The dermis contains langerin+ dendritic cells that develop and function independently of epidermal Langerhans cells

Langerhans cells (LCs) constitute a subset of dendritic cells (DCs) that express the lectin langerin and that reside in their immature state in epidermis. Paradoxically, in mice permitting diphtheria toxin (DT)–mediated ablation of LCs, epidermal LCs reappeared with kinetics that lagged behind that of their putative progeny found in lymph nodes (LNs). Using bone marrow (BM) chimeras, we showed that a major fraction of the langerin+, skin-derived DCs found in LNs originates from a developmental pathway that is independent from that of epidermal LCs. This pathway, the existence of which was unexpected, originates in the dermis and gives rise to langerin+ dermal DCs (DDCs) that should not be confused with epidermal LCs en route to LNs. It explains that after DT treatment, some langerin+, skin-derived DCs reappear in LNs long before LC-derived DCs. Using CD45 expression and BrdU-labeling kinetics, both LCs and langerin+ DDCs were found to coexist in wild-type mice. Moreover, DT-mediated ablation of epidermal LCs opened otherwise filled niches and permitted repopulation of adult noninflammatory epidermis with BM-derived LCs. Our results stress that the langerin+ DC network is more complex than originally thought and have implications for the development of transcutaneous vaccines and the improvement of humanized mouse models.

[1]  F. Ginhoux,et al.  Blood-derived dermal langerin+ dendritic cells survey the skin in the steady state , 2007, The Journal of experimental medicine.

[2]  J. Villadangos,et al.  Intrinsic and cooperative antigen-presenting functions of dendritic-cell subsets in vivo , 2007, Nature Reviews Immunology.

[3]  Yong‐jun Liu,et al.  Development of dendritic-cell lineages. , 2007, Immunity.

[4]  M. Nussenzweig,et al.  Origin of dendritic cells in peripheral lymphoid organs of mice , 2007, Nature Immunology.

[5]  M. Manz.  Human-hemato-lymphoid-system mice: opportunities and challenges. , 2007, Immunity.

[6]  Y. Kooyk,et al.  Langerin is a natural barrier to HIV-1 transmission by Langerhans cells , 2007, Nature Medicine.

[7]  M. McElrath,et al.  Initial Events in Establishing Vaginal Entry and Infection by Human Immunodeficiency Virus Type-1 , 2007, Immunity.

[8]  Valerie Horsley,et al.  Epithelial Stem Cells: Turning over New Leaves , 2007, Cell.

[9]  F. Ginhoux,et al.  Identification of a radio-resistant and cycling dermal dendritic cell population in mice and men , 2006, The Journal of experimental medicine.

[10]  Li Wu,et al.  Intrasplenic steady-state dendritic cell precursors that are distinct from monocytes , 2006, Nature Immunology.

[11]  F. Ginhoux,et al.  Langerhans cells arise from monocytes in vivo , 2006, Nature Immunology.

[12]  M. Shlomchik,et al.  Epidermal langerhans cell-deficient mice develop enhanced contact hypersensitivity. , 2005, Immunity.

[13]  N. Romani,et al.  Mouse lymphoid tissue contains distinct subsets of langerin/CD207 dendritic cells, only one of which represents epidermal-derived Langerhans cells. , 2005, The Journal of investigative dermatology.

[14]  Clare L. Bennett,et al.  Inducible ablation of mouse Langerhans cells diminishes but fails to abrogate contact hypersensitivity , 2005, The Journal of cell biology.

[15]  P. Perrin,et al.  Dynamics and function of Langerhans cells in vivo: dermal dendritic cells colonize lymph node areas distinct from slower migrating Langerhans cells. , 2005, Immunity.

[16]  T. Banks,et al.  Intrinsic lymphotoxin-beta receptor requirement for homeostasis of lymphoid tissue dendritic cells. , 2005, Immunity.

[17]  B. Malissen,et al.  Disruption of the langerin/CD207 Gene Abolishes Birbeck Granules without a Marked Loss of Langerhans Cell Function , 2005, Molecular and Cellular Biology.

[18]  G. Belz,et al.  Transfer of antigen between migrating and lymph node-resident DCs in peripheral T-cell tolerance and immunity. , 2004, Trends in immunology.

[19]  Hua Tang,et al.  Splenic stroma drives mature dendritic cells to differentiate into regulatory dendritic cells , 2004, Nature Immunology.

[20]  A. Elbe-Bürger,et al.  Ontogeny of Langerin/CD207 expression in the epidermis of mice. , 2004, The Journal of investigative dermatology.

[21]  G. Belz,et al.  Epidermal Viral Immunity Induced by CD8α+ Dendritic Cells But Not by Langerhans Cells , 2003, Science.

[22]  N. Romani,et al.  Visualization and characterization of migratory Langerhans cells in murine skin and lymph nodes by antibodies against Langerin/CD207. , 2003, The Journal of investigative dermatology.

[23]  D. Tough,et al.  Developmental kinetics and lifespan of dendritic cells in mouse lymphoid organs. , 2002, Blood.

[24]  Steffen Jung,et al.  In vivo depletion of CD11c+ dendritic cells abrogates priming of CD8+ T cells by exogenous cell-associated antigens. , 2002, Immunity.

[25]  Michel C. Nussenzweig,et al.  Avoiding horror autotoxicus: The importance of dendritic cells in peripheral T cell tolerance , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[26]  Steffen Jung,et al.  Inflammatory Chemokine Transport and Presentation in HEV , 2001, The Journal of experimental medicine.

[27]  C. Benoist,et al.  The Dendritic Cell Populations of Mouse Lymph Nodes1 , 2001, The Journal of Immunology.

[28]  Li Wu,et al.  CD4 and CD8 Expression by Dendritic Cell Subtypes in Mouse Thymus and Spleen1 , 2000, The Journal of Immunology.

[29]  Shalin H. Naik,et al.  Steady-state and inflammatory dendritic-cell development , 2007, Nature Reviews Immunology.

[30]  F. Ginhoux,et al.  Identifi cation of a radio-resistant and cycling dermal dendritic cell population in mice and men , 2006 .

[31]  Adriana T Larregina,et al.  Changing paradigms in cutaneous immunology: adapting with dendritic cells. , 2005, The Journal of investigative dermatology.

[32]  I. Weissman,et al.  Langerhans cells renew in the skin throughout life under steady-state conditions , 2003, Nature Immunology.

[33]  R. Steinman.  Inaugural Article : avoiding horror autotoxicus. The importance of dendritic cells in peripheral T cell tolerance , 2002 .

[34]  J. Davoust,et al.  Langerin, a novel C-type lectin specific to Langerhans cells, is an endocytic receptor that induces the formation of Birbeck granules. , 2000, Immunity.