Vaginal epithelial dendritic cells renew from bone marrow precursors.

Dendritic cells (DCs) represent key professional antigen-presenting cells capable of initiating primary immune responses. A specialized subset of DCs, the Langerhans cells (LCs), are located in the stratified squamous epithelial layer of the skin and within the mucosal epithelial lining of the vaginal and oral cavities. The vaginal mucosa undergoes cyclic changes under the control of sex hormones, and the renewal characteristics of the vaginal epithelial DCs (VEDCs) remain unknown. Here, we examined the origin of VEDCs. In contrast to the skin epidermal LCs, the DCs in the epithelium of the vagina were found to be repopulated mainly by nonmonocyte bone-marrow-derived precursors, with a half-life of 13 days under steady-state conditions. Upon infection with HSV-2, the Gr-1(hi) monocytes were found to give rise to VEDCs. Furthermore, flow cytometric analysis of the VEDCs revealed the presence of at least three distinct populations, namely, CD11b(+)F4/80(hi), CD11b(+)F4/80(int), and CD11b(-)F4/80(-). Importantly, these VEDC populations expressed CD207 at low levels and had a constitutively more activated phenotype compared with the skin LCs. Collectively, our results revealed mucosa-specific features of the VEDCs with respect to their phenotype, activation status, and homeostatic renewal potential.

Structural studies of langerin and Birbeck granule: a macromolecular organization model.

Dendritic cells, a sentinel immunity cell lineage, include different cell subsets that express various C-type lectins. For example, epidermal Langerhans cells express langerin, and some dermal dendritic cells express DC-SIGN. Langerin is a crucial component of Birbeck granules, the Langerhans cell hallmark organelle, and may have a preventive role toward HIV, by its internalization into Birbeck granules. Since langerin carbohydrate recognition domain (CRD) is crucial for HIV interaction and Birbeck granule formation, we produced the CRD of human langerin and solved its structure at 1.5 A resolution. On this basis gp120 high-mannose oligosaccharide binding has been evaluated by molecular modeling. Hydrodynamic studies reveal a very elongated shape of recombinant langerin extracellular domain (ECD). A molecular model of the langerin ECD, integrating the CRD structure, has been generated and validated by comparison with hydrodynamic parameters. In parallel, Langerhans cells were isolated from human skin. From their analysis by electron microscopy and the langerin ECD model, an ultrastructural organization is proposed for Birbeck granules. To delineate the role of the different langerin domains in Birbeck granule formation, we generated truncated and mutated langerin constructs. After transfection into a fibroblastic cell line, we highlighted, in accordance with our model, the role of the CRD in the membrane zipping occurring in BG formation as well as some contribution of the cytoplasmic domain. Finally, we have shown that langerin ECD triggering with a specific mAb promotes global rearrangements of LC morphology. Our results open the way to the definition of a new membrane deformation mechanism.

Expression of langerin/CD207 reveals dendritic cell heterogeneity between inbred mouse strains.

Langerin/CD207 is expressed by a subset of dendritic cells (DC), the epithelial Langerhans cells. However, langerin is also detected among lymphoid tissue DC. Here, we describe striking differences in langerin-expressing cells between inbred mouse strains. While langerin+ cells are observed in comparable numbers and with comparable phenotypes in the epidermis, two distinct DC subsets bear langerin in peripheral, skin-draining lymph nodes of BALB/c mice (CD11c(high) CD8alpha(high) and CD11c(low) CD8alpha(low)), whereas only the latter subset is present in C57BL/6 mice. The CD11c(high) subset is detected in mesenteric lymph nodes and spleen of BALB/c mice, but is virtually absent from C57BL/6 mice. Similar differences are observed in other mouse strains. CD11c(low) langerin+ cells represent skin-derived Langerhans cells, as demonstrated by their high expression of DEC-205/CD205, maturation markers, and recruitment to skin-draining lymph nodes upon imiquimod-induced inflammation. It will be of interest to determine the role of lymphoid tissue-resident compared to skin-derived langerin+ DC.

Disruption of the langerin/CD207 gene abolishes Birbeck granules without a marked loss of Langerhans cell function.

Langerin is a C-type lectin expressed by a subset of dendritic leukocytes, the Langerhans cells (LC). Langerin is a cell surface receptor that induces the formation of an LC-specific organelle, the Birbeck granule (BG). We generated a langerin(-/-) mouse on a C57BL/6 background which did not display any macroscopic aberrant development. In the absence of langerin, LC were detected in normal numbers in the epidermis but the cells lacked BG. LC of langerin(-/-) mice did not present other phenotypic alterations compared to wild-type littermates. Functionally, the langerin(-/-) LC were able to capture antigen, to migrate towards skin draining lymph nodes, and to undergo phenotypic maturation. In addition, langerin(-/-) mice were not impaired in their capacity to process native OVA protein for I-A(b)-restricted presentation to CD4(+) T lymphocytes or for H-2K(b)-restricted cross-presentation to CD8(+) T lymphocytes. langerin(-/-) mice inoculated with mannosylated or skin-tropic microorganisms did not display an altered pathogen susceptibility. Finally, chemical mutagenesis resulted in a similar rate of skin tumor development in langerin(-/-) and wild-type mice. Overall, our data indicate that langerin and BG are dispensable for a number of LC functions. The langerin(-/-) C57BL/6 mouse should be a valuable model for further functional exploration of langerin and the role of BG.

Human CD34+ CD11b- cord blood stem cells generate in vitro a CD34- CD11b+ subset that is enriched in langerin+ Langerhans dendritic cell precursors.

OBJECTIVE: We investigated whether the expression of CD11b on precursors derived in vitro from CD34+ hematopoietic stem cells was related to their ability to generate CD11b- and CD11b+ Langerhans dendritic cells (LC). METHODS: Human CD34+ cells purified from cord blood were cultured with FLT3 ligand, thrombopoietin, and stem cell factor (FTS) for 2 weeks, analyzed, and sorted by FACS. Sorted fractions were cultured as above, or differentiated into LC with GM-CSF, IL-4, and TGF-beta1 (G4-TGF) for 6 days. The capacity of LC to internalize langerin and dextran was assessed. RESULTS: Ex vivo, human CD34+ cells were CD11b- and mostly CLA+. After 2 weeks of culture with FTS, CD34- CLA- CD11b- and CD34- CLA- CD11b+ cells emerged. CD11b- cells were the most ancestral because they were the only ones to proliferate with FTS, and constantly generated CD11b+ cells. Both CD11b- and CD11b+ sorted cells generated E-cadherin+ langerin+ LC after incubation with G4-TGF. The former fraction contained 46% +/- 15% of E-cadherin+ and 10% +/- 5% of langerin+ cells, whereas in the latter fraction these values reached respectively 66% +/- 23% and 30% +/- 16% (mean +/- SD, n = 7, p < 0.056). Looking at functional properties, CD11b- and CD11b+ LC were similar in terms of langerin and dextran endocytosis. By contrast, only CD11b+ LC internalized fluorescent LPS. CONCLUSION: Human CD34+ CD11b- cells differentiate in FTS culture into a CD34- CD11b- precursor that in turn generates CD34- CD11b+ cells. These cells are enriched in LC precursors compared to CD34- CD11b- cells. Both CD11b- and CD11b+ LC are generated in vitro, and each fraction may assume different functions in inflammatory situations.

Migratory Langerhans cells in mouse lymph nodes in steady state and inflammation.

Dendritic cells cells induce immunity or-in the steady state-maintain peripheral tolerance. Little is known in that regard about Langerhans cells. Therefore, we investigated migrating Langerhans cells in the steady-state versus inflammation. Increased numbers of Langerhans cells, as determined by immunostaining for Langerin/CD207, appeared in the lymph nodes in response to a contact allergen. Whereas a large proportion of Langerhans cells expressed CD86 in the steady state, CD40, and CD80 were found on a smaller percentage. During inflammation, more CD40(+), CD80(+), CD274/B7-H1/PD-L1(+), and CD273/B7-DC/PD-L2(+) Langerhans cells were found in the lymph nodes, and they expressed higher levels of these molecules. CD275/inducible T cell co-stimulator (ICOS) ligand was not detected. Langerhans cells in the nodes of contact allergen-treated mice produced more IL-12p40/70. This correlated with more interferon-gamma being produced by activated lymph node T cells. Epicutaneous immunization with ovalbumin under inflammatory conditions led to a more vigorous proliferation of antigen-specific CD4 T cells in vitro and in vivo as compared with immunization in the steady state. The latter modality, however did not induce strong CD4 T cell tolerance in this model. Thus, the overall phenotype of Langerhans cells is not an indicator for their immunogenic or tolerogenic potential.

Mouse lymphoid tissue contains distinct subsets of langerin/CD207 dendritic cells, only one of which represents epidermal-derived Langerhans cells.

Langerin/CD207 is a C-type lectin associated with formation of Birbeck granules (BG) in Langerhans cells (LC). Here, we describe a monoclonal antibody (mAb 205C1) recognizing the extracellular domain of mouse langerin. Cell-surface langerin was detected in all epidermal LC, which presented a uniform phenotype. Two subpopulations of langerin+ cells were identified in peripheral lymph nodes (LN). One population (subset 1) was CD11c(low/+)/CD8alpha(-/low)/CD11b+/CD40+/CD86+. The other population (subset 2) was CD11c(high)/CD8alpha+/CD11b(low), and lacked CD40 and CD86. Only subset 1 was fluorescein 5-isothiocyanate (FITC+) following painting onto epidermis, and the appearance of such FITC+ cells in draining LN was inhibited by pertussis toxin. Mesenteric LN, spleen, and thymus contained only a single population of langerin+ DC, corresponding to peripheral LN subset 2. Unexpectedly, BG were absent from spleen CD8alpha+ DC despite expression of langerin, and these organelles were not induced by mAb 205C1. Collectively, we demonstrate that two langerin+ DC populations (subsets 1 and 2) co-exist in mouse lymphoid tissue. Subset 1 unequivocally identifies epidermal LC-derived DC. The distribution of subset 2 indicates a non-LC origin of these langerin+ cells. These findings should facilitate our understanding of the role played by langerin in lymphoid organ DC subsets.

Ontogeny of Langerin/CD207 expression in the epidermis of mice.

C-type lectin receptors help Langerhans cells (LC) to take up and process pathogens. Langerin/CD207 is a mannose-binding C-type lectin that is specifically expressed by LC. It is involved in antigen uptake in an as yet poorly defined way, and it is a major molecular constituent of Birbeck granules. We studied the emergence of Langerin expression in LC in epidermal sheets and cell suspensions during ontogeny. Langerin appears later than MHC II expression. Intracellular Langerin expression becomes apparent 2-3 d after birth. Only 10 days after birth all LC co-express Langerin. The intensity of Langerin expression reaches adult levels by 3 wk after birth. Early Langerin expression appears to correlate at least in part with the physical presence of Birbeck granules.

A model system using tape stripping for characterization of Langerhans cell-precursors in vivo.

Little is known about the immigration of bone marrow-derived progenitors of Langerhans cells (LC) into the epidermis. We developed an in vivo system based on the tape stripping method that allowed us to study the immigration of LC into the epidermis after intradermal injection of bone marrow-derived dendritic cells (DC). Tape stripping induced a mechanical disruption of the epidermal barrier that led to skin inflammation and subsequent emigration of LC and dermal DC from the skin. Emigrating LC and dermal DC were observed in lymphatic vessels, and the numbers of LC and dermal DC in the draining lymph node increased. Up to 500 times more injected precursors migrated into tape-stripped epidermis as compared with unstripped epidermis. Newly immigrated cells were slender with one or two dendrites and acquired a more dendritic morphology after 2-4 days. They were both MHC II-positive and negative and they did not express Langerin/CD207, nor macrophage-mannose receptor/CD206 and Fc-epsilon receptor I. In contrast, all cells that had entered the epidermis expressed CD11c and CCR6, suggesting that they were LC. We conclude that this experimental system may serve as a valuable tool for the further characterization of LC-precursors and the conditions necessary for LC-immigration into the epidermis.

Visualization and characterization of migratory Langerhans cells in murine skin and lymph nodes by antibodies against Langerin/CD207.

Dendritic cells are professional antigen-presenting cells that initiate primary immunity. Migration from sites of antigen uptake to lymphoid organs is crucial for the generation of immune responses. We investigated the migratory pathways specifically of epidermal Langerhans cells by tracing them from the epidermis to the draining lymph nodes. This was possible with a new monoclonal antibody, directed against murine Langerin/CD207, a type II lectin specific for Langerhans cells. In situ, resident, and activated Langerhans cells express Langerin in the epidermis and on their way through dermal lymphatic vessels. Both emigrated and trypsinization-derived Langerhans cells expressed high levels of Langerin intracellularly but reduced it upon prolonged culture periods. Sizeable numbers of Langerin+ cells were found in skin draining lymph nodes but not in mesenteric nodes. Langerin+ cells localized to the T cells areas and rarely to B cell zones. Numbers of Langerin-expressing cells increased after application of a contact sensitizer. In the steady state, Langerhans cells in the skin-draining nodes expressed maturation markers, such as 2A1 and costimulatory molecules CD86 and CD40. These molecules, CD86 and CD40, were further upregulated upon inflammatory stimuli such as contact sensitization. Thus, the novel anti-Langerin monoclonal antibody permits the unequivocal visualization of migratory Langerhans cells in the lymph nodes for the first time and thereby allows to dissect the relative immunogenic or tolerogenic contributions of Langerhans cells and other types of dendritic cells.

Langerin/CD207 sheds light on formation of birbeck granules and their possible function in Langerhans cells.

Langerhans cells (LCs) are immature dendritic cells of epidermis and epithelia, playing a sentinel role through their specialized function in antigen capture, and their capacity to migrate to secondary lymphoid tissue to initiate specific immunity. A unique feature of LCs is the presence of Birbeck granules (BGs), which are disks of two limiting membranes, separated by leaflets with periodic "zipperlike" striations. The recent identification of Langerin/CD207 has allowed researchers to decipher the mechanism of BG formation and approach an understanding of their function. Langerin is a type II lectin with mannose specificity expressed by LCs in epidermis and epithelia. Remarkably, transfection of Langerin cDNA into fibroblasts creates a dense network of membrane structures with features typical of BGs. Furthermore, mutated and deleted forms of Langerin have been engineered to map the functional domains essential for BG formation. Langerin is a potent LC-specific regulator of membrane superimposition and zippering, representing a key molecule to trace LCs and to probe BG function.

Roles of lymphoid cells in the differentiation of Langerhans dendritic cells in mice.

Langerhans dendritic cells are antigen presenting cells (APC) that reside within the epidermis and are capable of stimulating naive T cells. Reciprocally, lymphocytes may play a role in Langerhans cells (LC) differentiation. Our results show that the differentiation of skin LC is unaffected in the absence of lymphocytes and/or signaling through the common cytokine receptor gamma chain (gammac) required for IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21 signaling. Migration of LC and other dendritic cells (DC) from the skin to the draining lymph nodes (LNs) after FITC skin sensitization, is unaffected in the absence of lymphocytes or CD40. FITC+ LC/DC sorted from the LNs of lymphoid deficient or control mice stimulated naive T cells with similar efficiency. However, while the absence of lymphocytes did not appear to affect the phenotype or number of emigrating LN DC/LC, their persistence in the LN appears to depend on alphabeta T cells. Thus, DC are strikingly reduced in numbers in the peripheral LNs of T-cell deficient mice. Finally, CD8alpha expression on skin emigrants was low and dependent on the presence of CD8+ lymphocytes, while spleen CD8+ DC were present in the absence of lymphocytes. We conclude that the presence of T cells is not required for the differentiation and migration of resident skin DC but is critical for the maintenance of DC and LC migrating into the LNs.

Diagnostic relevance of Langerin detection in cells from bronchoalveolar lavage of patients with pulmonary Langerhans cell histiocytosis, sarcoidosis and idiopathic pulmonary fibrosis.

The diagnosis of pulmonary Langerhans cell histiocytosis might be refined by demonstrating reliability of a new cell marker, i.e., Langerin (CD207), used on bronchoalveolar lavage fluid. For this purpose, we collected material from patients with this disease and also with sarcoidosis and idiopathic pulmonary fibrosis as controls. In addition to the immunocytochemical detection of Langerin, we examined the expression profiles of CD1a and the macrophage tandem-repeat mannose receptor (CD206). To test accessibility of Langerin, a C-type lectin, for mannosides, we employed reverse lectin histochemistry using mannose-containing neoglycoproteins. The analysis revealed a significantly increased percentage of CD1a- and Langerin-positive cells in pulmonary Langerhans cell histiocytosis in comparison with both other studied diseases. No expression of the 175-kDa mannose-binding lectin (CD206) in Langerhans cells was observed. Evidently, binding sites on the cells were not accessible for the mannose-containing neoglycoligand. These results provide evidence for the usefulness of Langerin-directed immuno- and glycohistochemical monitoring of bronchoalveolar lavage fluid in the diagnosis of pulmonary Langerhans cell histiocytosis.

Immunohistochemical tracking of an immune response in mammary Paget's disease.

Dendritic cells (DC) are the most potent antigen-presenting cells of the organism. They are specialized to capture, process, and present antigen via the MHC class II as well as the MHC class I pathways to CD4+ and CD8+ T cells, respectively. This results in T cell-mediated immune responses that are likely to counteract the generation and propagation of tumors in vivo. Therefore, we studied the distribution of dendritic cells in mammary Paget's disease. Paraffin-embedded samples of Paget's disease of the breast (n=27) and of disease-free epidermis of the nipple (n=10) were investigated immunohistochemically for the presence of dendritic cells, in particular of Langerhans cells, using antibodies against S-100, CD1a, and HLA-DR, as well as novel reagents against Langerin/CD207, DC-LAMP/CD208 and p55 (Fascin), the latter two being specific for mature dendritic cells. Paget samples presented a decrease of CD1a+, S-100+, and Langerin+ intraepidermal Langerhans cells in almost all cases. This was paralleled by a concentration of immature dendritic cells in the tumor-infiltrated tissue itself. Similar to infiltrating breast carcinoma we observed a marked increase of DC-LAMP+ and p55+ mature dendritic cells in the corial tissue beneath the tumor. These cells were almost always found in ribbon-like or nodular lymphocytic infiltrates. Moreover, rare mature dendritic cells were also found in the Paget cell-infiltrated epidermis of the nipple, i.e. in the tumorous lesion itself. These findings may indicate an effective ongoing anti-tumor immune response in this part of spreading breast cancer.

Long-term deposition of inhaled antigen in lung resident CD11b-CD11c+ cells.

In this study we report the characterization of a population of lung resident CD11b(-)CD11c(+) cells that are able to take up inhaled antigen and retain it for extended periods of time. Ovalbumin conjugated to fluorescein-isothiocyanate (FITC-OVA) administered intranasally to mice was taken up by two main populations of cells in the lung, a migratory CD11c(+)CD11b(+) population consisting of dendritic cells (DC), which rapidly transported antigen to the draining lymph node (LN), and a resident CD11b(-)CD11c(+) population that retained engulfed antigen without apparently degrading it for up to 8 wk after administration. The FITC(+)CD11b(-)CD11c(+) cells did not migrate to draining LN at a detectable rate, and did not up-regulate expression of costimulatory molecules in response to LPS treatment. FITC(+)CD11b(-)CD11c(+) cells were found in the lung and bronchoalveolar lavage fluid, and their distribution was compatible with macrophages. Although FITC(+)CD11b(-)CD11c(+) cells expressed the DC marker DEC205 and other molecules associated with antigen-presenting cell function, they did not induce proliferation of antigen-specific CD4(+) T cells in vitro or acute cytokine production by activated CD4(+) T cells in vivo. Thus, FITC(+)CD11b(-)CD11c(+) cells appear to represent an intermediate cell type sharing properties with DC and macrophages. These cells may have a role in modulating the responses of lung resident T cells to inhaled antigens.

Peroxisome proliferator-activated receptor-alpha activation inhibits Langerhans cell function.

Epidermal Langerhans cells (LC) play a pivotal role in initiating and maintaining primary immune responses in the skin. In the present study, we asked whether peroxisome proliferator-activated receptor-alpha (PPARalpha) activation modulates LC function. Our results show that PPARalpha is expressed in immature LC and is down-regulated in mature LC suggesting that an early decrease of PPARalpha expression in LC may allow them to mature after contact with an Ag. We further show that pharmacologic PPARalpha activation inhibits LC maturation, migratory capacity, cytokine expression, and the ability to drive T cell proliferation. Moreover, PPARalpha activation inhibits NF-kappaB but not stress-activated protein kinase/JNK, p38MAPK, and ERK1/2. In conclusion, PPARalpha activation by endogenous ligands may provide a molecular signal that allows LC to remain in an immature state within the epidermis for extended periods of time despite minor environmental stimuli.

Lymph node resident rather than skin-derived dendritic cells initiate specific T cell responses after Leishmania major infection.

Langerhans cells have been thought to play a major role as APCs for induction of specific immune responses to Leishmania major. Although their requirement for control of infection has been challenged recently, it remains unclear whether they can transport Ag to lymph nodes and promote initiation of T cell responses. Moreover, the role of dermal dendritic cells (DCs), another population of skin DCs, has so far not been addressed. We have investigated the origin and characterized the cell population responsible for initial activation of L. major-specific T cells in susceptible and resistant mice. We found that Ag presentation in draining lymph nodes peaks as early as 24 h after infection and is mainly mediated by a population of CD11c(high)CD11b(high)Gr-1-CD8-langerin- DCs residing in lymph nodes and acquiring soluble Ags possibly drained through the conduit network. In contrast, skin-derived DCs, including Langerhans cells and dermal DCs, migrated poorly to lymph nodes and played a minor role in early T cell activation. Furthermore, prevention of migration through early removal of the infection site did not affect Ag presentation by CD11c(high) CD11b(high) DCs and activation of Leishmania major-specific naive CD4+ T cells in vivo.

Development of intravital intermittent confocal imaging system for studying Langerhans cell turnover.

Although several studies have suggested relatively slow turnover of Langerhans cells (LCs), their actual lifespan remains elusive. Here we report the development of a new intravital imaging system for studying LC efflux and influx. Epidermal LCs expressing enhanced green fluorescent protein (EGFP) were visualized in anesthetized I-Abeta-EGFP knock-in mice by confocal microscopy. By overlaying two sets of EGFP+ LC images recorded in the same microscopic fields at time 0 and 24 hours later, we identified LC subpopulations that had disappeared from or newly emerged in the epidermis during that period. Of >10,000 LCs analyzed in this manner, an overwhelming majority (97.8+/-0.2%) of LCs showed no significant changes in the x-y locations, whereas 1.3+/-0.1% of the LCs that were found at time 0 became undetectable 24 hours later, representing LC efflux. Conversely, 0.9+/-0.1% of the LCs that were found at time 24 hours were not detectable at time 0, representing LC influx. From these frequencies, we estimated the half-life of epidermal LCs to range from 53 to 78 days, providing new insights into the immunobiology of LCs. Our intermittent imaging approach may be regarded as a technical breakthrough enabling direct visual assessment of LC turnover in living animals.

High-risk human papilloma virus infection decreases the frequency of dendritic Langerhans' cells in the human female genital tract.

Dendritic cells (DC) are often arranged in planar layers in tissues with high antigenic exposure, such as skin and mucosae. Providing an en face view, this arrangement optimizes in situ analysis regarding morphology (even of individual dendrites), topographic distribution (regular/clustered) and quantification. The few reports on human genital DC usually utilize single markers and conventional sections, restricting immunolabelling only to cell parts sectioned by the cut. To better assess DC in situ, we labelled epithelial sheets, prepared from fresh cervix biopsies, with antibodies to major histocompatibility complex (MHC)-CII, CD1a and Langerin, revealing (with each of these markers) a dense DC network in a planar-like, regular distribution. Using the hybrid capture system to detect the high-risk mucotropic human papilloma virus (HPV) group, 16 positive and five negative women were studied and the results were compared between these groups. DC frequency per area was substantially reduced (to approximately 50% for the three markers) in samples from all HPV-infected patients compared with samples from controls. Unlike HPV(-) samples, Langerin(+) DC in HPV(+) cervix exhibited a highly accentuated dendritic appearance. We believe this to be the first study using these three DC-restricted markers (Langerin, CD1a and MHC-CII) in cervical epithelial sheets from high-risk HPV(+) donors and also the first study to demonstrate the morphological and quantitative changes triggered by high-risk HPV infection. Cervical DC reduction in early, premalignant high-risk HPV infection might represent viral subversion strategies interfering with efficient antigen handling by the immune system's peripheral sentinels, the DC, perhaps hampering appropriate recruitment and subsequent development of effector (cytotoxic) T cells.

Cutaneous dendritic cells.

Cutaneous dendritic cells (DC) include epidermal Langerhans cells (LC), interstitial/dermal dendritic cells (DDC), as well as plasmacytoid DC (pDC) that occur under pathological conditions. These immune cells have a spectrum of different functions with implications that extend far beyond the skin. They have the potential to internalize particulate agents and macromolecules, and display migratory properties that endow them with the unique capacity to journey between skin and draining lymph nodes where they encounter antigen-specific T lymphocytes. Herein, we will review the features of human and mouse cutaneous DC, emphasizing characteristics representative of their life-cycle stages that occur within the skin.