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The origins and functions of dendritic cells and macrophages in the skin

Key Points

  • Differential expression of CD64, CC-chemokine receptor 2 and the tyrosine protein kinase MER (MERTK) enables the complexity of mononuclear phagocytes in mouse skin to be resolved. XC-chemokine receptor 1 (XCR1)+CD11b conventional dendritic cells (cDCs), CD11b+ cDCs, Langerhans cells (LCs), monocyte-derived DCs and macrophages can be readily distinguished on the basis of the expression of these markers.

  • The study of transcriptomic signatures, and of migratory and T cell-stimulatory properties, has unravelled the functional specialization that exists among skin antigen-presenting cell (APC) types.

  • The ability to migrate to the lymph nodes so as to interact with naive T cells remains a cardinal feature of epidermal LCs and dermal cDCs. By contrast, the macrophages and monocyte-derived DCs of the healthy dermis are unable to migrate to the lymph nodes and thus exert their functions in the dermis.

  • Whereas macrophages are primarily endowed with phagocytic and anti-inflammatory properties, the T cell-stimulatory capacity of dermal monocyte-derived DCs indicates that they might contribute to the maintenance of the many T cell types that are found in healthy dermis.

  • The different APC types that are found in the skin do not contribute equally to the establishment of inflammatory skin diseases and further knowledge of their relative contributions will be essential for improving current therapeutic approaches.

  • The DC and macrophage subsets that have been identified in the mouse skin can be aligned with functionally equivalent human subsets, which will inform the translation of knowledge from mouse models to human settings.

Abstract

Immune cell populations in the skin are predominantly comprised of dendritic cells (DCs) and macrophages. A lack of consensus regarding how to define these cell types has hampered research in this area. In this Review, we focus on recent advances that, based on ontogeny and global gene-expression profiles, have succeeded in discriminating DCs from macrophages in the skin. We discuss how these studies have enabled researchers to revisit the origin, diversity and T cell-stimulatory properties of these cells, and have led to unifying principles that extend across tissues and species. By aligning the DC and macrophage subsets that are found in mouse skin with those that are present in human skin, these studies also provide crucial information for developing intradermal vaccines and for managing inflammatory skin conditions.

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Figure 1: Antigen-presenting cell populations of the healthy skin.
Figure 2: Subsets of skin dendritic cells and macrophages.
Figure 3: Origin of dermal macrophages.

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Acknowledgements

The authors thank M. Dalod, M. Guilliams, A. Mowat, H. Luche and D. Terhorst for their helpful discussions. B.M. is supported by Centre National de la Recherche Scientifique (CNRS), France, the Enhanced Epidermal Antigen Specific Immunotherapy (EE-ASI) European Collaborative Research Project and a European Research Council Advanced Grant ('Integrate' Project). S.T. is supported by the NANOASIT EuroNanoMed Project, France. S.H. is supported by the Institut National de la Santé et de la Recherche Médicale (INSERM), France, the Agence Nationale de la Recherche (ANR; SkinDC Project) and the EE-ASI European Collaborative Research Project.

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Glossary

Stratum corneum

The outermost layer of the epidermis, which consists of dead keratinocytes.

Mononuclear phagocyte system

A subgroup of leukocytes that comprises monocytes, macrophages and dendritic cells.

Contact hypersensitivity

Hapten-specific T cell-mediated skin inflammation that is induced by painting a hapten onto the skin. During the sensitization phase, hapten-bearing skin dendritic cells migrate to the lymph nodes where they induce hapten-specific T cells. Re-exposure to the same hapten results in the activation of the specific T cells in the dermis, which triggers the inflammatory process that is responsible for the cutaneous lesion.

Transcriptomic signature

The complete set of RNA transcripts that is produced by a given cell type at any one time.

Autofluorescent

Some cells contain molecules that become fluorescent when excited by radiation of suitable wavelength. This autofluorescence arises from endogenous fluorophores and differs from fluorescent signals that are obtained after adding antibodies that are conjugated to fluorophores.

Kupffer cells

Specialized macrophages located in the liver that line the walls of the sinusoids.

Microglia

Resident macrophages of the brain and spinal cord.

Incomplete Freund's adjuvant

A solution prepared from non-metabolizable oils that is the most commonly used adjuvant in research.

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Malissen, B., Tamoutounour, S. & Henri, S. The origins and functions of dendritic cells and macrophages in the skin. Nat Rev Immunol 14, 417–428 (2014). https://doi.org/10.1038/nri3683

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