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.

Ontogeny and function of murine epidermal Langerhans cells

Abstract

Langerhans cells (LCs) are epidermis-resident antigen-presenting cells that share a common ontogeny with macrophages but function as dendritic cells (DCs). Their development, recruitment and retention in the epidermis is orchestrated by interactions with keratinocytes through multiple mechanisms. LC and dermal DC subsets often show functional redundancy, but LCs are required for specific types of adaptive immune responses when antigen is concentrated in the epidermis. This Review will focus on those developmental and functional properties that are unique to LCs.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Antigen-presenting cells in the skin.
Figure 2: KCs and TGF-β control LC migration.
Figure 3: Mouse skin DC subsets drive distinct T cell phenotypes.

References

  1. 1

    Rowden, G., Lewis, M.G. & Sullivan, A.K. Ia antigen expression on human epidermal Langerhans cells. Nature 268, 247–248 (1977).

    CAS  PubMed  Article  Google Scholar 

  2. 2

    Klareskog, L., Tjernlund, U., Forsum, U. & Peterson, P.A. Epidermal Langerhans cells express Ia antigens. Nature 268, 248–250 (1977).

    CAS  PubMed  Article  Google Scholar 

  3. 3

    Stingl, G. et al. Epidermal Langerhans cells bear Fc and C3 receptors. Nature 268, 245–246 (1977).

    CAS  PubMed  Article  Google Scholar 

  4. 4

    Silberberg-Sinakin, I., Thorbecke, G.J., Baer, R.L., Rosenthal, S.A. & Berezowsky, V. Antigen-bearing langerhans cells in skin, dermal lymphatics and in lymph nodes. Cell. Immunol. 25, 137–151 (1976).

    CAS  PubMed  Article  Google Scholar 

  5. 5

    Schuler, G. & Steinman, R.M. Murine epidermal Langerhans cells mature into potent immunostimulatory dendritic cells in vitro. J. Exp. Med. 161, 526–546 (1985).

    CAS  PubMed  Article  Google Scholar 

  6. 6

    Steinman, R.M. The dendritic cell system and its role in immunogenicity. Annu. Rev. Immunol. 9, 271–296 (1991).

    CAS  PubMed  Article  Google Scholar 

  7. 7

    Wilson, N.S. & Villadangos, J.A. Lymphoid organ dendritic cells: beyond the Langerhans cells paradigm. Immunol. Cell Biol. 82, 91–98 (2004).

    PubMed  Article  Google Scholar 

  8. 8

    Steinman, R.M. & Nussenzweig, M.C. Avoiding horror autotoxicus: the importance of dendritic cells in peripheral T cell tolerance. Proc. Natl. Acad. Sci. USA 99, 351–358 (2002).

    CAS  PubMed  Article  Google Scholar 

  9. 9

    Kashem, S.W., Haniffa, M. & Kaplan, D.H. Antigen-presenting cells in the skin. Annu. Rev. Immunol. 35, 469–499 (2017).

    CAS  PubMed  Article  Google Scholar 

  10. 10

    Ginhoux, F. et al. Langerhans cells arise from monocytes in vivo. Nat. Immunol. 7, 265–273 (2006). The authors demonstrated that repopulation of the epidermis by LCs after inflammation requires Gr-1hi monocytes and the receptor for the cytokine CSF-1. This indicated that monocytes, not pre-DCs, are the precursors of LCs.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  11. 11

    Hoeffel, G. et al. Adult Langerhans cells derive predominantly from embryonic fetal liver monocytes with a minor contribution of yolk sac-derived macrophages. J. Exp. Med. 209, 1167–1181 (2012). This study showed that LCs that develop during ontogeny arise mainly from embryonic fetal liver monocytes. This confirmed that LC ontogeny is distinct from that of DCs.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  12. 12

    Chorro, L. et al. Langerhans cell (LC) proliferation mediates neonatal development, homeostasis, and inflammation-associated expansion of the epidermal LC network. J. Exp. Med. 206, 3089–3100 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  13. 13

    Tripp, C.H. et al. Ontogeny of Langerin/CD207 expression in the epidermis of mice. J. Invest. Dermatol. 122, 670–672 (2004).

    CAS  PubMed  Article  Google Scholar 

  14. 14

    Fainaru, O. et al. Runx3 regulates mouse TGF-beta-mediated dendritic cell function and its absence results in airway inflammation. EMBO J. 23, 969–979 (2004).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  15. 15

    Hacker, C. et al. Transcriptional profiling identifies Id2 function in dendritic cell development. Nat. Immunol. 4, 380–386 (2003).

    CAS  PubMed  Article  Google Scholar 

  16. 16

    Greter, M. et al. Stroma-derived interleukin-34 controls the development and maintenance of langerhans cells and the maintenance of microglia. Immunity 37, 1050–1060 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  17. 17

    Wang, Y. et al. IL-34 is a tissue-restricted ligand of CSF1R required for the development of Langerhans cells and microglia. Nat. Immunol. 13, 753–760 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  18. 18

    Merad, M. et al. Langerhans cells renew in the skin throughout life under steady-state conditions. Nat. Immunol. 3, 1135–1141 (2002). In this landmark paper, LCs were shown to undergo self-renewal in the skin and remain of host origin in bone-marrow chimeras. This introduced a key tool for the investigation of LCs and was the first indication that LCs have an ontogeny distinct from that of other DC subsets.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  19. 19

    Ginhoux, F. et al. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330, 841–845 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  20. 20

    Guilliams, M. et al. Dendritic cells, monocytes and macrophages: a unified nomenclature based on ontogeny. Nat. Rev. Immunol. 14, 571–578 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  21. 21

    Satpathy, A.T., Wu, X., Albring, J.C. & Murphy, K.M. Re(de)fining the dendritic cell lineage. Nat. Immunol. 13, 1145–1154 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  22. 22

    Miller, J.C. et al. Deciphering the transcriptional network of the dendritic cell lineage. Nat. Immunol. 13, 888–899 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  23. 23

    Carpentier, S. et al. Comparative genomics analysis of mononuclear phagocyte subsets confirms homology between lymphoid tissue-resident and dermal XCR1+ DCs in mouse and human and distinguishes them from Langerhans cells. J. Immunol. Methods 432, 35–49 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  24. 24

    Gosselin, D. et al. Environment drives selection and function of enhancers controlling tissue-specific macrophage identities. Cell 159, 1327–1340 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  25. 25

    Lavin, Y. et al. Tissue-resident macrophage enhancer landscapes are shaped by the local microenvironment. Cell 159, 1312–1326 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  26. 26

    Guilliams, M. & Scott, C.L. Does niche competition determine the origin of tissue-resident macrophages? Nat. Rev. Immunol. 17, 451–460 (2017).

    CAS  PubMed  Article  Google Scholar 

  27. 27

    Chopin, M. et al. Langerhans cells are generated by two distinct PU.1-dependent transcriptional networks. J. Exp. Med. 210, 2967–2980 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  28. 28

    Bauer, T. et al. Identification of Axl as a downstream effector of TGF-β1 during Langerhans cell differentiation and epidermal homeostasis. J. Exp. Med. 209, 2033–2047 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  29. 29

    Yasmin, N. et al. Identification of bone morphogenetic protein 7 (BMP7) as an instructive factor for human epidermal Langerhans cell differentiation. J. Exp. Med. 210, 2597–2610 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  30. 30

    Borkowski, T.A., Letterio, J.J., Farr, A.G. & Udey, M.C. A role for endogenous transforming growth factor beta 1 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  31. 31

    Kel, J.M., Girard-Madoux, M.J.H., Reizis, B. & Clausen, B.E. TGF-β is required to maintain the pool of immature Langerhans cells in the epidermis. J. Immunol. 185, 3248–3255 (2010).

    CAS  PubMed  Article  Google Scholar 

  32. 32

    Bobr, A. et al. Autocrine/paracrine TGF-β1 inhibits Langerhans cell migration. Proc. Natl. Acad. Sci. USA 109, 10492–10497 (2012).

    CAS  PubMed  Article  Google Scholar 

  33. 33

    Sparber, F. et al. The late endosomal adaptor molecule p14 (LAMTOR2) regulates TGFβ1-mediated homeostasis of Langerhans cells. J. Invest. Dermatol. 135, 119–129 (2015).

    CAS  PubMed  Article  Google Scholar 

  34. 34

    Kaplan, D.H. et al. Autocrine/paracrine TGFβ1 is required for the development of epidermal Langerhans cells. J. Exp. Med. 204, 2545–2552 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  35. 35

    Mohammed, J. et al. Stromal cells control the epithelial residence of DCs and memory T cells by regulated activation of TGF-β. Nat. Immunol. 17, 414–421 (2016). This research showed that transactivation of inactive TGF-β–LAP by Arg-Gly-Asp (RGD)-binding integrins expressed by spatially distinct KCs is needed to prevent spontaneous LC migration. This indicates that KCs control LC migration in some contexts.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  36. 36

    Yang, Z. et al. Absence of integrin-mediated TGFβ1 activation in vivo recapitulates the phenotype of TGFβ1-null mice. J. Cell Biol. 176, 787–793 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  37. 37

    Katz, S.I., Tamaki, K. & Sachs, D.H. Epidermal Langerhans cells are derived from cells originating in bone marrow. Nature 282, 324–326 (1979).

    CAS  PubMed  Article  Google Scholar 

  38. 38

    Ghigo, C. et al. Multicolor fate mapping of Langerhans cell homeostasis. J. Exp. Med. 210, 1657–1664 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  39. 39

    Price, J.G. et al. CDKN1A regulates Langerhans cell survival and promotes Treg cell generation upon exposure to ionizing irradiation. Nat. Immunol. 16, 1060–1068 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  40. 40

    Nagao, K. et al. Stress-induced production of chemokines by hair follicles regulates the trafficking of dendritic cells in skin. Nat. Immunol. 13, 744–752 (2012). This study showed that precursors of LCs are recruited into the epidermis by CCR2–CCL2 and CCR6–CCL20 during inflammation. Those precursors enter the epidermis at the follicular isthmus and infundibulum and are actively excluded from the bulge by CCR8–CCL8.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  41. 41

    Seré, K. et al. Two distinct types of Langerhans cells populate the skin during steady state and inflammation. Immunity 37, 905–916 (2012).

    PubMed  Article  CAS  Google Scholar 

  42. 42

    Martini, E. et al. Dynamic changes in resident and infiltrating epidermal dendritic cells in active and resolved psoriasis. J. Invest. Dermatol. 137, 865–873 (2017).

    CAS  PubMed  Article  Google Scholar 

  43. 43

    Singh, T.P. et al. Monocyte-derived inflammatory Langerhans cells and dermal dendritic cells mediate psoriasis-like inflammation. Nat. Commun. 7, 13581 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  44. 44

    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).

    CAS  PubMed  Article  Google Scholar 

  45. 45

    Ouwehand, K. et al. CXCL12 is essential for migration of activated Langerhans cells from epidermis to dermis. Eur. J. Immunol. 38, 3050–3059 (2008).

    CAS  PubMed  Article  Google Scholar 

  46. 46

    Villablanca, E.J. & Mora, J.R. A two-step model for Langerhans cell migration to skin-draining LN. Eur. J. Immunol. 38, 2975–2980 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  47. 47

    Gaiser, M.R. et al. Cancer-associated epithelial cell adhesion molecule (EpCAM; CD326) enables epidermal Langerhans cell motility and migration in vivo. Proc. Natl. Acad. Sci. USA 109, E889–E897 (2012).

    CAS  PubMed  Article  Google Scholar 

  48. 48

    Tan, S.-Y., Roediger, B. & Weninger, W. The role of chemokines in cutaneous immunosurveillance. Immunol. Cell Biol. 93, 337–346 (2015).

    CAS  PubMed  Article  Google Scholar 

  49. 49

    Griffiths, C.E.M., Dearman, R.J., Cumberbatch, M. & Kimber, I. Cytokines and Langerhans cell mobilisation in mouse and man. Cytokine 32, 67–70 (2005).

    CAS  PubMed  Article  Google Scholar 

  50. 50

    Antonopoulos, C. et al. Functional caspase-1 is required for Langerhans cell migration and optimal contact sensitization in mice. J. Immunol. 166, 3672–3677 (2001).

    CAS  PubMed  Article  Google Scholar 

  51. 51

    Wang, B. et al. Tumour necrosis factor receptor II (p75) signalling is required for the migration of Langerhans' cells. Immunology 88, 284–288 (1996).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  52. 52

    Shornick, L.P., Bisarya, A.K. & Chaplin, D.D. IL-1β is essential for langerhans cell activation and antigen delivery to the lymph nodes during contact sensitization: evidence for a dermal source of IL-1β. Cell. Immunol. 211, 105–112 (2001).

    CAS  PubMed  Article  Google Scholar 

  53. 53

    Eaton, L.H., Roberts, R.A., Kimber, I., Dearman, R.J. & Metryka, A. Skin sensitization induced Langerhans' cell mobilization: variable requirements for tumour necrosis factor-α. Immunology 144, 139–148 (2015).

    CAS  PubMed  Article  Google Scholar 

  54. 54

    Haley, K. et al. Langerhans cells require MyD88-dependent signals for Candida albicans response but not for contact hypersensitivity or migration. J. Immunol. 188, 4334–4339 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  55. 55

    Didovic, S., Opitz, F.V., Holzmann, B., Förster, I. & Weighardt, H. Requirement of MyD88 signaling in keratinocytes for Langerhans cell migration and initiation of atopic dermatitis-like symptoms in mice. Eur. J. Immunol. 46, 981–992 (2016).

    CAS  PubMed  Article  Google Scholar 

  56. 56

    Clausen, B.E. & Stoitzner, P. Functional specialization of skin dendritic cell subsets in regulating T cell responses. Front. Immunol. 6, 417 (2015).

    Article  Google Scholar 

  57. 57

    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 identification of Langerin as an LC-specific marker opened the field of LC research by facilitating the accurate identification of LCs in LNs and allowing the development of genetic mouse models with ablation of LCs.

    CAS  PubMed  Article  Google Scholar 

  58. 58

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  59. 59

    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).

    CAS  PubMed  Article  Google Scholar 

  60. 60

    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).

    CAS  PubMed  Article  Google Scholar 

  61. 61

    Bobr, A. et al. Acute ablation of Langerhans cells enhances skin immune responses. J. Immunol. 185, 4724–4728 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  62. 62

    Bursch, L.S. et al. Identification of a novel population of Langerin+ dendritic cells. J. Exp. Med. 204, 3147–3156 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  63. 63

    Haniffa, M. et al. Human tissues contain CD141hi cross-presenting dendritic cells with functional homology to mouse CD103+ nonlymphoid dendritic cells. Immunity 37, 60–73 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  64. 64

    Jongbloed, S.L. et al. Human CD141+ (BDCA-3)+ dendritic cells (DCs) represent a unique myeloid DC subset that cross-presents necrotic cell antigens. J. Exp. Med. 207, 1247–1260 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  65. 65

    Merad, M., Sathe, P., Helft, J., Miller, J. & Mortha, A. The dendritic cell lineage: ontogeny and function of dendritic cells and their subsets in the steady state and the inflamed setting. Annu. Rev. Immunol. 31, 563–604 (2013).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  66. 66

    Igyártó, B.Z. et al. Skin-resident murine dendritic cell subsets promote distinct and opposing antigen-specific T helper cell responses. Immunity 35, 260–272 (2011).

    PubMed  Article  CAS  Google Scholar 

  67. 67

    Bedoui, S. et al. Cross-presentation of viral and self antigens by skin-derived CD103+ dendritic cells. Nat. Immunol. 10, 488–495 (2009).

    CAS  PubMed  Article  Google Scholar 

  68. 68

    Naik, S. et al. Commensal-dendritic-cell interaction specifies a unique protective skin immune signature. Nature 520, 104–108 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  69. 69

    Hildner, K. et al. Batf3 deficiency reveals a critical role for CD8α+ dendritic cells in cytotoxic T cell immunity. Science 322, 1097–1100 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  70. 70

    Henri, S. et al. CD207+CD103+ dermal dendritic cells cross-present keratinocyte-derived antigens irrespective of the presence of Langerhans cells. J. Exp. Med. 207, 189–206 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  71. 71

    Stoitzner, P. et al. Langerhans cells cross-present antigen derived from skin. Proc. Natl. Acad. Sci. USA 103, 7783–7788 (2006).

    CAS  PubMed  Article  Google Scholar 

  72. 72

    Zaric, M. et al. Dissolving microneedle delivery of nanoparticle-encapsulated antigen elicits efficient cross-priming and Th1 immune responses by murine Langerhans cells. J. Invest. Dermatol. 135, 425–434 (2015).

    CAS  PubMed  Article  Google Scholar 

  73. 73

    Flacher, V. et al. Murine Langerin+ dermal dendritic cells prime CD8+ T cells while Langerhans cells induce cross-tolerance. EMBO Mol. Med. 6, 1191–1204 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  74. 74

    Strandt, H. et al. Neoantigen expression in steady-state langerhans cells induces CTL tolerance. J. Immunol. 199, 1626–1634 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  75. 75

    Bennett, C.L. et al. Langerhans cells regulate cutaneous injury by licensing CD8 effector cells recruited to the skin. Blood 117, 7063–7069 (2011). In this study, in a model of graft-versus-host disease in which LCs expressed alloantigen, they were needed to license infiltrating epidermal CD8+ T cells to secrete interferon-γ and other effector molecules. This work demonstrates an important LC–T cell interaction in the epidermis.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  76. 76

    Kashem, S.W. et al. Candida albicans morphology and dendritic cell subsets determine T helper cell differentiation. Immunity 42, 356–366 (2015). This work showed that T H 17 responses to epicutaneous C. albicans skin infection require LCs. Dermal DCs were unable to promote T H 17 cells due to the restriction of Dectin-1 ligands to yeast forms that do not penetrate into the dermis. This supports a model in which LCs are required for T H 17 responses to antigen concentrated in the epidermis.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  77. 77

    Mathers, A.R. et al. Differential capability of human cutaneous dendritic cell subsets to initiate Th17 responses. J. Immunol. 182, 921–933 (2009).

    CAS  PubMed  Article  Google Scholar 

  78. 78

    Kobayashi, T. et al. Dysbiosis and Staphylococcus aureus colonization drives inflammation in atopic dermatitis. Immunity 42, 756–766 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  79. 79

    Linehan, J.L. et al. Generation of Th17 cells in response to intranasal infection requires TGF-β1 from dendritic cells and IL-6 from CD301b+ dendritic cells. Proc. Natl. Acad. Sci. USA 112, 12782–12787 (2015).

    CAS  PubMed  Article  Google Scholar 

  80. 80

    Schlitzer, A. et al. IRF4 transcription factor-dependent CD11b+ dendritic cells in human and mouse control mucosal IL-17 cytokine responses. Immunity 38, 970–983 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  81. 81

    Kubo, A., Nagao, K., Yokouchi, M., Sasaki, H. & Amagai, M. External antigen uptake by Langerhans cells with reorganization of epidermal tight junction barriers. J. Exp. Med. 206, 2937–2946 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  82. 82

    Ouchi, T. et al. Langerhans cell antigen capture through tight junctions confers preemptive immunity in experimental staphylococcal scalded skin syndrome. J. Exp. Med. 208, 2607–2613 (2011). This work demonstrated that LCs acquire epicutaneously applied protein antigen and are required for the development of protective antibody responses in a model of staphylococcal scalded-skin syndrome. This established that LCs are required for humoral responses to superficial antigen.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  83. 83

    Levin, C. et al. Critical role for skin-derived migratory DCs and Langerhans cells in TFH and GC responses after intradermal immunization. J. Invest. Dermatol. http://dx.doi.org/10.1016/j.jid.2017.04.016 (2017).

  84. 84

    Zimara, N. et al. Langerhans cells promote early germinal center formation in response to Leishmania-derived cutaneous antigens. Eur. J. Immunol. 44, 2955–2967 (2014).

    CAS  PubMed  Article  Google Scholar 

  85. 85

    Yao, C. et al. Skin dendritic cells induce follicular helper T cells and protective humoral immune responses. J. Allergy Clin. Immunol. 136, 1387–1397 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  86. 86

    Lahoud, M.H. et al. Targeting antigen to mouse dendritic cells via Clec9A induces potent CD4 T cell responses biased toward a follicular helper phenotype. J. Immunol. 187, 842–850 (2011).

    CAS  PubMed  Article  Google Scholar 

  87. 87

    Park, H.Y. et al. Evolution of B cell responses to Clec9A-targeted antigen. J. Immunol. 191, 4919–4925 (2013).

    CAS  PubMed  Article  Google Scholar 

  88. 88

    Nakajima, S. et al. Langerhans cells are critical in epicutaneous sensitization with protein antigen via thymic stromal lymphopoietin receptor signaling. J. Allergy Clin. Immunol. 129, 1048–1055 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  89. 89

    Deckers, J. et al. Epicutaneous sensitization to house dust mite allergen requires interferon regulatory factor 4-dependent dermal dendritic cells. J. Allergy Clin. Immunol. http://dx.doi.org/10.1016/j.jaci.2016.12.970 (2017).

  90. 90

    Gao, Y. et al. Control of T helper 2 responses by transcription factor IRF4-dependent dendritic cells. Immunity 39, 722–732 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  91. 91

    Kumamoto, Y. et al. CD301b+ dermal dendritic cells drive T helper 2 cell-mediated immunity. Immunity 39, 733–743 (2013).

    CAS  PubMed  Article  Google Scholar 

  92. 92

    Bell, B.D. et al. The transcription factor STAT5 is critical in dendritic cells for the development of TH2 but not TH1 responses. Nat. Immunol. 14, 364–371 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  93. 93

    Hawiger, D. et al. Dendritic cells induce peripheral T cell unresponsiveness under steady state conditions in vivo. J. Exp. Med. 194, 769–779 (2001).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  94. 94

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  95. 95

    Joffre, O.P., Sancho, D., Zelenay, S., Keller, A.M. & Reis e Sousa, C. Efficient and versatile manipulation of the peripheral CD4+ T-cell compartment by antigen targeting to DNGR-1/CLEC9A. Eur. J. Immunol. 40, 1255–1265 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  96. 96

    Seneschal, J., Clark, R.A., Gehad, A., Baecher-Allan, C.M. & Kupper, T.S. Human epidermal Langerhans cells maintain immune homeostasis in skin by activating skin resident regulatory T cells. Immunity 36, 873–884 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  97. 97

    Idoyaga, J. et al. Specialized role of migratory dendritic cells in peripheral tolerance induction. J. Clin. Invest. 123, 844–854 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. 98

    Kautz-Neu, K. et al. Langerhans cells are negative regulators of the anti-Leishmania response. J. Exp. Med. 208, 885–891 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  99. 99

    Gomez de Agüero, M. et al. Langerhans cells protect from allergic contact dermatitis in mice by tolerizing CD8+ T cells and activating Foxp3+ regulatory T cells. J. Clin. Invest. 122, 1700–1711 (2012).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  100. 100

    Anandasabapathy, N. et al. Flt3L controls the development of radiosensitive dendritic cells in the meninges and choroid plexus of the steady-state mouse brain. J. Exp. Med. 208, 1695–1705 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  101. 101

    Guilliams, M. et al. Skin-draining lymph nodes contain dermis-derived CD103 dendritic cells that constitutively produce retinoic acid and induce Foxp3+ regulatory T cells. Blood 115, 1958–1968 (2010).

    CAS  PubMed  Article  Google Scholar 

  102. 102

    Li, D. et al. Targeting self- and foreign antigens to dendritic cells via DC-ASGPR generates IL-10-producing suppressive CD4+ T cells. J. Exp. Med. 209, 109–121 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  103. 103

    Nirschl, C.J. et al. IFNγ-dependent tissue-immune homeostasis is co-opted in the tumor microenvironment. Cell 170, 127–141 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  104. 104

    Kaplan, D.H., Igyártó, B.Z. & Gaspari, A.A. Early immune events in the induction of allergic contact dermatitis. Nat. Rev. Immunol. 12, 114–124 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  105. 105

    Honda, T. et al. Compensatory role of Langerhans cells and langerin-positive dermal dendritic cells in the sensitization phase of murine contact hypersensitivity. J. Allergy Clin. Immunol. 125, 1154–1156 (2010).

    PubMed  Article  Google Scholar 

  106. 106

    Noordegraaf, M., Flacher, V., Stoitzner, P. & Clausen, B.E. Functional redundancy of Langerhans cells and Langerin+ dermal dendritic cells in contact hypersensitivity. J. Invest. Dermatol. 130, 2752–2759 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  107. 107

    Kim, J.H. et al. CD1a on Langerhans cells controls inflammatory skin disease. Nat. Immunol. 17, 1159–1166 (2016). This study showed that CD1a expressed by human LCs, but not that expressed by mouse LCs, is required for allergic contact dermatitis in response to urushiol and psoriasis. This demonstrated that LCs are required for allergic contact dermatitis in response to CD1a-binding antigen and possibly to self lipids in autoimmunity.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  108. 108

    Kobayashi, C. et al. GM-CSF-independent CD1a expression in epidermal Langerhans cells: evidence from human CD1A genome-transgenic mice. J. Invest. Dermatol. 132, 241–244 (2012).

    CAS  PubMed  Article  Google Scholar 

  109. 109

    Igyarto, B.Z. et al. Langerhans cells suppress contact hypersensitivity responses via cognate CD4 interaction and langerhans cell-derived IL-10. J. Immunol. 183, 5085–5093 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  110. 110

    Scholz, F., Naik, S., Sutterwala, F.S. & Kaplan, D.H. Langerhans cells suppress CD49a+ NK cell-mediated skin inflammation. J. Immunol. 195, 2335–2342 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

Download references

Acknowledgements

Supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the US National Institutes of Health (R01AR060744, R01AR067187, and R01AR071720). We would like to apologize to all authors whose work was not cited or discussed in depth. Given the length limitation, we were unable to be comprehensive in this review.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Daniel H Kaplan.

Ethics declarations

Competing interests

The author declares no competing financial interests.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Kaplan, D. Ontogeny and function of murine epidermal Langerhans cells. Nat Immunol 18, 1068–1075 (2017). https://doi.org/10.1038/ni.3815

Download citation

Further reading

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