Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Dermal-resident CD14+ cells differentiate into Langerhans cells

Abstract

Epidermal Langerhans cells (LCs) show extraordinary immunostimulatory capacity and play a key role in the initiation and regulation of immune responses. Studies of LC biology are currently the focus of efforts to engineer immune responses and to better understand the immunopathology of cutaneous diseases. Here we identified and characterized a population of LC precursors that were resident in human skin. These immediate precursors expressed CD14, langerin and functional CCR6. When cultured with transforming growth factor-β1 alone, they had the potential to differentiate into epidermal LCs; when cultured in the presence of granulocyte macrophage–colony-stimulating factor and interleukin 4 they differentiated into functionally mature dendritic cells. Identification and characterization of these LC precursors provided insight into LC biology and the mechanism(s) through which LCs repopulate the epidermis.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Comparative phenotypes of different skin migratory cell populations and detection of S-100, CD68 and FXIIIa in miCD14+ and miCD14 cell cytoplasm.
Figure 2: Morphology of miCD14+ and miCD14 cells.
Figure 3: Differentiation of miCD14+ cells into LCs in the presence of various cytokine combinations.
Figure 4: CD14+ cells reside in dermis and migrate actively from skin explants.
Figure 5: miCD14+ and mCD14 cells show distinct capacities for antigen uptake.
Figure 6: miCD14 + cells express CCR6 and migrate in response to the CCR6 ligand MIP-3α.
Figure 7: GM-CSF, IL-4 and TGF-β1 do not induce proliferation of miCD14+ cells, whereas TGF-β1 alone or in combination with GM-CSF + IL-4 increases viability of miCD14+ cells.
Figure 8: Distinct allostimulatory capacity of miCD14+ cells that differentiated into LCs in response to various cytokines.

Similar content being viewed by others

References

  1. Banchereau, J. & Steinman, R. M. Dendritic cells and the control of the immunity. Nature 392, 245–252 (1998).

    Article  CAS  PubMed  Google Scholar 

  2. Larregina, A. T. & Falo, L. D. Jr in Dendritic Cells 2nd edn Ch. 23 (eds Lotze, M. T.& Thomson, A. W.) 301–314 (Academic Press, London, UK, 2001).

    Book  Google Scholar 

  3. Cumberbach, M., Dearman, R. J. & Kimber, I. Langerhans cells require signals from both tumor necrosis factor α and IL-1β for migration. Immunology 92, 388–395 (1997).

    Article  Google Scholar 

  4. Macatonia, S. E., Knight, S. C., Edwards, A. J., Griffiths, S. & Fryer, P. Localization of antigen in lymph node dendritic cells after exposure to the contact sensitizer fluorescein isothiocyanate. J. Exp. Med. 166, 1654–1667 (1987).

    Article  CAS  PubMed  Google Scholar 

  5. Larsen, C. P. et al. Migration and maturation of Langerhans cells in skin transplants and explants. J. Exp. Med. 172, 1483–1493 (1990).

    Article  CAS  PubMed  Google Scholar 

  6. Larregina, A. T. & Falo, L. D. Jr Generating and regulating immune responses through cutaneous gene delivery. Hum Gene Ther. 11, 2301–2305 (2000).

    Article  CAS  PubMed  Google Scholar 

  7. Banchereau, J. et al. Immune and clinical responses in patients with metastatic melanoma to CD34(+) progenitor-derived dendritic cell vaccine. Cancer Res. 61, 6451–6458 (2001).

    CAS  PubMed  Google Scholar 

  8. Valladeau, J. et al. Langerin, a novel c-type lectin specific to Langerhans cells, is an endocytic receptor that induces the formation of Birbeck granules. Immunity 12, 71–81 (2000).

    Article  CAS  PubMed  Google Scholar 

  9. Koszik, F. et al. Expression of monoclonal antibody HECA-452 defined E-selectin ligands on Langerhans cells in normal and diseased skin. J. Invest. Dermatol. 102, 773–780 (1994).

    Article  CAS  PubMed  Google Scholar 

  10. Birbeck, M. S., Breathnach, A. S. & Everall, J. D. An electronmicroscopy study of basal melanocytes and high level clear cells (Langerhans cells) in vitiligo. Am. J. Dermatopathol. 37, 51–64 (1961).

    Google Scholar 

  11. Tang, A., Amagani, M., Granger, L. G., Stanley, J. R. & Udey, M. C. Adhesion of epidermal Langerhans cells to keratinocytes mediated by E-cadherin. Nature 361, 82–85 (1993).

    Article  CAS  PubMed  Google Scholar 

  12. Caux, C., Dezutter-Dambuyant, C., Schmitt, D. & Banchereau, J. GM-CSF and TNF-α cooperate in the generation of dendritic Langerhans cells. Nature 360, 258–261 (1992).

    Article  CAS  PubMed  Google Scholar 

  13. Caux, C. et al. CD34+ hematopoietic progenitors from human cord blood differentiate along two independent dendritic cell pathways in response to GM-CSF and TNF-α. J. Exp. Med. 184, 695–706 (1996).

    Article  CAS  PubMed  Google Scholar 

  14. Strunk, D. et al. Generation of human dendritic cells/Langerhans cells from CD34+ circulating hematopietic progenitors cells. Blood 87, 1292–1302 (1996).

    CAS  PubMed  Google Scholar 

  15. Ito, T. et al. A CD1a+ /CD11c+ subset of human blood dendritic cells is a direct precursor of Langerhans cells. J. Immunol. 163,1409–1419 (1999).

    CAS  PubMed  Google Scholar 

  16. Caux, C., Vanbervliet, B., Massacrier, C., Durand, I. & Banchereau, J. Interleukin-3 cooperates with tumor necrosis factor α for the development of human dendritic/Langerhans cells from cord blood CD34+ hematopoietic progenitor cells. Blood 87, 2376–2385 (1996).

    CAS  PubMed  Google Scholar 

  17. Strobel, H. et al. Flt3 ligand in cooperation with transforming growth factor-β1 potentiates in vitro development of Langerhans-type dendritic cells and allows single cell dendritic cell cluster formation under serum free conditions. Blood 90, 1425–1434 (1996).

    Google Scholar 

  18. Strobel, H., Riedl, E., Bello Fernandez, C. & Knapp, W. Epidermal Langerhans cells development and differentiation. Immunobiology 198, 588–605 (1997).

    Article  Google Scholar 

  19. Geissmann, F. et al. Transforming growth factor-β1, in the presence of Granulocyte/ Macrophage Colony Stimulating Factor and interleukin 4, induces differentiation of human peripheral blood monocytes into dendritic Langerhans cells. J. Exp. Med. 187, 961–966 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Borkowski, T. A., Letterio, J. J, Farr, A. G. & Udey, M. C. A role of endogenous transforming growth factor β1 in Langerhans cell biology: the skin of Transforming growth factor β1 null mice is devoid of epidermal Langerhans cells. J. Exp. Med. 184, 2417–2422 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Borkowski, T. A. et al. A role of endogenous TGFβ1 in Langerhans cell biology. Further characterization of the epidermal Langerhans cell defect in TGFβ1 null mice. J. Clin. Invest. 100, 575–581 (1996).

    Article  Google Scholar 

  22. Charbonnier, A. S. et al. Macrophage inflammatory protein 3α is involved in the constitutive trafficking of epidermal Langerhans cells. J. Exp. Med. 190, 1755–1768 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. 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 functional distinctive subsets. J. Immunol. 151, 6535–6445 (1993).

    CAS  PubMed  Google Scholar 

  24. Lenz, A., Heine, G., 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. 92, 2587–2596 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Pope, M. et al. Both dendritic cells and memory T lymphocytes emigrate from organ cultures of human skin and form distinctive dendritic-T cell conjugates. J. Invest. Dermatol. 104, 11–17 (1995).

    Article  CAS  PubMed  Google Scholar 

  26. Morelli, A., Larregina, A., Chuluyan, E., Kolkowski, E. & Fainboim L. Expression and modulation of C5a receptor (CD88) on skin dendritic cells. Chemotactic effect of C5a on skin migratory dendritic cells. Immunology 84, 126–134 (1996).

    Article  Google Scholar 

  27. Albert, M. L. et al. Immature dendritic cells phagocytose apoptotic cells via αvβ5 and CD36, and cross-present antigens to cytotoxic T lymphocytes. J. Exp. Med. 188, 1359–1368 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Cocchia, D., Michetti, F. & Donato, R. Immunochemical and immunocytochemical localization of S-100 antigen in normal human skin. Nature 294, 85–87 (1981).

    Article  CAS  PubMed  Google Scholar 

  29. Cerio, R., Griffiths, C. E., Cooper, K. D., Nickoloff, B. J. & Headington, J. T. Characterization of factor XIIIa positive dermal dendritic cells in normal and inflammed skin. Br. J. Dermatol. 121, 421–431 (1989).

    Article  CAS  PubMed  Google Scholar 

  30. Randolph, G. J. et al. A physiologic function for p-glycoprotein (MDR-1) during the migration of dendritic cells from skin via afferent lymphatic vessels. Proc. Natl Acad. Sci. USA 95, 6924–6929 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Reis e Sousa, C., Stahl, P. D. & Austyn, J. M. Phagocytosis of antigens by Langerhans cells in vitro. J. Exp. Med. 178, 509–519 (1993).

    Article  CAS  PubMed  Google Scholar 

  32. Dezutter-Dambuyant, C. et al. Quantitative evaluation of two distinct cell populations expressing HLA-DR antigens in normal human epidermis. Br. J. Dermatol. 3, 1–11 (1984).

    Article  Google Scholar 

  33. Nestle, F. O. & Nickoloff, B. J. A fresh morphological and functional look at dermal dendritic cells. J. Cutan. Pathol. 22, 385–393 (1995).

    Article  CAS  PubMed  Google Scholar 

  34. Murphy, G. F., Messadi, D., Fonferko, E. & Hancock, W. W. Phenotypic transformation of macrophages to Langerhans cells in the skin. Am. J. Pathol. 123, 401–406 (1986).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Meunier, L., Bata-Csorgo, Z. & Cooper, K. D. In human dermis, ultraviolet radiation induces expansion of a CD36+CD11b+CD1 macrophage subset by infiltration and proliferation; CD1+ Langerhans-like dendritic antigen-presenting cells are concomitantly depleted. J. Invest. Dermatol. 105, 782–788 (1995).

    Article  CAS  PubMed  Google Scholar 

  36. Kang, K., Hammerberg, C., Meunier, L. & Cooper, K. D. CD11b+ macrophages that infiltrate human epidermis after in vivo ultraviolet exposure potently produce IL-10 and represent the major secretory source of epidermal IL-10 protein. J. Immunol. 153, 5256–5264 (1994).

    CAS  PubMed  Google Scholar 

  37. Mori, M. et al. Dendritic cells in cutaneous lupus erythematosus: a clue to the pathogenesis of lesions. Histopathology 24, 311–321 (1994).

    Article  PubMed  Google Scholar 

  38. Ruco, L. P. et al. Expression of macrophage-associated antigens in tissues involved by Langerhans' cell histiocytosis (histiocytosis X). Am. J. Clin. Pathol. 92, 273–279 (1989).

    Article  CAS  PubMed  Google Scholar 

  39. Riedl, E., Strobl, H., Majdic, O. & Knapp, W. TGF-β 1 promotes in vitro generation of dendritic cells by protecting progenitor cells from apoptosis. J. Immunol. 158, 1591–1597 (1997).

    CAS  PubMed  Google Scholar 

  40. Larregina, A. T. et al. Pattern of cytokine receptors expressed by human dendritic cells migrated from dermal explants. Immunology 91, 303–313 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Polit, F. D. in Data Analysis and Statistics for Nursing Research Ch 7 (ed. Polit, F. D.) 156–191 (Appleton & Lange, Stamford, CT, 1996).

    Google Scholar 

Download references

Acknowledgements

We thank F. Shagas and A. C. Bursick for technical assistance and personnel from Magee Women's Hospital for human skin samples. Supported by the Dermatology Foundation (A. T. L.) and grants from the American Heart Association (to A. E. M.) and National Institutes of Health: RO1 AI43916 and PO1 CA73743 (to L. D. F.) and RO1 DK49745 and RO1 AI41011 (to A. W. T.).

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Adriana T. Larregina or Louis D. Falo Jr..

Rights and permissions

Reprints and permissions

About this article

Cite this article

Larregina, A., Morelli, A., Spencer, L. et al. Dermal-resident CD14+ cells differentiate into Langerhans cells. Nat Immunol 2, 1151–1158 (2001). https://doi.org/10.1038/ni731

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ni731

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing