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.
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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Banchereau, J. & Steinman, R. M. Dendritic cells and the control of immunity. Nature 392, 245–252 (1998).
Valladeau, J. et al. Langerin, a novel C-type lectin specific to Langerhans cells, is an endocytic receptor that induces the formation of Birbeck granules. Immunity 12, 71–81 (2000). This paper was the first to identify langerin on the surface of human LCs and to show that langerin induces the formation of Birbeck granules.
Turville, S. G. et al. Diversity of receptors binding HIV on dendritic cell subsets. Nature Immunol. 3, 975–983 (2002).
de Witte, L. et al. Langerin is a natural barrier to HIV-1 transmission by Langerhans cells. Nature Med. 13, 367–371 (2007). This study reveals that langerin leads to HIV-1 degradation.
Ginhoux, F. et al. Blood-derived dermal langerin+ dendritic cells survey the skin in the steady state. J. Exp. Med. 204, 3133–3146 (2007). Together with references 6 and 7, this paper reports the presence of langerin+ DCs in the skin that develop and function independently of LCs.
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).
Bursch, L. S. et al. Identification of a novel population of Langerin+ dendritic cells. J. Exp. Med. 204, 3147–3156 (2007).
Wang, L. et al. Langerin expressing cells promote skin immune responses under defined conditions. J. Immunol. 180, 4722–4727 (2008).
Ginhoux, F. et al. Langerhans cells arise from monocytes in vivo. Nature Immunol. 7, 265–273 (2006). The first demonstration that LCs are absent in Mcsfr−/− mice and that monocytes repopulate LCs in inflamed skin in vivo in mice.
Langerhans, P. Uber die Nerven der menschlichen Haut. Virchows. Arch. Pathol. 44, 325–337 (1868). In this paper, entitled “On the nerves of the human skin”, Paul Langerhans reported for the first time the presence of large cells with long dendrites in the epidermis of human skin.
Stingl, G., Tamaki, K. & Katz, S. I. Origin and function of epidermal Langerhans cells. Immunol. Rev. 53, 149–174 (1980).
Schuler, G. et al. Murine epidermal Langerhans cells as a model to study tissue dendritic cells. Adv. Exp. Med. Biol. 329, 243–249 (1993).
Valladeau, J. & Saeland, S. Cutaneous dendritic cells. Semin. Immunol. 17, 273–283 (2005).
Tigelaar, R. E., Lewis, J. M. & Bergstresser, P. R. TCR γ/δ+ dendritic epidermal T cells as constituents of skin-associated lymphoid tissue. J. Invest. Dermatol. 94, 58S–63S (1990).
Birbeck, M. D., Breathnach, A. S. & Everall, J. D. An electron microscope study of basal melanocytes and high-level clear cells (langerhans cells) in vitiligo. J. Invest. Dermatol. 37, 51 (1961). This is the first description of the presence of the conspiscuous Birbeck granules in Langerhans cells.
Wolff, K. The fine structure of the Langerhans cell granule. J. Cell Biol. 35, 468–473 (1967).
Tang, A., Amagai, M., Granger, L. G., Stanley, J. R. & Udey, M. C. Adhesion of epidermal Langerhans cells to keratinocytes mediated by E-cadherin. Nature 361, 82–85 (1993).
Cepek, K. L. et al. Adhesion between epithelial cells and T lymphocytes mediated by E-cadherin and the αEβ7 integrin. Nature 372, 190–193 (1994). This study reports for the first time that the integrin CD103 (also known as α E -integrin, part of the α E b 7 -integrin heterodimer) expressed on the cell surface of T cells can bind the adhesion molecule E-cadherin on epithelial cells.
Borkowski, T. A., Letterio, J. J., Farr, A. G. & Udey, M. C. A role for endogenous transforming growth factor β1 in Langerhans cell biology: the skin of transforming growth factor β1 null mice is devoid of epidermal Langerhans cells. J. Exp. Med. 184, 2417–2422 (1996). This study is the first demonstration that TGFβ1 is crucial for LC development in vivo.
Inaba, K. et al. Tissue distribution of the DEC-205 protein that is detected by the monoclonal antibody NLDC-145. I. Expression on dendritic cells and other subsets of mouse leukocytes. Cell. Immunol. 163, 148–156 (1995).
Jiang, W. et al. The receptor DEC-205 expressed by dendritic cells and thymic epithelial cells is involved in antigen processing. Nature 375, 151–155 (1995).
Fithian, E. et al. Reactivity of Langerhans cells with hybridoma antibody. Proc. Natl Acad. Sci. USA 78, 2541–2544 (1981).
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).
Ronger-Savle, S. et al. TGFβ inhibits CD1d expression on dendritic cells. J. Invest. Dermatol. 124, 116–118 (2005).
Mc Dermott, R. et al. Birbeck granules are subdomains of endosomal recycling compartment in human epidermal Langerhans cells, which form where langerin accumulates. Mol. Biol. Cell 13, 317–335 (2002).
Valladeau, J. et al. Identification of mouse langerin/CD207 in Langerhans cells and some dendritic cells of lymphoid tissues. J. Immunol. 168, 782–792 (2002).
Takahara, K. et al. Identification and expression of mouse Langerin (CD207) in dendritic cells. Int. Immunol. 14, 433–444 (2002).
Kissenpfennig, A. et al. Disruption of the langerin/CD207 gene abolishes Birbeck granules without a marked loss of Langerhans cell function. Mol. Cell Biol. 25, 88–99 (2005).
Verdijk, P. et al. A lack of Birbeck granules in Langerhans cells is associated with a naturally occurring point mutation in the human Langerin gene. J. Invest. Dermatol. 124, 714–717 (2005).
Kelly, R. H., Balfour, B. M., Armstrong, J. A. & Griffiths, S. Functional anatomy of lymph nodes. II. Peripheral lymph-borne mononuclear cells. Anat. Rec. 190, 5–21 (1978). This is one of the first studies to show the presence of veiled (dendritic) cells in lymphatic vessels.
Drexhage, H. A., Mullink, H., de Groot, J., Clarke, J. & Balfour, B. M. A study of cells present in peripheral lymph of pigs with special reference to a type of cell resembling the Langerhans cell. Cell Tissue Res. 202, 407–430 (1979).
Hemmi, H. et al. Skin antigens in the steady state are trafficked to regional lymph nodes by transforming growth factor-β-dependent cells. Int. Immunol. 13, 695–704 (2001).
Stoitzner, P., Tripp, C. H., Douillard, P., Saeland, S. & Romani, N. Migratory Langerhans cells in mouse lymph nodes in steady state and inflammation. J. Invest. Dermatol. 125, 116–125 (2005).
Macatonia, S. E., Knight, S. C., Edwards, A. J., Griffiths, S. & Fryer, P. Localization of antigen on lymph node dendritic cells after exposure to the contact sensitizer fluorescein isothiocyanate. Functional and morphological studies. J. Exp. Med. 166, 1654–1667 (1987).
Randolph, G. J., Ochando, J. & Partida-Sanchez, S. Migration of dendritic cell subsets and their precursors. Annu. Rev. Immunol. 26, 293–316 (2008).
Larsen, C. P. et al. Migration and maturation of Langerhans cells in skin transplants and explants. J. Exp. Med. 172, 1483–1493 (1990).
Pierre, P. et al. Developmental regulation of MHC class II transport in mouse dendritic cells. Nature 388, 787–792 (1997).
Ruedl, C., Koebel, P., Bachmann, M., Hess, M. & Karjalainen, K. Anatomical origin of dendritic cells determines their life span in peripheral lymph nodes. J. Immunol. 165, 4910–4916 (2000).
Ohl, L. et al. CCR7 governs skin dendritic cell migration under inflammatory and steady-state conditions. Immunity 21, 279–288 (2004). This is the first paper to identify the crucial role of CCR7 in skin-DC migration to the draining lymph nodes.
Jakob, T., Ring, J. & Udey, M. C. Multistep navigation of Langerhans/dendritic cells in and out of the skin. J. Allergy Clin. Immunol. 108, 688–696 (2001).
Inaba, K. et al. High levels of a major histocompatibility complex II–self peptide complex on dendritic cells from the T cell areas of lymph nodes. J. Exp. Med. 186, 665–672 (1997).
Katz, S. I., Tamaki, K. & Sachs, D. H. Epidermal Langerhans cells are derived from cells originating in bone marrow. Nature 282, 324–326 (1979).
Frelinger, J. G., Hood, L., Hill, S. & Frelinger, J. A. Mouse epidermal Ia molecules have a bone marrow origin. Nature 282, 321–323 (1979). References 42 and 43 were the two first studies to show the haematopoietic origin of LCs.
Merad, M. et al. Langerhans cells renew in the skin throughout life under steady-state conditions. Nature Immunol. 3, 1135–1141 (2002). This is the first paper to describe how LCs replenish in situ in the steady state but are repopulated by blood precursor cells during skin injury. This paper also describes for the first time that LC repopulation in inflamed skin depends on CCR2.
Iijima, N., Linehan, M. M., Saeland, S. & Iwasaki, A. Vaginal epithelial dendritic cells renew from bone marrow precursors. Proc. Natl Acad. Sci. USA 104, 19061–19066 (2007).
Holt, P. G., Haining, S., Nelson, D. J. & Sedgwick, J. D. Origin and steady-state turnover of class II MHC-bearing dendritic cells in the epithelium of the conducting airways. J. Immunol. 153, 256–261 (1994).
Liu, K. et al. Origin of dendritic cells in peripheral lymphoid organs of mice. Nature Immunol. 8, 578–583 (2007). This study shows that DCs cycle in situ in lymphoid organs but are maintained by circulating precursor cells.
Merad, M. et al. Depletion of host Langerhans cells before transplantation of donor alloreactive T cells prevents skin graft-versus-host disease. Nature Med. 10, 510–517 (2004).
Vishwanath, M. et al. Development of intravital intermittent confocal imaging system for studying Langerhans cell turnover. J. Invest. Dermatol. 126, 2452–2457 (2006).
Kamath, A. T., Henri, S., Battye, F., Tough, D. F. & Shortman, K. Developmental kinetics and lifespan of dendritic cells in mouse lymphoid organs. Blood 100, 1734–1741 (2002).
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).
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). References 51 and 52 were the first two papers to describe the langerin–DTR mice.
Jung, S. et al. In vivo depletion of CD11c+ dendritic cells abrogates priming of CD8+ T cells by exogenous cell-associated antigens. Immunity 17, 211–220 (2002). This is the first study demonstrating that elimination of DCs in vivo abrogates priming of CD8+ T cells against systemic pathogen infection.
Czernielewski, J., Vaigot, P. & Prunieras, M. Epidermal Langerhans cells — a cycling cell population. J. Invest. Dermatol. 84, 424–426 (1985). The first study to report that LCs cycle in situ.
Czernielewski, J. M. & Demarchez, M. Further evidence for the self-reproducing capacity of Langerhans cells in human skin. J. Invest. Dermatol. 88, 17–20 (1987).
Giacometti, L. & Montagna, W. Langerhans cells: uptake of tritiated thymidine. Science 157, 439–440 (1967).
Krueger, G. G., Daynes, R. A. & Emam, M. Biology of Langerhans cells: selective migration of Langerhans cells into allogeneic and xenogeneic grafts on nude mice. Proc. Natl Acad. Sci. USA 80, 1650–1654 (1983).
Kanitakis, J., Petruzzo, P. & Dubernard, J. M. Turnover of epidermal Langerhans' cells. N. Engl. J. Med. 351, 2661–2662 (2004). A study showing that in one patient that received a limb graft, LCs remained of host origin and were not replaced by blood-derived precursor cells for over 1 year after transplant.
Collin, M. P. et al. The fate of human Langerhans cells in hematopoietic stem cell transplantation. J. Exp. Med. 203, 27–33 (2006). This study shows that, in the absence of graft-versus-host disease, host LCs can remain in the skin despite complete donor-derived chimerism in the blood.
Collin, M. P., Bogunovic, M. & Merad, M. DC homeostasis in hematopoietic stem cell transplantation. Cytotherapy 9, 521–531 (2007).
Miyauchi, S. & Hashimoto, K. Epidermal Langerhans cells undergo mitosis during the early recovery phase after ultraviolet-B irradiation. J. Invest. Dermatol. 88, 703–708 (1987).
Kumamoto, T. et al. Hair follicles serve as local reservoirs of skin mast cell precursors. Blood 102, 1654–1660 (2003). This is the first demonstration that the hair follicle is also a reservoir for the mast-cell precursor.
Blanpain, C. & Fuchs, E. Epidermal stem cells of the skin. Annu. Rev. Cell Dev. Biol. 22, 339–373 (2006).
Gilliam, A. C. et al. The human hair follicle: a reservoir of CD40+ B7-deficient Langerhans cells that repopulate epidermis after UVB exposure. J. Invest. Dermatol. 110, 422–427 (1998). This study shows that after exposure to ultraviolet B radiation that depletes epidermal LCs but does not affect the hair follicle, LCs are repopulated from the hair follicle.
Bennett, C. L., Noordegraaf, M., Martina, C. A. & Clausen, B. E. Langerhans cells are required for efficient presentation of topically applied hapten to T cells. J. Immunol. 179, 6830–6835 (2007). This is one of the first demonstrations that LCs are required to initiate T-cell priming against topical antigens.
Kaplan, D. H. et al. Autocrine/paracrine TGFβ1 is required for the development of epidermal Langerhans cells. J. Exp. Med. 204, 2545–2552 (2007). This study shows that autocrine TGFβ1 is required for LC development.
Strobl, H. et al. TGF-β 1 promotes in vitro development of dendritic cells from CD34+ hemopoietic progenitors. J. Immunol. 157, 1499–1507 (1996).
Geissmann, F. et al. Transforming growth factor β1, in the presence of granulocyte/macrophage colony-stimulating factor and interleukin 4, induces differentiation of human peripheral blood monocytes into dendritic Langerhans cells. J. Exp. Med. 187, 961–966 (1998). This is the first demonstration that human monocytes can differentiate into LCs in vitro.
Hacker, C. et al. Transcriptional profiling identifies Id2 function in dendritic cell development. Nature Immunol. 4, 380–386 (2003). This is the first demonstration that ID2 is required for LC development.
Fainaru, O. et al. Runx3 regulates mouse TGF-β-mediated dendritic cell function and its absence results in airway inflammation. EMBO J. 23, 969–979 (2004).
Witmer-Pack, M. D. et al. Identification of macrophages and dendritic cells in the osteopetrotic (op/op) mouse. J. Cell Sci. 104, 1021–1029 (1993).
Lin, H. et al. Discovery of a cytokine and its receptor by functional screening of the extracellular proteome. Science 320, 807–811 (2008).
Stanley, E. R. et al. Biology and action of colony-stimulating factor-1. Mol. Reprod. Dev. 46, 4–10 (1997).
Onai, N., Obata-Onai, A., Schmid, M. A. & Manz, M. G. Flt3 in regulation of type-I interferon producing and dendritic cell development. Ann. NY Acad. Sci. 1106, 253–261 (2007).
Bogunovic, M. et al. Identification of a radio-resistant and cycling dermal dendritic cell population in mice and men. J. Exp. Med. 203, 2627–2638 (2006).
Sato, N. et al. CC chemokine receptor (CCR)2 is required for langerhans cell migration and localization of T helper cell type 1 (Th1)-inducing dendritic cells. Absence of CCR2 shifts the Leishmania major-resistant phenotype to a susceptible state dominated by Th2 cytokines, B cell outgrowth, and sustained neutrophilic inflammation. J. Exp. Med. 192, 205–218 (2000).
Cook, D. N. et al. CCR6 mediates dendritic cell localization, lymphocyte homeostasis, and immune responses in mucosal tissue. Immunity 12, 495–503 (2000).
Vanbervliet, B. et al. Sequential involvement of CCR2 and CCR6 ligands for immature dendritic cell recruitment: possible role at inflamed epithelial surfaces. Eur. J. Immunol. 32, 231–242 (2002).
Larregina, A. T. et al. Dermal-resident CD14+ cells differentiate into Langerhans cells. Nature Immunol. 2, 1151–1158 (2001).
Schaerli, P., Willimann, K., Ebert, L. M., Walz, A. & Moser, B. Cutaneous CXCL14 targets. Blood precursors to epidermal niches for Langerhans cell differentiation. Immunity 23, 331–342 (2005).
Reis e Sousa, C. Dendritic cells in a mature stage. Nature Rev. Immunol. 6, 476–483 (2006).
Jiang, A. et al. Disruption of E-cadherin-mediated adhesion induces a functionally distinct pathway of dendritic cellmaturation. Immunity 27, 610–624 (2007). This is the first paper to describe an alternative DC-maturation pathway that leads to the upregulation of CCR7 without inducing cytokine release and is thought to have a key role in the induction of tolerance.
Banchereau, J. et al. Immunobiology of dendritic cells. Annu. Rev. Immunol. 18, 767–811 (2000).
Stoitzner, P. et al. Visualization and characterization of migratory Langerhans cells in murine skin and lymph nodes by antibodies against Langerin/CD207. J. Invest. Dermatol. 120, 266–274 (2003).
Geissmann, F. et al. Accumulation of immature Langerhans cells in human lymph nodes draining chronically inflamed skin. J. Exp. Med. 196, 417–430 (2002).
Douillard, P. et al. Mouse lymphoid tissue contains distinct subsets of langerin/CD207 dendritic cells, only one of which represents epidermal-derived Langerhans cells. J. Invest. Dermatol. 125, 983–994 (2005).
Cheong, C. et al. Production of monoclonal antibodies that recognize the extracellular domain of mouse langerin/CD207. J. Immunol. Methods 324, 48–62 (2007).
Flacher, V. et al. Expression of langerin/CD207 reveals dendritic cell heterogeneity between inbred mouse strains. Immunology 123, 339–347 (2008).
Mayer, W. J. et al. Characterization of antigen-presenting cells in fresh and cultured human corneas using novel dendritic cell markers. Invest. Ophthalmol. Vis. Sci. 48, 4459–4467 (2007).
Santoro, A. et al. Recruitment of dendritic cells in oral lichen planus. J. Pathol. 205, 426–434 (2005).
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).
Johansson-Lindbom, B. et al. Functional specialization of gut CD103+ dendritic cells in the regulation of tissue-selective T cell homing. J. Exp. Med. 202, 1063–1073 (2005).
Chikwava, K. & Jaffe, R. Langerin (CD207) staining in normal pediatric tissues, reactive lymph nodes, and childhood histiocytic disorders. Pediatr. Dev. Pathol. 7, 607–614 (2004). This is the first identification of langerin+CD1a+ cells in human tissue other than the skin.
Segerer, S. et al. Compartment specific expression of dendritic cell markers in human glomerulonephritis. Kidney Int. 73, 533–537 (2008). This is the first identification of langerin+CD1a+ cells in human kidneys.
Jaensson, E. et al. Small intestinal CD103+ dendritic cells display unique functional properties that are conserved between mice and humans. J. Exp. Med. 205, 2139–2149 (2008).
Kamath, A. T. et al. The development, maturation, and turnover rate of mouse spleen dendritic cell populations. J. Immunol. 165, 6762–6770 (2000).
Fogg, D. K. et al. A clonogenic bone marrow progenitor specific for macrophages and dendritic cells. Science 311, 83–87 (2006).
Massberg, S. et al. Immunosurveillance by hematopoietic progenitor cells trafficking through blood, lymph, and peripheral tissues. Cell 131, 994–1008 (2007).
Bonifaz, L. et al. Efficient targeting of protein antigen to the dendritic cell receptor DEC-205 in the steady state leads to antigen presentation on major histocompatibility complex class I products and peripheral CD8+T cell tolerance. J. Exp. Med. 196, 1627–1638 (2002). This is the first demonstration that targeting antigens to DCs in the steady state leads to tolerance.
Dudziak, D. et al. Differential antigen processing by dendritic cell subsets in vivo. Science 315, 107–111 (2007).
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 study was the first to show that Langerhans cells can differentiate in vitro into DCs that can prime naive T cells.
Allan, R. S. et al. Epidermal viral immunity induced by CD8α+ dendritic cells but not by Langerhans cells. Science 301, 1925–1928 (2003). This study shows that LCs are unable to prime CD8+ T cells following epidermal HSV infection.
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). This study shows that migratory skin DCs prime antigen-specific T cells after lentivirus-vector infection of the skin.
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).
Bosnjak, L. et al. Herpes simplex virus infection of human dendritic cells induces apoptosis and allows cross-presentation via uninfected dendritic cells. J. Immunol. 174, 2220–2227 (2005).
Leon, B., Lopez-Bravo, M. & Ardavin, C. Monocyte-derived dendritic cells formed at the infection site control the induction of protective T helper 1 responses against Leishmania. Immunity 26, 519–531 (2007).
Sacks, D. L. Metacyclogenesis in Leishmania promastigotes. Exp. Parasitol. 69, 100–103 (1989).
Belkaid, Y. et al. CD8+ T cells are required for primary immunity in C57BL/6 mice following low-dose, intradermal challenge with Leishmania major. J. Immunol. 168, 3992–4000 (2002).
Klechevsky, E. et al. Functional specializations of human epidermal langerhans cells and CD14+ dermal dendritic cells. Immunity 29, 497–510 (2008). This study shows that human LCs are efficient at cross-presenting antigens to CD8+ T cells and at inducing T H 1-cell responses, whereas dermal DCs are better at priming follicular T-helper cells and inducing B-cell antibody switching.
Ueno, H. et al. Dendritic cell subsets in health and disease. Immunol. Rev. 219, 118–142 (2007).
Stoecklinger, A. et al. Epidermal langerhans cells are dispensable for humoral and cell-mediated immunity elicited by gene gun immunization. J. Immunol. 179, 886–893 (2007).
Stoitzner, P. et al. Tumor immunotherapy by epicutaneous immunization requires langerhans cells. J. Immunol. 180, 1991–1998 (2008). This is the first demonstration that LCs are required for the induction of the antitumour immune response following epidermal vaccination with tumour antigens.
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).
Steinman, R. M., Hawiger, D. & Nussenzweig, M. C. Tolerogenic dendritic cells. Annu. Rev. Immunol. 21, 685–711 (2003).
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).
Loser, K. et al. Epidermal RANKL controls regulatory T-cell numbers via activation of dendritic cells. Nature Med. 12, 1372–1379 (2006).
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).
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).
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).
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).
Coppes-Zantinga, A. & Egeler, R. M. The Langerhans cell histiocytosis X files revealed. Br. J. Haematol. 116, 3–9 (2002).
Nezelof, C., Basset, F. & Rousseau, M. F. Histiocytosis X histogenetic arguments for a Langerhans cell origin. Biomedicine 18, 365–371 (1973).
Geissmann, F. et al. Differentiation of Langerhans cells in Langerhans cell histiocytosis. Blood 97, 1241–1248 (2001).
Emile, J. F., Fraitag, S., Leborgne, M., de Prost, Y. & Brousse, N. In situ expression of activation markers by Langerhans' cells containing GM-CSF. Adv. Exp. Med. Biol. 378, 101–103 (1995).
Nezelof, C. & Basset, F. An hypothesis Langerhans cell histiocytosis: the failure of the immune system to switch from an innate to an adaptive mode. Pediatr. Blood Cancer 42, 398–400 (2004). This is the first study showing that cells in histiocytosis X lesions contain Birbeck granules, which suggests their potential LC origin, and proposed that the term histiocytosis X should be replaced with the term Langerhans-cell histiocytosis.
Yu, R. C., Chu, C., Buluwela, L. & Chu, A. C. Clonal proliferation of Langerhans cells in Langerhans cell histiocytosis. Lancet 343, 767–768 (1994).
Willman, C. L. et al. Langerhans'-cell histiocytosis (histiocytosis X) — a clonal proliferative disease. N. Engl. J. Med. 331, 154–160 (1994).
Senechal, B. et al. Expansion of regulatory T cells in patients with Langerhans cell histiocytosis. PLoS Med. 4, e253 (2007).
Schouten, B. et al. Expression of cell cycle-related gene products in Langerhans cell histiocytosis. J. Pediatr. Hematol. Oncol. 24, 727–732 (2002).
Savell, V. H. Jr, Sherman, T., Scheuermann, R. H., Siddiqui, A. M. & Margraf, L. R. Bcl-2 expression in Langerhans' cell histiocytosis. Pediatr. Dev. Pathol. 1, 210–215 (1998).
Bjorck, P., Banchereau, J. & Flores-Romo, L. CD40 ligation counteracts Fas-induced apoptosis of human dendritic cells. Int. Immunol. 9, 365–372 (1997).
Wong, B. R. et al. TRANCE (tumor necrosis factor [TNF]-related activation-induced cytokine), a new TNF family member predominantly expressed in T cells, is a dendritic cell-specific survival factor. J. Exp. Med. 186, 2075–2080 (1997).
Bechan, G. I., Egeler, R. M. & Arceci, R. J. Biology of Langerhans cells and Langerhans cell histiocytosis. Int. Rev. Cytol. 254, 1–43 (2006).
Steiner, Q. G. et al. In vivo transformation of mouse conventional CD8α+ dendritic cells leads to progressive multisystem histiocytosis. Blood 111, 2073–2082 (2008).
Pileri, S. A. et al. Tumours of histiocytes and accessory dendritic cells: an immunohistochemical approach to classification from the International Lymphoma Study Group based on 61 cases. Histopathology 41, 1–29 (2002).
Figdor, C. G., van Kooyk, Y. & Adema, G. J. C-type lectin receptors on dendritic cells and Langerhans cells. Nature Rev. Immunol. 2, 77–84 (2002).
Idoyaga, J. et al. Cutting Edge: Langerin/CD207 receptor on dendritic cells mediates efficient antigen presentation on MHC I and II products in vivo. J. Immunol. 180, 3647–3650 (2008).
Piguet, V. & Steinman, R. M. The interaction of HIV with dendritic cells: outcomes and pathways. Trends Immunol. 28, 503–510 (2007).
Hladik, F. & McElrath, M. J. Setting the stage: host invasion by HIV. Nature Rev. Immunol. 8, 447–457 (2008).
Fahrbach, K. M. et al. Activated CD34-derived Langerhans cells mediate transinfection with human immunodeficiency virus. J. Virol. 81, 6858–6868 (2007).
Riedl, E., Tada, Y. & Udey, M. C. Identification and characterization of an alternatively spliced isoform of mouse Langerin/CD207. J. Invest. Dermatol. 123, 78–86 (2004).
Ward, E. M., Stambach, N. S., Drickamer, K. & Taylor, M. E. Polymorphisms in human langerin affect stability and sugar binding activity. J. Biol. Chem. 281, 15450–15456 (2006).
Boes, M. et al. T-cell engagement of dendritic cells rapidly rearranges MHC class II transport. Nature 418, 983–988 (2002).
Fukuzumi, T. et al. Differences in irradiation susceptibility and turnover between mucosal and connective tissue-type mast cells of mice. Exp. Hematol. 18, 843–847 (1990).
Matsumoto, Y. & Fujiwara, M. Absence of donor-type major histocompatibility complex class I antigen-bearing microglia in the rat central nervous system of radiation bone marrow chimeras. J. Neuroimmunol. 17, 71–82 (1987).
Berland, R. & Wortis, H. H. Origins and functions of B-1 cells with notes on the role of CD5. Annu. Rev. Immunol. 20, 253–300 (2002).
Merad, M. & Ginhoux, F. Dendritic cell genealogy: a new stem or just another branch? Nature Immunol. 8, 1199–1201 (2007).
Takahashi, K. et al. Heterogeneity of dendritic cells in human superficial lymph node: in vitro maturation of immature dendritic cells into mature or activated interdigitating reticulum cells. Am. J. Pathol. 153, 745–755 (1998).
Schiavoni, G. et al. ICSBP is critically involved in the normal development and trafficking of Langerhans cells and dermal dendritic cells. Blood 103, 2221–2228 (2004).
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.
- 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.
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.
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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