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Skin immune sentinels in health and disease

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.

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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.

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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.

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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.

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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

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