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Origin, homeostasis and function of Langerhans cells and other langerin-expressing dendritic cells

Key Points

  • In contrast to most dendritic-cell populations, Langerhans cells repopulate locally throughout life in the steady state, independently of any input from the blood circulation.

  • In contrast to quiescent skin, in major inflammatory skin injuries (such as exposure to ultraviolet B radiation) Langerhans cells are replaced by circulating monocytes.

  • Langerhans cells repopulate locally after a lethal dose of radiation and remain of host origin following congenic bone-marrow transplantation. By contrast, following allogeneic bone-marrow transplantation, cutaneous graft-versus-host disease occurs and leads to the elimination of recipient Langerhans cells and their replacement with donor-derived cells.

  • Langerhans cells are absent in mice that lack the macrophage colony-stimulating factor (M-CSF) receptor but remain unaffected in mice that lack the receptor for FMS-like-tyrosine-kinase 3 ligand (FLT3).

  • Langerin is not uniquely expressed by Langerhans cells in the skin, but is also expressed by dendritic cells in stratified epithelial surfaces and by a subset of dendritic cells that is present in most connective tissues, including the dermis, lung, kidney and liver. Langerin+ dendritic cells can be distinguished from Langerhans cells based on the expression of the integrin CD103 and the low expression of CD11b.

Abstract

Langerhans cells (LCs) are a specialized subset of dendritic cells (DCs) that populate the epidermal layer of the skin. Langerin is a lectin that serves as a valuable marker for LCs in mice and humans. In recent years, new mouse models have led to the identification of other langerin+ DC subsets that are not present in the epidermis, including a subset of DCs that is found in most non-lymphoid tissues. In this Review we describe new developments in the understanding of the biology of LCs and other langerin+ DCs and discuss the challenges that remain in identifying the role of different DC subsets in tissue immunity.

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Figure 1: Phenotype of antigen-presenting cells in quiescent skin in mice.
Figure 2: Homeostasis of dermal langerin+ dendritic cells in quiescent skin.
Figure 3: Homeostasis of dermal langerin+ dendritic cells in inflamed skin.

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Acknowledgements

We are grateful to R. Steinman, N. Romani, M. Udey and J. Helft for the critical review of the manuscript. We thank P. and E. Kontoyannis for their continuous support of Langerhans and Langerhans-cell histiocytosis research. We apologize to the colleagues whose work we have failed to cite owing to space limitations. M.M. is supported by the National Institutes of Health (grant numbers R01CA1121100 and R01AI0086899). F.G. is supported by the leukemia and the lymphoma research foundation.

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Glossary

Langerhans cells

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

Single-nucleotide polymorphism

(SNP). A variation in DNA sequence in which one of the four nucleotides is substituted for another (for example, C for A). SNPs are the most frequent type of polymorphism in the genome.

Keratinocyte

The main cell type of the epidermis, which represents 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 cell

A T cell that expresses the γδ T-cell receptor. γδ T cells are present in the skin, vagina and intestinal epithelium as intraepithelial lymphocytes. Although the exact function of γδ T cells is unknown, it has been suggested that mucosal γδ T cells are involved in innate immune responses.

Birbeck granules

Granules that consist of superimposed membranes separated by repetitive zipper-like striations and contain a vesicle at one end of the membrane, which gives the granules its typical tennis-racquet shape15,16. Although the function of Birbeck granules is poorly understood, they might function in antigen presentation, as langerin was shown to route antigens from the cell surface to these structures.

C-type lectin receptor

A receptor that binds glycosylated ligands and has many roles, such as in cell adhesion, endocytosis, natural-killer-cell target recognition and dendritic-cell activation.

Bromodeoxyuridine labelling

(BrdU labelling). A technique in which dividing cells that have been exposed to BrdU incorporate it into their DNA. These cells can be identified by intracellular staining with antibodies that are specific for BrdU. Non-dividing cells do not incorporate BrdU.

Congenic mice

Syngeneic mice that differ only at a single locus. Most studies in this Review have used mice that express a different isoform of the CD45 gene (Cd45.1 and Cd45.2). This CD45 protein is expressed by all haematopoietic cells, allowing to trace the donor-derived haematopoiesis in the recipient mouse.

Graft-versus-host disease

(GVHD). Tissue damage in a recipient of allogeneic tissue (usually a bone-marrow transplant) that results from the activity of donor cytotoxic T cells recognizing the tissues of the recipient as foreign. GVHD varies markedly in its extent, but it can be life threatening in severe cases. Damage to the liver, skin and gut mucosa are common clinical manifestations.

Pattern-recognition receptor

A host receptor (such as a Toll-like receptor) that can sense pathogen-associated molecular patterns and initiate signalling cascades (which involve the activation of nuclear factor-κB) that lead to an innate immune response.

Peyer's patches

Collections of lymphoid tissue that are located in the mucosa of the small intestine, and have an outer epithelial-cell layer consisting of specialized epithelial cells called M cells.

Cross-present

The ability of certain antigen-presenting cells to load peptides that are derived from exogenous antigens onto MHC class I molecules. This property is atypical, because most cells exclusively present peptides from their endogenous proteins on MHC class I molecules. Cross-presentation is essential for the initiation of immune responses to viruses that do not infect antigen-presenting cells.

Follicular T-helper cell

A T helper cell that is essential in determining B-cell antibody class switching.

Contact-hypersensitivity response

A disease in which the contact allergens, which are co-applied with a suboptimal dose of haptens, are thought to activate an innate immune response that is important in the recruitment of hapten-specific T cells to the skin and the induction of the clinical symptoms.

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Merad, M., Ginhoux, F. & Collin, M. Origin, homeostasis and function of Langerhans cells and other langerin-expressing dendritic cells. Nat Rev Immunol 8, 935–947 (2008). https://doi.org/10.1038/nri2455

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