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.

  • Review Article
  • Published:

Skin immune sentinels in health and disease

Nature Reviews Immunology volume 9, pages 679–691 (2009)Cite this article

Key Points

  • Human skin and the immune cells that it contains provide essential protection of the human body from injury and infection.

  • Keratinocytes are a first line of defence and sense danger through alert systems such as the inflammasome and Toll-like receptors. They mediate an inflammatory response by secreting pro-inflammatory cytokines.

  • A subpopulation of CD103+ dendritic cells is strategically positioned for cross-presentation of skin-tropic pathogens.

  • Recent data have highlighted a key role of tissue-resident rather than circulating T cells in skin homeostasis and pathology.

  • Important lessons for human skin immunology have been learnt from immunologically targeted therapies in inflammatory skin disorders such as psoriasis.

Abstract

Human skin and its immune cells provide essential protection of the human body from injury and infection. Recent studies reinforce the importance of keratinocytes as sensors of danger through alert systems such as the inflammasome. In addition, newly identified CD103+ dendritic cells are strategically positioned for cross-presentation of skin-tropic pathogens and accumulating data highlight a key role of tissue-resident rather than circulating T cells in skin homeostasis and pathology. This Review focuses on recent progress in dissecting the functional role of skin immune cells in skin disease.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1: Skin anatomy and cellular effectors.
Figure 2: Keratinocytes as sensors of danger.
Figure 3: Skin-resident immune sentinels.
Figure 4: Unconventional T cells in the skin.
Figure 5: Psoriasis immunopathogenesis.

Similar content being viewed by others

References

  1. Streilein, J. W. Skin-associated lymphoid tissues (SALT): origins and functions. J. Invest. Dermatol. 80, 12S–16S (1983). This is a milestone paper introducing the concept of SALT for the first time and describing the skin in conjunction with draining lymph nodes as an immune-competent organ.

    Article  PubMed  Google Scholar 

  2. Bos, J. D. & Kapsenberg, M. L. The skin immune system (SIS): its cellular constituents and their interactions. Immunol. Today 7, 235–240 (1986).

    Article  CAS  PubMed  Google Scholar 

  3. Stingl, G. & Bergstresser, P. R. Dendritic cells: a major story unfolds. Immunol. Today 16, 330–333 (1995).

    Article  CAS  PubMed  Google Scholar 

  4. Nickoloff, B. J. (ed.) Dermal Immune System (CRC, Boca Raton, 1993).

    Google Scholar 

  5. Proksch, E., Brandner, J. M. & Jensen, J. M. The skin: an indispensable barrier. Exp. Dermatol. 17, 1063–1072 (2008).

    Article  PubMed  Google Scholar 

  6. Krueger, G. G. & Stingl, G. Immunology/inflammation of the skin — a 50-year perspective. J. Invest. Dermatol. 92, 32S–51S (1989).

    Article  CAS  PubMed  Google Scholar 

  7. Janeway, C. A. Jr. Approaching the asymptote? Evolution and revolution in immunology. Cold Spring Harb. Symp. Quant. Biol. 54, 1–13 (1989).

    Article  CAS  PubMed  Google Scholar 

  8. Lebre, M. C. et al. Human keratinocytes express functional Toll-like receptor 3, 4, 5, and 9. J. Invest. Dermatol. 127, 331–341 (2007).

    Article  CAS  PubMed  Google Scholar 

  9. Kalali, B. N. et al. Double-stranded RNA induces an antiviral defense status in epidermal keratinocytes through TLR3-, PKR-, and MDA5/RIG-I-mediated differential signaling. J. Immunol. 181, 2694–2704 (2008).

    Article  CAS  PubMed  Google Scholar 

  10. Miller, L. S. & Modlin, R. L. Human keratinocyte Toll-like receptors promote distinct immune responses. J. Invest. Dermatol. 127, 262–263 (2007).

    Article  CAS  PubMed  Google Scholar 

  11. Martinon, F., Mayor, A. & Tschopp, J. The inflammasomes: guardians of the body. Annu. Rev. Immunol. 27, 229–265 (2009).

    Article  CAS  PubMed  Google Scholar 

  12. Feldmeyer, L. et al. The inflammasome mediates UVB-induced activation and secretion of interleukin-1β by keratinocytes. Curr. Biol. 17, 1140–1145 (2007).

    Article  CAS  PubMed  Google Scholar 

  13. Keller, M., Ruegg, A., Werner, S. & Beer, H. D. Active caspase-1 is a regulator of unconventional protein secretion. Cell 132, 818–831 (2008). References 12 and 13 are key papers showing that the inflammasome machinery is responsible for UV-induced secretion of IL-1β by human keratinocytes.

    Article  CAS  PubMed  Google Scholar 

  14. Watanabe, H. et al. Activation of the IL-1β-processing inflammasome is involved in contact hypersensitivity. J. Invest. Dermatol. 127, 1956–1963 (2007).

    Article  CAS  PubMed  Google Scholar 

  15. Gilliet, M. & Lande, R. Antimicrobial peptides and self-DNA in autoimmune skin inflammation. Curr. Opin. Immunol. 20, 401–407 (2008).

    Article  CAS  PubMed  Google Scholar 

  16. Lai, Y. & Gallo, R. L. AMPed up immunity: how antimicrobial peptides have multiple roles in immune defense. Trends Immunol. 30, 131–141 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Weaver, C. T., Hatton, R. D., Mangan, P. R. & Harrington, L. E. IL-17 family cytokines and the expanding diversity of effector T cell lineages. Annu. Rev. Immunol. 25, 821–852 (2007).

    Article  CAS  PubMed  Google Scholar 

  18. Liang, S. C. et al. Interleukin (IL)-22 and IL-17 are coexpressed by Th17 cells and cooperatively enhance expression of antimicrobial peptides. J. Exp. Med. 203, 2271–2279 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Kolls, J. K., McCray, P. B. Jr & Chan, Y. R. Cytokine-mediated regulation of antimicrobial proteins. Nature Rev. Immunol. 8, 829–835 (2008).

    Article  CAS  Google Scholar 

  20. Harder, J., Bartels, J., Christophers, E. & Schroder, J. M. A peptide antibiotic from human skin. Nature 387, 861 (1997).

    Article  CAS  PubMed  Google Scholar 

  21. Lande, R. et al. Plasmacytoid dendritic cells sense self-DNA coupled with antimicrobial peptide. Nature 449, 564–569 (2007). A landmark paper showing that LL37 can convert inert self DNA into a potent pro-inflammatory trigger for pDC IFNα production through TLR9-dependent mechanisms, suggesting that this pathway might drive autoimmunity in the context of skin inflammation but also other autoimmune-type disorders.

    Article  CAS  PubMed  Google Scholar 

  22. Schauber, J. et al. Injury enhances TLR2 function and antimicrobial peptide expression through a vitamin D-dependent mechanism. J. Clin. Invest. 117, 803–811 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Peric, M. et al. IL-17A enhances vitamin D3-induced expression of cathelicidin antimicrobial peptide in human keratinocytes. J. Immunol. 181, 8504–8512 (2008).

    Article  CAS  PubMed  Google Scholar 

  24. Albanesi, C., Scarponi, C., Giustizieri, M. L. & Girolomoni, G. Keratinocytes in inflammatory skin diseases. Curr. Drug Targets Inflamm. Allergy 4, 329–334 (2005).

    Article  CAS  PubMed  Google Scholar 

  25. Arend, W. P., Palmer, G. & Gabay, C. IL-1, IL-18, and IL-33 families of cytokines. Immunol. Rev. 223, 20–38 (2008).

    Article  CAS  PubMed  Google Scholar 

  26. Lee, P. et al. Dynamic expression of epidermal caspase 8 simulates a wound healing response. Nature 458, 519–523 (2009).

    Article  CAS  PubMed  Google Scholar 

  27. Groves, R. W., Mizutani, H., Kieffer, J. D. & Kupper, T. S. Inflammatory skin disease in transgenic mice that express high levels of interleukin 1α in basal epidermis. Proc. Natl Acad. Sci. USA 92, 11874–11878 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Blumberg, H. et al. Opposing activities of two novel members of the IL-1 ligand family regulate skin inflammation. J. Exp. Med. 204, 2603–2614 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Soumelis, V. et al. Human epithelial cells trigger dendritic cell mediated allergic inflammation by producing TSLP. Nature Immunol. 3, 673–680 (2002).

    Article  CAS  Google Scholar 

  30. Dieu-Nosjean, M. C. et al. Macrophage inflammatory protein 3α is expressed at inflamed epithelial surfaces and is the most potent chemokine known in attracting Langerhans cell precursors. J. Exp. Med. 192, 705–718 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Nickoloff, B. J. & Turka, L. A. Immunological functions of non-professional antigen-presenting cells: new insights from studies of T-cell interactions with keratinocytes. Immunol. Today 15, 464–469 (1994).

    Article  CAS  PubMed  Google Scholar 

  32. Gaspari, A. A. & Katz, S. I. Induction of in vivo hyporesponsiveness to contact allergens by hapten-modified Ia+ keratinocytes. J. Immunol. 147, 4155–4161 (1991).

    CAS  PubMed  Google Scholar 

  33. Nickoloff, B. J. et al. Accessory cell function of keratinocytes for superantigens. Dependence on lymphocyte function-associated antigen-1/intercellular adhesion molecule-1 interaction. J. Immunol. 150, 2148–2159 (1993).

    CAS  PubMed  Google Scholar 

  34. Black, A. P. et al. Human keratinocyte induction of rapid effector function in antigen-specific memory CD4+ and CD8+ T cells. Eur. J. Immunol. 37, 1485–1493 (2007).

    Article  CAS  PubMed  Google Scholar 

  35. Griffiths, C. E. & Nickoloff, B. J. Keratinocyte intercellular adhesion molecule-1 (ICAM-1) expression precedes dermal T lymphocytic infiltration in allergic contact dermatitis (Rhus dermatitis). Am. J. Pathol. 135, 1045–1053 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Kupper, T. S. The activated keratinocyte: a model for inducible cytokine production by non-bone marrow-derived cells in cutaneous inflammatory and immune responses. J. Invest. Dermatol. 94, 146S–150S (1990).

    Article  Google Scholar 

  37. Luger, T. A. & Schwarz, T. Evidence for an epidermal cytokine network. J. Invest. Dermatol. 95, 100S–104S (1990).

  38. Barker, J. N., Mitra, R. S., Griffiths, C. E., Dixit, V. M. & Nickoloff, B. J. Keratinocytes as initiators of inflammation. Lancet 337, 211–214 (1991).

    Article  CAS  PubMed  Google Scholar 

  39. Mehling, A. et al. Overexpression of CD40 ligand in murine epidermis results in chronic skin inflammation and systemic autoimmunity. J. Exp. Med. 194, 615–628 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Zenz, R. et al. Psoriasis-like skin disease and arthritis caused by inducible epidermal deletion of Jun proteins. Nature 437, 369–375 (2005).

    Article  CAS  PubMed  Google Scholar 

  41. Pasparakis, M. et al. TNF-mediated inflammatory skin disease in mice with epidermis-specific deletion of IKK2. Nature 417, 861–866 (2002).

    Article  CAS  PubMed  Google Scholar 

  42. Eckmann, L. et al. Opposing functions of IKKβ during acute and chronic intestinal inflammation. Proc. Natl Acad. Sci. USA 105, 15058–15063 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Sano, S. et al. Stat3 links activated keratinocytes and immunocytes required for development of psoriasis in a novel transgenic mouse model. Nature Med. 11, 43–49 (2005).

    Article  CAS  PubMed  Google Scholar 

  44. Oppenheim, D. E. et al. Sustained localized expression of ligand for the activating NKG2D receptor impairs natural cytotoxicity in vivo and reduces tumor immunosurveillance. Nature Immunol. 6, 928–937 (2005).

    Article  CAS  Google Scholar 

  45. Strid, J. et al. Acute upregulation of an NKG2D ligand promotes rapid reorganization of a local immune compartment with pleiotropic effects on carcinogenesis. Nature Immunol. 9, 146–154 (2008). This paper provides insights into the early phases of tissue immunosurveillance, establishing that upregulation of the NKG2D ligand RAE1α can promote considerable reorganization of the skin immune compartment.

    Article  CAS  Google Scholar 

  46. 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 

  47. 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 

  48. 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). References 46–48 describe a newly discovered population of skin DCs: langerin+ non-Langerhans cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Nagao, K. et al. Murine epidermal Langerhans cells and langerin-expressing dermal dendritic cells are unrelated and exhibit distinct functions. Proc. Natl Acad. Sci. USA 106, 3312–3317 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Merad, M., Ginhoux, F. & Collin, M. Origin, homeostasis and function of Langerhans cells and other langerin-expressing dendritic cells. Nature Rev. Immunol. 8, 935–947 (2008).

    Article  CAS  Google Scholar 

  51. Romani, N. et al. Epidermal Langerhans cells — changing views on their function in vivo. Immunol. Lett. 106, 119–125 (2006).

    Article  CAS  PubMed  Google Scholar 

  52. Hunger, R. E. et al. Langerhans cells utilize CD1a and langerin to efficiently present nonpeptide antigens to T cells. J. Clin. Invest. 113, 701–708 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Klechevsky, E. et al. Functional specializations of human epidermal Langerhans cells and CD14+ dermal dendritic cells. Immunity 29, 497–510 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. 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 

  55. 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 

  56. Bedoui, S. et al. Cross-presentation of viral and self antigens by skin-derived CD103+ dendritic cells. Nature Immunol. 10, 488–495 (2009). This paper establishes that CD103+ DCs are the key cross-presenting APCs in the skin.

    Article  CAS  Google Scholar 

  57. Schuler, G. & Steinman, R. M. Murine epidermal Langerhans cells mature into potent immunostimulatory dendritic cells in vitro. J. Exp. Med. 161, 526–546 (1985). This key paper describes the concept of immature DCs (specialized for antigen processing) and mature DCs (specialized for antigen presentation) for the first time, using the example of Langerhans cells.

    Article  CAS  PubMed  Google Scholar 

  58. Grabbe, S., Steinbrink, K., Steinert, M., Luger, T. A. & Schwarz, T. Removal of the majority of epidermal Langerhans cells by topical or systemic steroid application enhances the effector phase of murine contact hypersensitivity. J. Immunol. 155, 4207–4217 (1995).

    CAS  PubMed  Google Scholar 

  59. Kaplan, D. H., Kissenpfennig, A. & Clausen, B. E. Insights into Langerhans cell function from Langerhans cell ablation models. Eur. J. Immunol. 38, 2369–2376 (2008).

    Article  CAS  PubMed  Google Scholar 

  60. 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 

  61. 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 

  62. Wollenberg, A. et al. Expression and function of the mannose receptor CD206 on epidermal dendritic cells in inflammatory skin diseases. J. Invest. Dermatol. 118, 327–334 (2002).

    Article  CAS  PubMed  Google Scholar 

  63. Bieber, T. The pro- and anti-inflammatory properties of human antigen-presenting cells expressing the high affinity receptor for IgE (FcɛRI). Immunobiology 212, 499–503 (2007).

    Article  CAS  PubMed  Google Scholar 

  64. Guttman-Yassky, E. et al. Major differences in inflammatory dendritic cells and their products distinguish atopic dermatitis from psoriasis. J. Allergy Clin. Immunol. 119, 1210–1217 (2007).

    Article  CAS  PubMed  Google Scholar 

  65. 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 

  66. Fukunaga, A., Khaskhely, N. M., Sreevidya, C. S., Byrne, S. N. & Ullrich, S. E. Dermal dendritic cells, and not Langerhans cells, play an essential role in inducing an immune response. J. Immunol. 180, 3057–3064 (2008).

    Article  CAS  PubMed  Google Scholar 

  67. Auffray, C., Sieweke, M. H. & Geissmann, F. Blood monocytes: development, heterogeneity, and relationship with dendritic cells. Annu. Rev. Immunol. 27, 669–692 (2009).

    Article  CAS  PubMed  Google Scholar 

  68. Lopez-Bravo, M. & Ardavin, C. In vivo induction of immune responses to pathogens by conventional dendritic cells. Immunity 29, 343–351 (2008).

    Article  CAS  PubMed  Google Scholar 

  69. Zaba, L. C., Fuentes-Duculan, J., Steinman, R. M., Krueger, J. G. & Lowes, M. A. Normal human dermis contains distinct populations of CD11c+BDCA-1+ dendritic cells and CD163+FXIIIA+ macrophages. J. Clin. Invest. 117, 2517–2525 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Ochoa, M. T., Loncaric, A., Krutzik, S. R., Becker, T. C. & Modlin, R. L. “Dermal dendritic cells” comprise two distinct populations: CD1+ dendritic cells and CD209+ macrophages. J. Invest. Dermatol. 128, 2225–2231 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Nestle, F. O. & Nickoloff, B. J. Deepening our understanding of immune sentinels in the skin. J. Clin. Invest. 117, 2382–2385 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. 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. 151, 6535–6545 (1993).

    CAS  PubMed  Google Scholar 

  73. 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. 92, 2587–2596 (1993). References 72 and 73 provided the first functional characterization of human dermal DCs.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Larregina, A. T. et al. Dermal-resident CD14+ cells differentiate into Langerhans cells. Nature Immunol. 2, 1151–1158 (2001).

    Article  CAS  Google Scholar 

  75. Angel, C. E. et al. CD14+ antigen-presenting cells in human dermis are less mature than their CD1a+ counterparts. Int. Immunol. 19, 1271–1279 (2007).

    Article  CAS  PubMed  Google Scholar 

  76. Boyman, O. et al. Activation of dendritic antigen-presenting cells expressing common heat shock protein receptor CD91 during induction of psoriasis. Br. J. Dermatol. 152, 1211–1218 (2005).

    Article  CAS  PubMed  Google Scholar 

  77. Serbina, N. V., Salazar-Mather, T. P., Biron, C. A., Kuziel, W. A. & Pamer, E. G. TNF/iNOS-producing dendritic cells mediate innate immune defense against bacterial infection. Immunity 19, 59–70 (2003).

    Article  CAS  PubMed  Google Scholar 

  78. Lowes, M. A. et al. Increase in TNF-α and inducible nitric oxide synthase-expressing dendritic cells in psoriasis and reduction with efalizumab (anti-CD11a). Proc. Natl Acad. Sci. USA 102, 19057–19062 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Blanco, P., Palucka, A. K., Gill, M., Pascual, V. & Banchereau, J. Induction of dendritic cell differentiation by IFN-α in systemic lupus erythematosus. Science 294, 1540–1543 (2001).

    Article  CAS  PubMed  Google Scholar 

  80. Nestle, F. O. et al. Plasmacytoid predendritic cells initiate psoriasis through interferon-α production. J. Exp. Med. 202, 135–143 (2005). References 79 and 80 establish the functional role of pDCs and their production of IFNα in the pathogenesis of immune-mediated diseases such as systemic lupus erythematosus and psoriasis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Boyman, O., Conrad, C., Tonel, G., Gilliet, M. & Nestle, F. O. The pathogenic role of tissue-resident immune cells in psoriasis. Trends Immunol. 28, 51–57 (2007).

    Article  PubMed  Google Scholar 

  82. van Furth, R., Nibbering, P. H., van Dissel, J. T. & Diesselhoff-den Dulk, M. M. The characterization, origin, and kinetics of skin macrophages during inflammation. J. Invest. Dermatol. 85, 398–402 (1985).

    Article  CAS  PubMed  Google Scholar 

  83. Clark, R. A. et al. The vast majority of CLA+ T cells are resident in normal skin. J. Immunol. 176, 4431–4439 (2006). This is an important paper showing that normal skin harbours a large number of skin-homing memory T cells, which are 2.8-fold more abundant than T cells circulating in the blood.

    Article  CAS  PubMed  Google Scholar 

  84. Andrew, W. & Andrew, N. V. Lymphocytes in the normal epidermis of the rat and of man. Anat. Rec. 104, 217–241 (1949).

    Article  CAS  PubMed  Google Scholar 

  85. Bos, J. D. et al. The skin immune system (SIS): distribution and immunophenotype of lymphocyte subpopulations in normal human skin. J. Invest. Dermatol. 88, 569–573 (1987).

    Article  CAS  PubMed  Google Scholar 

  86. Foster, C. A. et al. Human epidermal T cells predominantly belong to the lineage expressing alpha/beta T cell receptor. J. Exp. Med. 171, 997–1013 (1990).

    Article  CAS  PubMed  Google Scholar 

  87. Bos, J. D. & Kapsenberg, M. L. The skin immune system: progress in cutaneous biology. Immunol. Today 14, 75–78 (1993).

    Article  CAS  PubMed  Google Scholar 

  88. Mora, J. R. et al. Reciprocal and dynamic control of CD8 T cell homing by dendritic cells from skin- and gut-associated lymphoid tissues. J. Exp. Med. 201, 303–316 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Edele, F. et al. Cutting edge: instructive role of peripheral tissue cells in the imprinting of T cell homing receptor patterns. J. Immunol. 181, 3745–3749 (2008).

    Article  CAS  PubMed  Google Scholar 

  90. Sigmundsdottir, H. & Butcher, E. C. Environmental cues, dendritic cells and the programming of tissue-selective lymphocyte trafficking. Nature Immunol. 9, 981–987 (2008).

    Article  CAS  Google Scholar 

  91. Di Cesare, A., Di Meglio, P. & Nestle, F. O. The IL-23/Th17 axis in immunopathogenesis of psoriasis. J. Invest. Dermatol. 129, 1339–1350 (2009).

    Article  CAS  PubMed  Google Scholar 

  92. Di Cesare, A., Di Meglio, P. & Nestle, F. O. A role for Th17 cells in the immunopathogenesis of atopic dermatitis? J. Invest. Dermatol. 128, 2569–2571 (2008).

    Article  CAS  Google Scholar 

  93. de Beaucoudrey, L. et al. Mutations in STAT3 and IL12RB1 impair the development of human IL-17-producing T cells. J. Exp. Med. 205, 1543–1550 (2008). Studying patients with immune deficiencies, these authors describe IL-12Rβ1- and STAT3-dependent signals as key components of T H 17 cell differentiation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Milner, J. D. et al. Impaired TH17 cell differentiation in subjects with autosomal dominant hyper-IgE syndrome. Nature 452, 773–776 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Eyerich, K. et al. Patients with chronic mucocutaneous candidiasis exhibit reduced production of Th17-associated cytokines IL-17 and IL-22. J. Invest. Dermatol. 128, 2640–2645 (2008).

    Article  CAS  PubMed  Google Scholar 

  96. Duhen, T., Geiger, R., Jarrossay, D., Lanzavecchia, A. & Sallusto, F. Production of interleukin 22 but not interleukin 17 by a subset of human skin-homing memory T cells. Nature Immunol. 10, 857–863 (2009).

    Article  CAS  Google Scholar 

  97. Trifari, S., Kaplan, C. D., Tran, E. H., Crellin, N. K. & Spits, H. Identification of a human helper T cell population that has abundant production of interleukin 22 and is distinct from TH-17, TH1 and TH2 cells. Nature Immunol. 10, 864–871 (2009).

    Article  CAS  Google Scholar 

  98. Nograles, K. E. et al. IL-22-producing “T22” T cells account for upregulated IL-22 in atopic dermatitis despite reduced IL-17-producing TH17 T cells. J. Allergy Clin. Immunol. 123, 1244–1252 (2009). References 96–98 describe T H 22 cells as a skin-homing T H cell population that secretes IL-22 but not IL-17 or IFNγ.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Luster, A. D., Alon, R. & von Andrian, U. H. Immune cell migration in inflammation: present and future therapeutic targets. Nature Immunol. 6, 1182–1190 (2005).

    Article  CAS  Google Scholar 

  100. Kupper, T. S. & Fuhlbrigge, R. C. Immune surveillance in the skin: mechanisms and clinical consequences. Nature Rev. Immunol. 4, 211–222 (2004).

    Article  CAS  Google Scholar 

  101. Boyman, O. et al. Spontaneous development of psoriasis in a new animal model shows an essential role for resident T cells and tumor necrosis factor-α. J. Exp. Med. 199, 731–736 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Conrad, C. et al. α1β1 integrin is crucial for accumulation of epidermal T cells and the development of psoriasis. Nature Med. 13, 836–842 (2007). References 101 and 102 both use a new psoriasis xenotransplantation model to show evidence for a functional role of tissue-resident T cells in the pathogenesis of psoriasis. They also identify the binding of VLA1 on T cells to collagen IV as a key checkpoint for T cell entry into the epidermis during inflammation.

    Article  CAS  PubMed  Google Scholar 

  103. 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 

  104. Gebhardt, T. et al. Memory T cells in nonlymphoid tissue that provide enhanced local immunity during infection with herpes simplex virus. Nature Immunol. 10, 524–530 (2009). Using an HSV infection model, this paper describes a unique and protective skin-resident memory T cell subset, supporting a role of tissue-resident T cells in the memory response to infection.

    Article  CAS  Google Scholar 

  105. Woodland, D. L. & Kohlmeier, J. E. Migration, maintenance and recall of memory T cells in peripheral tissues. Nature Rev. Immunol. 9, 153–161 (2009).

    Article  CAS  Google Scholar 

  106. Hayday, A. & Tigelaar, R. Immunoregulation in the tissues by γδ T cells. Nature Rev. Immunol. 3, 233–242 (2003).

    Article  CAS  Google Scholar 

  107. Kronenberg, M. Toward an understanding of NKT cell biology: progress and paradoxes. Annu. Rev. Immunol. 23, 877–900 (2005).

    Article  CAS  PubMed  Google Scholar 

  108. Bergstresser, P. R., Sullivan, S., Streilein, J. W. & Tigelaar, R. E. Origin and function of Thy-1+ dendritic epidermal cells in mice. J. Invest. Dermatol. 85, 85S–90S (1985).

  109. Girardi, M. Immunosurveillance and immunoregulation by γδ T cells. J. Invest. Dermatol. 126, 25–31 (2006).

    Article  CAS  PubMed  Google Scholar 

  110. Boyden, L. M. et al. Skint1, the prototype of a newly identified immunoglobulin superfamily gene cluster, positively selects epidermal γδ T cells. Nature Genet. 40, 656–662 (2008).

    Article  CAS  PubMed  Google Scholar 

  111. Strid, J., Tigelaar, R. E. & Hayday, A. C. Skin immune surveillance by T cells — a new order? Semin. Immunol. 21, 110–120 (2009).

    Article  CAS  PubMed  Google Scholar 

  112. Girardi, M. et al. Regulation of cutaneous malignancy by γδ T cells. Science 294, 605–609 (2001).

    Article  CAS  PubMed  Google Scholar 

  113. Girardi, M. et al. Resident skin-specific γδ T cells provide local, nonredundant regulation of cutaneous inflammation. J. Exp. Med. 195, 855–867 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Roberts, S. J. et al. Characterizing tumor-promoting T cells in chemically induced cutaneous carcinogenesis. Proc. Natl Acad. Sci. USA 104, 6770–6775 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Holtmeier, W. & Kabelitz, D. γδ T cells link innate and adaptive immune responses. Chem. Immunol. Allergy 86, 151–183 (2005).

    Article  CAS  PubMed  Google Scholar 

  116. Toulon, A. et al. A role for human skin-resident T cells in wound healing. J. Exp. Med. 206, 743–750 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Agerberth, B. et al. The human antimicrobial and chemotactic peptides LL-37 and α-defensins are expressed by specific lymphocyte and monocyte populations. Blood 96, 3086–3093 (2000).

    CAS  PubMed  Google Scholar 

  118. Nickoloff, B. J. Skin innate immune system in psoriasis: friend or foe? J. Clin. Invest. 104, 1161–1164 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Nickoloff, B. J., Bonish, B., Huang, B. B. & Porcelli, S. A. Characterization of a T cell line bearing natural killer receptors and capable of creating psoriasis in a SCID mouse model system. J. Dermatol. Sci. 24, 212–225 (2000).

    Article  CAS  PubMed  Google Scholar 

  120. Bonish, B. et al. Overexpression of CD1d by keratinocytes in psoriasis and CD1d-dependent IFN-γ production by NK-T cells. J. Immunol. 165, 4076–4085 (2000).

    Article  CAS  PubMed  Google Scholar 

  121. Gober, M. D., Fishelevich, R., Zhao, Y., Unutmaz, D. & Gaspari, A. A. Human natural killer T cells infiltrate into the skin at elicitation sites of allergic contact dermatitis. J. Invest. Dermatol. 128, 1460–1469 (2008).

    Article  CAS  PubMed  Google Scholar 

  122. Gorbachev, A. V. & Fairchild, R. L. Activated NKT cells increase dendritic cell migration and enhance CD8+ T cell responses in the skin. Eur. J. Immunol. 36, 2494–2503 (2006).

    Article  CAS  PubMed  Google Scholar 

  123. Grabbe, S. & Schwarz, T. Immunoregulatory mechanisms involved in elicitation of allergic contact hypersensitivity. Immunol. Today 19, 37–44 (1998).

    Article  CAS  PubMed  Google Scholar 

  124. Gober, M. D. & Gaspari, A. A. Allergic contact dermatitis. Curr. Dir. Autoimmun. 10, 1–26 (2008).

    Article  CAS  PubMed  Google Scholar 

  125. Lonsdorf, A. S. & Enk, A. H. Immunologie des allergischen kontaktekzems. Hautarzt 60, 32–41 (2009) (in German).

    Article  CAS  PubMed  Google Scholar 

  126. Martin, S. F. & Jakob, T. From innate to adaptive immune responses in contact hypersensitivity. Curr. Opin. Allergy Clin. Immunol. 8, 289–293 (2008).

    Article  CAS  PubMed  Google Scholar 

  127. Nestle, F. O., Kaplan, D. H. & Barker, J. Psoriasis. N. Engl. J. Med. 361, 496–509 (2009).

    Article  CAS  PubMed  Google Scholar 

  128. Ellis, C. N. et al. Cyclosporine improves psoriasis in a double-blind study. JAMA 256, 3110–3116 (1986).

    Article  CAS  PubMed  Google Scholar 

  129. Prinz, J. C. et al. Selection of conserved TCR VDJ rearrangements in chronic psoriatic plaques indicates a common antigen in psoriasis vulgaris. Eur. J. Immunol. 29, 3360–3368 (1999).

    Article  CAS  PubMed  Google Scholar 

  130. Austin, L. M., Ozawa, M., Kikuchi, T., Walters, I. B. & Krueger, J. G. The majority of epidermal T cells in Psoriasis vulgaris lesions can produce type 1 cytokines, interferon-γ, interleukin-2, and tumor necrosis factor-α, defining TC1 (cytotoxic T lymphocyte) and TH1 effector populations: a type 1 differentiation bias is also measured in circulating blood T cells in psoriatic patients. J. Invest. Dermatol. 113, 752–759 (1999).

    Article  CAS  PubMed  Google Scholar 

  131. Valdimarsson, H., Baker, B. S., Jonsdottir, I., Powles, A. & Fry, L. Psoriasis: a T-cell-mediated autoimmune disease induced by streptococcal superantigens? Immunol. Today 16, 145–149 (1995).

    Article  CAS  PubMed  Google Scholar 

  132. Lowes, M. A., Bowcock, A. M. & Krueger, J. G. Pathogenesis and therapy of psoriasis. Nature 445, 866–873 (2007).

    Article  CAS  PubMed  Google Scholar 

  133. Capon, F., Munro, M., Barker, J. & Trembath, R. Searching for the major histocompatibility complex psoriasis susceptibility gene. J. Invest. Dermatol. 118, 745–751 (2002).

    Article  CAS  PubMed  Google Scholar 

  134. de Cid, R. et al. Deletion of the late cornified envelope LCE3B and LCE3C genes as a susceptibility factor for psoriasis. Nature Genet. 41, 211–215 (2009).

    Article  CAS  PubMed  Google Scholar 

  135. Nair, R. P. et al. Genome-wide scan reveals association of psoriasis with IL-23 and NF-κB pathways. Nature Genet. 41, 199–204 (2009). A comprehensive whole-genome scan of psoriasis confirming association with gene variants in the IL-23 pathway and pointing towards new gene variants involved in the NF-κB pathway.

    Article  CAS  PubMed  Google Scholar 

  136. Cargill, M. et al. A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes. Am. J. Hum. Genet. 80, 273–290 (2007).

    Article  CAS  PubMed  Google Scholar 

  137. Capon, F. et al. Sequence variants in the genes for the interleukin-23 receptor (IL23R) and its ligand (IL12B) confer protection against psoriasis. Hum. Genet. 122, 201–206 (2007). References 136 and 137 are the first description of an association of psoriasis with IL23R gene variants in whole-genome association studies.

    Article  CAS  PubMed  Google Scholar 

  138. van der Fits, L. et al. Imiquimod-induced psoriasis-like skin inflammation in mice is mediated via the IL-23/IL-17 axis. J. Immunol. 182, 5836–5845 (2009).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We apologize to all the authors whose work could not be discussed and cited owing to space limitations. We thank R. Trembath, A. Hayday, J. Barker and F. Geissmann for discussions. We acknowledge support by the following grant funding bodies: Wellcome Trust Programme GR078173MA, National Institute of Health RO1AR040065, National Insitute for Health Research Comprehensive Biomedical Research Centre at Guy's and St. Thomas' Hospital and King's College London, Medical Research Council UK Programme G0601387, and Dunhill Medical Trust.

Author information

Authors and Affiliations

  1. St. John's Institute of Dermatology, King's College London; The National Institute for Health Research (NIHR) Biomedical Research Centre; and The Federation of Clinical Immunology (FOCIS) Centre of Excellence, King's College London, Floor 9 Tower Wing, Guy's Hospital,

    Frank O. Nestle & Paola Di Meglio

  2. The National Institute for Health Research (NIHR) Biomedical Research Centre, London, SE1 9RT, UK

    Frank O. Nestle & Paola Di Meglio

  3. Department of Pathology, Cardinal Bernardin Cancer Center, Loyola University Medical Center, Maywood, 60153, Illinois, USA

    Jian-Zhong Qin & Brian J. Nickoloff

Authors
  1. Frank O. Nestle
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Paola Di Meglio
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jian-Zhong Qin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Brian J. Nickoloff
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Frank O. Nestle.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

FURTHER INFORMATION

Frank O. Nestle's homepage

Glossary

Langerhans cell

A type of dendritic cell that is resident in the epidermal layer of the skin.

Keratinocytes

The major cell type of the epidermis, constituting more than 90% of epidermal cells. Keratinocytes form an effective barrier against the entry of foreign matter and infectious agents into the body and minimize moisture loss.

γδ T cells

T cells that express heterodimers consisting of the γ- and δ-chains of the T cell receptor (TCR). They enter tissues such as the gut and skin without priming in lymphoid tissues, express limited or invariant TCRs and display a 'pseudo-memory' T cell phenotype allowing them to respond rapidly to antigen challenge.

Hapten

A molecule that can bind antibody but is thought not to elicit an immune response itself. Antibodies that are specific for a hapten can be generated when the hapten is chemically linked to a protein carrier that can elicit a T cell response.

Allergic contact dermatitis

A cutaneous inflammatory condition caused by a T cell-mediated hypersensitivity to defined allergens.

β-defensins and cathelicidins

Members of a family of small antimicrobial polypeptides that are abundant in neutrophils and epithelial cells. They contribute to host defence by disrupting the cytoplasmic membrane of microorganisms such as Escherichia coli or Candida albicans.

Tolerance

Denotes lymphocyte non-responsiveness to antigen, but implies an active process, not simply a passive lack of response.

LL37

A member of the cathelicidin family of antimicrobial peptides. LL37 has been proposed to have a specific role in psoriasis pathogenesis, contributing to breaking the tolerance to self DNA.

Graft-versus-host disease

(GVHD). A disease that results from donor allogeneic T cells that are transferred along with an allograft (such as a bone marrow, liver or gut allograft) attacking target recipient organs or tissues (such as the skin or gut). GVHD occurs in graft recipients that cannot eliminate the host-reactive donor T cells owing to immunosuppression, immunological immaturity or tolerance.

T cell anergy

A state of T cell unresponsiveness to stimulation with antigen. It can be induced by stimulation with a large amount of specific antigen in the absence of the engagement of co-stimulatory molecules.

Plasmacytoid DC

A dendritic cell (DC) that lacks myeloid markers such as CD11c and CD33 but expresses high levels of HLA-DR and CD123. These cells produce high levels of type I interferon after activation (for example, when stimulated through Toll-like receptors).

Cross-presentation

The initiation of a CD8+ T cell response to an antigen that is not present within antigen-presenting cells (APCs). This exogenous antigen must be taken up by APCs and then re-routed to the MHC class I pathway of antigen presentation.

Birbeck granules

Membrane-bound rod- or tennis racket-shaped structures with a central linear density, found in the cytoplasm of Langerhans cells. Their formation is induced by langerin.

Contact hypersensitivity

The inflammatory reaction that occurs after the first exposure to a 'sensitizer' hapten or antigen. This step requires dendritic cell migration to lymph nodes to prime contact-antigen-specific T cells.

Langerhans cell-deficient mice

Two main Langerhans cell-deficient mouse models have been developed using diphtheria toxin ablation. One model, in which diphtheria toxin receptor is constitutively expressed under the control of the human langerin promoter, shows selective depletion of langerin+ epidermal Langerhans cells. The other model, which uses the mouse langerin promoter, displays conditional depletion of all langerin+ DCs, including Langerhans cells in the epidermis, langerin+ DCs in the dermis and langerin+ DCs in lymph nodes.

Alternatively activated macrophage

A macrophage stimulated by interleukin-4 (IL-4) or IL-13 that expresses arginase 1, mannose receptor CD206 and IL-4 receptor-α. There may be pathogen-associated molecular patterns expressed by helminths that can also drive alternative activation of macrophages.

Invariant NKT cell

A cell type thought to be particularly important in bridging innate and adaptive immunity. iNKT cells are typified by a capacity for self-recognition and rapid release of cytokines such as interferon-γ.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Nestle, F., Di Meglio, P., Qin, JZ. et al. Skin immune sentinels in health and disease. Nat Rev Immunol 9, 679–691 (2009). https://doi.org/10.1038/nri2622

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nri2622

This article is cited by

Search

Advanced 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