (beta c) of the human interleukin-3 (IL-3), IL-5, and granulocyte-macrophage colony-stimulating factor receptors shows upregulation of beta c by IL-1 and tumor necrosis factor-alpha. Blood. 1992 Nov 1;80(9):2215–2220. [PubMed] [Google Scholar]
  50. Williams D. E., Bicknell D. C., Park L. S., Straneva J. E., Cooper S., Broxmeyer H. E. Purified murine granulocyte/macrophage progenitor cells express a high-affinity receptor for recombinant murine granulocyte/macrophage colony-stimulating factor. Proc Natl Acad Sci U S A. 1988 Jan;85(2):487–491. doi: 10.1073/pnas.85.2.487. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Witmer-Pack M. D., Hughes D. A., Schuler G., Lawson L., McWilliam A., Inaba K., Steinman R. M., Gordon S. Identification of macrophages and dendritic cells in the osteopetrotic (op/op) mouse. J Cell Sci. 1993 Apr;104(Pt 4):1021–1029. doi: 10.1242/jcs.104.4.1021. [DOI] [PubMed] [Google Scholar]
  52. 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]
  53. Wood G. S., Freudenthal P. S. CD5 monoclonal antibodies react with human peripheral blood dendritic cells. Am J Pathol. 1992 Oct;141(4):789–795. [PMC free article] [PubMed] [Google Scholar]

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

RESOURCES