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:

Cross-presentation of viral and self antigens by skin-derived CD103+ dendritic cells

Abstract

Skin-derived dendritic cells (DCs) include Langerhans cells, classical dermal DCs and a langerin-positive CD103+ dermal subset. We examined their involvement in the presentation of skin-associated viral and self antigens. Only the CD103+ subset efficiently presented antigens of herpes simplex virus type 1 to naive CD8+ T cells, although all subsets presented these antigens to CD4+ T cells. This showed that CD103+ DCs were the migratory subset most efficient at processing viral antigens into the major histocompatibility complex class I pathway, potentially through cross-presentation. This was supported by data showing only CD103+ DCs efficiently cross-presented skin-derived self antigens. This indicates CD103+ DCs are the main migratory subtype able to cross-present viral and self antigens, which identifies another level of specialization for skin DCs.

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: Progress of infection after inoculation of HSV-1 on scarified flank skin.
Figure 2: In vivo antigen presentation to HSV-specific CD8+ T cells after cutaneous HSV-1 infection.
Figure 3: Migratory DCs are involved in antigen presentation to CD8+ T cells after secondary viral infection of the skin.
Figure 4: CD103+ DCs present HSV-1 antigens to CD8+ T cells after secondary viral infection of the skin.
Figure 5: Many DC subsets present MHC class II–restricted viral antigen to gDT-II CD4+ T cells.
Figure 6: CD103+ DCs present skin-derived self antigen to CD8+ T cells.

Similar content being viewed by others

References

  1. Steinman, R.M. Lasker Basic Medical Research Award. Dendritic cells: versatile controllers of the immune system. Nat. Med. 13, 1155–1159 (2007).

    Article  CAS  PubMed  Google Scholar 

  2. Villadangos, J.A. & Heath, W.R. Life cycle, migration and antigen presenting functions of spleen and lymph node dendritic cells: limitations of the Langerhans cells paradigm. Semin. Immunol. 17, 262–272 (2005).

    Article  CAS  PubMed  Google Scholar 

  3. Shortman, K. & Liu, Y. Mouse and human dendritic cell subtypes. Nat. Rev. Immunol. 2, 151–161 (2002).

    Article  CAS  PubMed  Google Scholar 

  4. Shortman, K. & Naik, S.H. Steady-state and inflammatory dendritic-cell development. Nat. Rev. Immunol. 7, 19–30 (2007).

    Article  CAS  PubMed  Google Scholar 

  5. Heath, W.R. et al. Cross-presentation, dendritic cell subsets, and the generation of immunity to cellular antigens. Immunol. Rev. 199, 9–26 (2004).

    Article  CAS  PubMed  Google Scholar 

  6. Jakubzick, C. et al. Lymph-migrating, tissue-derived dendritic cells are minor constituents within steady-state lymph nodes. J. Exp. Med. 205, 2839–2850 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Wakim, L.M., Waithman, J., van Rooijen, N., Heath, W.R. & Carbone, F.R. Dendritic cell-induced memory T cell activation in nonlymphoid tissues. Science 319, 198–202 (2008).

    Article  CAS  PubMed  Google Scholar 

  8. Itano, A.A. et al. Distinct dendritic cell populations sequentially present antigen to CD4+ T cells and stimulate different aspects of cell-mediated immunity. Immunity 19, 47–57 (2003).

    Article  CAS  PubMed  Google Scholar 

  9. Allan, R.S. et al. Migratory dendritic cells transfer antigen to a lymph node-resident dendritic cell population for efficient CTL priming. Immunity 25, 153–162 (2006).

    Article  CAS  PubMed  Google Scholar 

  10. Cella, M. et al. Plasmacytoid monocytes migrate to inflamed lymph nodes and produce large amounts of type I interferon. Nat. Med. 5, 919–923 (1999).

    Article  CAS  PubMed  Google Scholar 

  11. Diebold, S.S. et al. Viral infection switches non-plasmacytoid dendritic cells into high interferon producers. Nature 424, 324–328 (2003).

    Article  CAS  PubMed  Google Scholar 

  12. den Haan, J.M. & Bevan, M.J. Constitutive versus activation-dependent cross-presentation of immune complexes by CD8+ and CD8 dendritic cells in vivo. J. Exp. Med. 196, 817–827 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  14. Schnorrer, P. et al. The dominant role of CD8+ dendritic cells in cross-presentation is not dictated by antigen capture. Proc. Natl. Acad. Sci. USA 103, 10729–10734 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Smith, C.M. et al. Cutting edge: conventional CD8α+ dendritic cells are preferentially involved in CTL priming after footpad infection with herpes simplex virus-1. J. Immunol. 170, 4437–4440 (2003).

    Article  CAS  PubMed  Google Scholar 

  16. Allan, R.S. et al. Epidermal viral immunity induced by CD8α+ dendritic cells but not by Langerhans cells. Science 301, 1925–1928 (2003).

    Article  CAS  PubMed  Google Scholar 

  17. Belz, G.T., Shortman, K., Bevan, M.J. & Heath, W.R. CD8α+ dendritic cells selectively present MHC class I-restricted noncytolytic viral and intracellular bacterial antigens in vivo. J. Immunol. 175, 196–200 (2005).

    Article  CAS  PubMed  Google Scholar 

  18. Belz, G.T. et al. Cutting edge: Conventional CD8α+ dendritic cells are generally involved in priming CTL immunity to viruses. J. Immunol. 172, 1996–2000 (2004).

    Article  CAS  PubMed  Google Scholar 

  19. Belz, G.T. et al. Distinct migrating and nonmigrating dendritic cell populations are involved in MHC class I-restricted antigen presentation after lung infection with virus. Proc. Natl. Acad. Sci. USA 101, 8670–8675 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Wilson, N.S. et al. Systemic activation of dendritic cells by Toll-like receptor ligands or malaria infection impairs cross-presentation and antiviral immunity. Nat. Immunol. 7, 165–172 (2006).

    Article  CAS  PubMed  Google Scholar 

  21. He, Y., Zhang, J., Donahue, C. & Falo, L.D. Jr. Skin-derived dendritic cells induce potent CD8+ T cell immunity in recombinant lentivector-mediated genetic immunization. Immunity 24, 643–656 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Bennett, C.L. et al. Inducible ablation of mouse Langerhans cells diminishes but fails to abrogate contact hypersensitivity. J. Cell Biol. 169, 569–576 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Waithman, J. et al. Skin-derived dendritic cells can mediate deletional tolerance of class I-restricted self-reactive T cells. J. Immunol. 179, 4535–4541 (2007).

    Article  CAS  PubMed  Google Scholar 

  24. Kaplan, D.H., Jenison, M.C., Saeland, S., Shlomchik, W.D. & Shlomchik, M.J. Epidermal langerhans cell-deficient mice develop enhanced contact hypersensitivity. Immunity 23, 611–620 (2005).

    Article  CAS  PubMed  Google Scholar 

  25. Kissenpfennig, A. et al. Dynamics and function of Langerhans cells in vivo dermal dendritic cells colonize lymph node areas distinct from slower migrating Langerhans cells. Immunity 22, 643–654 (2005).

    Article  CAS  PubMed  Google Scholar 

  26. Bursch, L.S. et al. Identification of a novel population of Langerin+ dendritic cells. J. Exp. Med. 204, 3147–3156 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Poulin, L.F. et al. The dermis contains langerin+ dendritic cells that develop and function independently of epidermal Langerhans cells. J. Exp. Med. 204, 3119–3131 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Ginhoux, F. et al. Blood-derived dermal langerin+ dendritic cells survey the skin in the steady state. J. Exp. Med. 204, 3133–3146 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Simmons, A. & Nash, A.A. Zosteriform spread of herpes simplex virus as a model of recrudescence and its use to investigate the role of immune cells in prevention of recurrent disease. J. Virol. 52, 816–821 (1984).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. van Lint, A. et al. Herpes simplex virus-specific CD8+ T cells can clear established lytic infections from skin and nerves and can partially limit the early spread of virus after cutaneous inoculation. J. Immunol. 172, 392–397 (2004).

    Article  CAS  PubMed  Google Scholar 

  31. Azukizawa, H. et al. Induction of T-cell-mediated skin disease specific for antigen transgenically expressed in keratinocytes. Eur. J. Immunol. 33, 1879–1888 (2003).

    Article  CAS  PubMed  Google Scholar 

  32. Zhao, X. et al. Vaginal submucosal dendritic cells, but not Langerhans cells, induce protective Th1 responses to herpes simplex virus-2. J. Exp. Med. 197, 153–162 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Lee, H.K. et al. Differential roles of migratory and resident DCs in T cell priming after mucosal or skin HSV-1 infection. J. Exp. Med. 206, 359–370 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Stoitzner, P. et al. Langerhans cells cross-present antigen derived from skin. Proc. Natl. Acad. Sci. USA 103, 7783–7788 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. den Haan, J.M., Lehar, S.M. & Bevan, M.J. CD8+ but not CD8 dendritic cells cross-prime cytotoxic T cells in vivo. J. Exp. Med. 192, 1685–1696 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Sung, S.S. et al. A major lung CD103 (αE)-β7 integrin-positive epithelial dendritic cell population expressing Langerin and tight junction proteins. J. Immunol. 176, 2161–2172 (2006).

    Article  CAS  PubMed  Google Scholar 

  37. Hildner, K. et al. Batf3 deficiency reveals a critical role for CD8α+ dendritic cells in cytotoxic T cell immunity. Science 322, 1097–1100 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. GeurtsvanKessel, C.H. et al. Clearance of influenza virus from the lung depends on migratory langerin+CD11b but not plasmacytoid dendritic cells. J. Exp. Med. 205, 1621–1634 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. del Rio, M.L., Rodriguez-Barbosa, J.I., Kremmer, E. & Forster, R. CD103 and CD103+ bronchial lymph node dendritic cells are specialized in presenting and cross-presenting innocuous antigen to CD4+ and CD8+ T cells. J. Immunol. 178, 6861–6866 (2007).

    Article  CAS  PubMed  Google Scholar 

  40. Jakubzick, C., Helft, J., Kaplan, T.J. & Randolph, G.J. Optimization of methods to study pulmonary dendritic cell migration reveals distinct capacities of DC subsets to acquire soluble versus particulate antigen. J. Immunol. Methods 337, 121–131 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Stock, A.T., Mueller, S.N., van Lint, A.L., Heath, W.R. & Carbone, F.R. Cutting edge: prolonged antigen presentation after herpes simplex virus-1 skin infection. J. Immunol. 173, 2241–2244 (2004).

    Article  CAS  PubMed  Google Scholar 

  42. Salio, M., Cella, M., Suter, M. & Lanzavecchia, A. Inhibition of dendritic cell maturation by herpes simplex virus. Eur. J. Immunol. 29, 3245–3253 (1999).

    Article  CAS  PubMed  Google Scholar 

  43. Kruse, M. et al. Mature dendritic cells infected with herpes simplex virus type 1 exhibit inhibited T-cell stimulatory capacity. J. Virol. 74, 7127–7136 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Jones, C.A. et al. Herpes simplex virus type 2 induces rapid cell death and functional impairment of murine dendritic cells in vitro. J. Virol. 77, 11139–11149 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Mueller, S.N., Heath, W., McLain, J.D., Carbone, F.R. & Jones, C.M. Characterization of two TCR transgenic mouse lines specific for herpes simplex virus. Immunol. Cell Biol. 80, 156–163 (2002).

    Article  CAS  PubMed  Google Scholar 

  46. Hogquist, K.A. et al. T cell receptor antagonist peptides induce positive selection. Cell 76, 17–27 (1994).

    Article  CAS  PubMed  Google Scholar 

  47. Wakim, L.M., Jones, C.M., Gebhardt, T., Preston, C.M. & Carbone, F.R. CD8+ T-cell attenuation of cutaneous herpes simplex virus infection reduces the average viral copy number of the ensuing latent infection. Immunol. Cell Biol. 86, 666–675 (2008).

    Article  CAS  PubMed  Google Scholar 

  48. Belz, G.T., Bedoui, S., Kupresanin, F., Carbone, F.R. & Heath, W.R. Minimal activation of memory CD8+ T cell by tissue-derived dendritic cells favors the stimulation of naive CD8+ T cells. Nat. Immunol. 8, 1060–1066 (2007).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank the flow cytometry facilities and animal facility staff of the Walter and Eliza Hall Institute of Medical Research and K. Field; we also thank B. Davies and J. Langley for technical assistance. Supported by Deutsche Forschungsgemeinschaft (BE 3285-1/2 to S.B.), the National Health and Medical Research Council of Australia (W.R.H., F.R.C., A.G.B. and P.G.W.) and the Howard Hughes Medical Institute (W.R.H.).

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Francis R Carbone, Andrew G Brooks or William R Heath.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–9 (PDF 3098 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bedoui, S., Whitney, P., Waithman, J. et al. Cross-presentation of viral and self antigens by skin-derived CD103+ dendritic cells. Nat Immunol 10, 488–495 (2009). https://doi.org/10.1038/ni.1724

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ni.1724

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