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Resident and “Inflammatory” Dendritic Cells in Human Skin

      Dendritic cells (DCs) are a heterogeneous group of antigen-presenting leukocytes that are important in activation of both the innate and adaptive arms of the immune system. Although there are several different DC populations in the body, DCs are globally defined by their capacity for potent antigen presentation and naive T-cell activation. In noninflamed human skin during steady state, there are three main cutaneous DC populations: epidermal Langerhans cells, dermal myeloid DCs, and dermal plasmacytoid DCs. In psoriasis, a model for cutaneous inflammation, there is an additional population of myeloid dermal DCs—“inflammatory DCs”—which appears to be critical for disease pathogenesis.

      Abbreviations

      BDCA
      blood dendritic cell antigen
      DC
      dendritic cell
      IFN
      interferon
      LC
      Langerhans cell
      PDC
      plasmacytoid dendritic cell
      Tip-DC
      tumor necrosis factor and inducible nitric oxide synthase-producing DC

      Introduction

      The term “dendritic cell” (DC) was coined in 1973 when DCs in the lymph node were discovered by Ralph Steinman and Zanvil Cohn (
      • Steinman R.M.
      • Cohn Z.A.
      Identification of a novel cell type in peripheral lymphoid organs of mice. I. Morphology, quantitation, tissue distribution.
      ). These DCs were identified as potent antigen-presenting cells in the mixed leukocyte reaction. However, it took a number of years for scientists to understand the significance and potential roles of these cells, and now we know that they are central in generating and regulating immune responses. Retrospectively, it was appreciated that Langerhans cells (LCs) described in the epidermis of the skin nearly 140 years ago (
      • Langerhans P.
      Uber die Nerven der menschlichen Haut.
      ) were also DCs.
      DCs are a heterogeneous population of cells in the immune system, defined initially by their appearance, but more specifically by their potent ability to present antigen to T cells. Standardized characterization of human cutaneous DC populations is complicated by pleiomorphic phenotype and function during emigration from the skin for ex vivo study, and by the great number of potential surface and intracellular antigens that are present on these leukocytes. In addition, there are differences between human and murine DC networks. DC populations have been historically classified either spatially (circulating blood DCs, draining lymph node DCs, epidermal DCs, and dermal DCs), by their presumed origin (myeloid DCs, plasmacytoid DCs (pDCs)), by physiological or pathophysiological state (steady-state DCs, inflammatory DCs), or by antigen expression (Langerin, DEC-205 and so on). We review our current classification of DC subsets contained within human skin during steady state and inflammation (Figures 1 and 2). Our main message is that there are three cutaneous DC populations in the steady state—epidermal LCs, resident dermal myeloid DCs, and pDCs—and during inflammation there appears to be an additional population of myeloid dermal “inflammatory” DCs. Understanding these DCs may lead to new therapeutic targets for augmenting or suppressing inflammation during human disease (
      • Steinman R.M.
      • Banchereau J.
      Taking dendritic cells into medicine.
      ).
      Figure thumbnail gr1
      Figure 1Dendritic cell and macrophage populations in human skin during steady state and inflammation. Noninflamed skin contains epidermal Langerhans cells, CD1c/BDCA-1+ resident dermal DCs, plasmacytoid DCs, and macrophages. In addition, inflamed skin contains a large population of myeloid “inflammatory” DCs. Common markers used to identify these leukocyte populations are indicated.
      Figure thumbnail gr2
      Figure 2Dendritic cell populations in nonlesional and lesional psoriatic skin. H&E staining demonstrates characteristic features of psoriasis (right), with epidermal acanthosis, elongation of rete ridges, parakeratosis (retention of nuclei in stratum corneum), enlarged blood vessels, and marked leukocytic dermal infiltrate. Immunohistochemistry of nonlesional and lesional psoriatic skin for Langerhans cells (Langerin), resident dermal DCs (CD1c/BDCA-1+), resident and inflammatory myeloid DCs (CD11c), and plasmacytoid DCs (BDCA-2). (Insert) High power magnification of each cell type is approximately 60-μm length. Bar=100μm.

      Langerhans Cells

      LCs reside in the suprabasal layers of the epidermis wedged in between, and in close contact with, keratinocytes. The stellate appearance of these cells led researchers to believe that they were of neural origin until over 100 years later, when their role in antigen presentation was elucidated (
      • Braathen L.R.
      • Thorsby E.
      Studies on human epidermal Langerhans cells. I. Allo-activating and antigen-presenting capacity.
      ). LCs were initially identified by the electron-dense organelle, the Birbeck granule, which has a unique tennis-racket appearance. The function of Birbeck granules is still unclear, but likely includes receptor-mediated endocytosis and transport of cellular materials into the extracellular space (
      • Mc Dermott R.
      • Ziylan U.
      • Spehner D.
      • Bausinger H.
      • Lipsker D.
      • Mommaas M.
      • et al.
      Birbeck granules are subdomains of endosomal recycling compartment in human epidermal Langerhans cells, which form where Langerin accumulates.
      ). The first monoclonal antibody that clearly identified LCs bound to CD1a, a major histocompatibility complex I-like molecule that presents microbial lipids to T cells (
      • Thomas J.A.
      • Biggerstaff M.
      • Sloane J.P.
      • Easton D.F.
      Immunological and histochemical analysis of regional variations of epidermal Langerhans cells in normal human skin.
      ;
      • Barral D.C.
      • Brenner M.B.
      CD1 antigen presentation: how it works.
      ). More recently, the monoclonal antibody to Langerin/CD207 has been used to specifically recognize LCs (Figure 2). Langerin/CD207 is a membranous C-type lectin discovered by
      • Valladeau J.
      • Ravel O.
      • Dezutter-Dambuyant C.
      • Moore K.
      • Kleijmeer M.
      • Liu Y.
      • et al.
      Langerin, a novel C-type lectin specific to Langerhans cells, is an endocytic receptor that induces the formation of Birbeck granules.
      that recognizes mannosylated ligands found on the surface of a wide range of pathogens, including viruses, bacteria, fungi, and protozoa (
      • Figdor C.G.
      • van Kooyk Y.
      • Adema G.J.
      C-type lectin receptors on dendritic cells and Langerhans cells.
      ). Following receptor-mediated endocytosis, CD1a and Langerin/CD207 traffic to the Birbeck granule where they may participate in antigen processing (
      • Stössel H.
      • Koch F.
      • Kämpgen E.
      • Stöger P.
      • Lenz A.
      • Heufler C.
      • et al.
      Disappearance of certain acidic organelles (endosomes and Langerhans cell granules) accompanies loss of antigen processing capacity upon culture of epidermal Langerhans cells.
      ).
      Elegant studies by
      • Merad M.
      • Manz M.G.
      • Karsunky H.
      • Wagers A.
      • Peters W.
      • Charo I.
      • et al.
      Langerhans cells renew in the skin throughout life under steady-state conditions.
      ,
      • Merad M.
      • Hoffmann P.
      • Ranheim E.
      • Slaymaker S.
      • Manz M.G.
      • Lira S.A.
      • et al.
      Depletion of host Langerhans cells before transplantation of donor alloreactive T cells prevents skin graft-versus-host disease.
      have recently shed light on the origin and trafficking of LCs during steady state and inflammation It now seems clear that epidermal LCs are continuously replaced from a resident precursor pool (perhaps by self-renewal) throughout life under steady-state conditions (
      • Merad M.
      • Manz M.G.
      • Karsunky H.
      • Wagers A.
      • Peters W.
      • Charo I.
      • et al.
      Langerhans cells renew in the skin throughout life under steady-state conditions.
      ). However following inflammation, LCs are repopulated by blood precursors, most likely monocytes (
      • Ginhoux F.
      • Tacke F.
      • Angeli V.
      • Bogunovic M.
      • Loubeau M.
      • Dai X.M.
      • et al.
      Langerhans cells arise from monocytes in vivo.
      ). In human psoriasis vulgaris, there are variable reports of the number and arrangement of LCs in the epidermis adjacent to noninflamed epidermis. This may be due to different staining and counting methods used for analysis, or nonequivalent patient populations. In our studies on stable plaque psoriasis, we have found that LCs in lesional and nonlesional epidermis are of similar number per linear surface, with a redistribution to the upper layers of the thickened psoriatic epidermis, and express comparable antigen markers (Krueger JS, unpublished data). These observations are supported by studies showing that LC migration in psoriasis is impaired, leading to retention of LCs in psoriatic inflammation (
      • Cumberbatch M.
      • Singh M.
      • Dearman R.J.
      • Young H.S.
      • Kimber I.
      • Griffiths C.E.
      Impaired Langerhans cell migration in psoriasis.
      ). Further studies need to be performed to evaluate LCs during human disease states using these new markers.
      Interest in LCs has increased with three key observations. First, in mice, there is a newly discovered population of Langerin+ DCs in the dermis and skin-draining lymph nodes (
      • Bursch L.S.
      • Wang L.
      • Igyarto B.
      • Kissenpfennig A.
      • Malissen B.
      • Kaplan D.H.
      • et al.
      Identification of a novel population of Langerin+ dendritic cells.
      ;
      • Ginhoux F.
      • Collin M.P.
      • Bogunovic M.
      • Abel M.
      • Leboeuf M.
      • Helft J.
      • et al.
      Blood-derived dermal langerin+ dendritic cells survey the skin in the steady state.
      ;
      • Poulin L.F.
      • Henri S.
      • de Bovis B.
      • Devilard E.
      • Kissenpfennig A.
      • Malissen B.
      The dermis contains langerin+ dendritic cells that develop and function independently of epidermal Langerhans cells.
      ). These epidermal and dermal LC populations have distinct phenotypic and mitotic capacities, and the dermal Langerin+ LCs do not appear to be simply epidermal LCs en route to the draining lymph node (
      • Stoitzner P.
      • Holzmann S.
      • McLellan A.D.
      • Ivarsson L.
      • Stössel H.
      • Kapp M.
      • et al.
      Visualization and characterization of migratory Langerhans cells in murine skin and lymph nodes by antibodies against Langerin/CD207.
      ,
      • Stoitzner P.
      • Tripp C.H.
      • Douillard P.
      • Saeland S.
      • Romani N.
      Migratory Langerhans cells in mouse lymph nodes in steady state and inflammation.
      ;
      • Douillard P.
      • Stoitzner P.
      • Tripp C.H.
      • Clair-Moninot V.
      • Ait-Yahia S.
      • McLellan A.D.
      • et al.
      Mouse lymphoid tissue contains distinct subsets of langerin/CD207 dendritic cells, only one of which represents epidermal-derived Langerhans cells.
      ). Epidermal LCs are Langerin+CCR6+CCR7+/-, radioresistant, slowly self-replicating (
      • Merad M.
      • Manz M.G.
      • Karsunky H.
      • Wagers A.
      • Peters W.
      • Charo I.
      • et al.
      Langerhans cells renew in the skin throughout life under steady-state conditions.
      ), and are highly responsive to CCR6 agonist macrophage inflammatory protein-3α (CCL20) (
      • Larregina A.T.
      • Morelli A.E.
      • Spencer L.A.
      • Logar A.J.
      • Watkins S.C.
      • Thomson A.W.
      • et al.
      Dermal-resident CD14+ cells differentiate into Langerhans cells.
      ). In contrast, dermal LCs are Langerin+CCR2+CCR7+/-, radiosensitive, rapidly self-replicating, and are responsive to CCR2 agonist monocyte chemoattractant protein-1 (CCL2) (
      • Bursch L.S.
      • Wang L.
      • Igyarto B.
      • Kissenpfennig A.
      • Malissen B.
      • Kaplan D.H.
      • et al.
      Identification of a novel population of Langerin+ dendritic cells.
      ;
      • Ginhoux F.
      • Collin M.P.
      • Bogunovic M.
      • Abel M.
      • Leboeuf M.
      • Helft J.
      • et al.
      Blood-derived dermal langerin+ dendritic cells survey the skin in the steady state.
      ;
      • Poulin L.F.
      • Henri S.
      • de Bovis B.
      • Devilard E.
      • Kissenpfennig A.
      • Malissen B.
      The dermis contains langerin+ dendritic cells that develop and function independently of epidermal Langerhans cells.
      ), although CCR6 expression and responsiveness to CCL20 have not yet been investigated in these dermal Langerin+ CCR2+ cells. Langerin+CD1a+ dermal LCs may also exist in human skin (
      • Angel C.E.
      • George E.
      • Brooks A.E.
      • Ostrovsky L.L.
      • Brown T.L.
      • Dunbar P.R.
      Cutting edge: CD1a+ antigen-presenting cells in human dermis respond rapidly to CCR7 ligands.
      ), although we have not been able to identify many dermal LCs in normal or psoriatic skin in situ (unpublished data;
      • Lowes M.A.
      • Turton J.A.
      • Krueger J.G.
      • Barnetson R.S.
      Psoriasis vulgaris flare during efalizumab therapy does not preclude future use: a case series.
      ).
      Second, there is much debate concerning the pathophysiologial role of LCs. Until recently it was assumed that cutaneous antigens were locally processed by epidermal LCs, which then migrate out of the skin into the draining lymph node for efficient antigen presentation to T cells. During this journey to the lymph node, the LCs change their surface phenotype and “mature”, simultaneously downregulating antigen processing and acquiring improved ability for T-cell co-stimulation (
      • Larregina A.T.
      • Falo Jr, L.D.
      Changing paradigms in cutaneous immunology: adapting with dendritic cells.
      ). Recent studies have questioned the biological significance of this pathway as antigen-specific T-cell activation remains intact in LC-deficient murine models (
      • Mommaas M.
      • Mulder A.
      • Vermeer B.J.
      • Koning F.
      Functional human epidermal Langerhans cells that lack Birbeck granules.
      ;
      • Zhao X.
      • Deak E.
      • Soderberg K.
      • Linehan M.
      • Spezzano D.
      • Zhu J.
      • et al.
      Vaginal submucosal dendritic cells, but not Langerhans cells, induce protective Th1 responses to herpes simplex virus-2.
      ;
      • Ritter U.
      • Meissner A.
      • Scheidig C.
      • Körner H.
      CD8 alpha- and Langerin-negative dendritic cells, but not Langerhans cells, act as principal antigen-presenting cells in leishmaniasis.
      ;
      • Bennett C.L.
      • van Rijn E.
      • Jung S.
      • Inaba K.
      • Steinman R.M.
      • Kapsenberg M.L.
      • et al.
      Inducible ablation of mouse Langerhans cells diminishes but fails to abrogate contact hypersensitivity.
      ;
      • Kaplan D.H.
      • Jenison M.C.
      • Saeland S.
      • Shlomchik W.D.
      • Shlomchik M.J.
      Epidermal langerhans cell-deficient mice develop enhanced contact hypersensitivity.
      ;
      • Kissenpfennig A.
      • Ait-Yahia S.
      • Clair-Moninot V.
      • Stössel H.
      • Badell E.
      • Bordat Y.
      • et al.
      Disruption of the langerin/CD207 gene abolishes Birbeck granules without a marked loss of Langerhans cell function.
      ). However, inconsistent results were obtained in these studies that may be due to many factors, such as the mode of LC depletion (constitutive or induced), the site of challenge (epidermis versus epidermis and dermis), the dose of antigen, and the timing of contact hypersensitivity schedules. To date, no model claiming to show the redundancy of LCs in the induction of immunity has used a strictly epidermotropic pathogen, for example, papillomavirus. Third, another group recently published a novel role for these cells, describing how LCs expressing ligands for cytotoxic T cells unexpectedly promoted murine carcinogenesis (
      • Strid J.
      • Roberts S.J.
      • Filler R.B.
      • Lewis J.M.
      • Kwong B.Y.
      • Schpero W.
      • et al.
      Acute upregulation of an NKG2D ligand promotes rapid reorganization of a local immune compartment with pleiotropic effects on carcinogenesis.
      ).
      These new observations suggest that there is steady-state migration of LCs to skin-draining lymph nodes, perhaps to induce and maintain tolerance to cutaneous antigens (
      • Steinman R.M.
      • Nussenzweig M.C.
      Avoiding horror autotoxicus: the importance of dendritic cells in peripheral T cell tolerance.
      ). Thus a working hypothesis is emerging whereby DCs that reside in the dermis may be essential for the process of cutaneous immune activation, whereas LCs may be more important in sustaining cutanous immunological tolerance.

      Dermal Dcs

      The population of DCs that reside in the dermis of the skin are known as dermal DCs, and these are considered analogous to “interstitial DCs” found in the connective tissue and stroma of other organs (
      • Lenz A.
      • Heine M.
      • Schuler G.
      • Romani N.
      Human and murine dermis contain dendritic cells. Isolation by means of a novel method and phenotypical and functional characterization.
      ;
      • Nestle F.O.
      • Zheng X.G.
      • Thompson C.B.
      • Turka L.A.
      • Nickoloff B.J.
      Characterization of dermal dendritic cells obtained from normal human skin reveals phenotypic and functionally distinctive subsets.
      ;
      • Shortman K.
      • Naik S.H.
      Steady-state and inflammatory dendritic-cell development.
      ). These important cells have the capacity to take up cutaneous antigens, mature and migrate to draining local lymph nodes, and present these antigens to T and B cells (
      • Dubois B.
      • Massacrier C.
      • Vanbervliet B.
      • Fayette J.
      • Briere F.
      • Banchereau J.
      • et al.
      Critical role of IL-12 in dendritic cell-induced differentiation of naive B lymphocytes.
      ;
      • Nestle F.O.
      • Filgueira L.
      • Nickoloff B.J.
      • Burg G.
      Human dermal dendritic cells process and present soluble protein antigens.
      ;
      • Kissenpfennig A.
      • Henri S.
      • Dubois B.
      • Laplace-Builhe C.
      • Perrin P.
      • Romani N.
      • et al.
      Dynamics and function of Langerhans cells in vivo: dermal dendritic cells colonize lymph node areas distinct from slower migrating Langerhans cells.
      ). This process may be essential during skin infections, such as herpes simplex, as blockade of dermal DC migration from skin to lymph node may prevent effective cytotoxic T-cell activation (
      • Allan R.S.
      • Waithman J.
      • Bedoui S.
      • Jones C.M.
      • Villadangos J.A.
      • Zhan Y.
      • et al.
      Migratory dendritic cells transfer antigen to a lymph node-resident dendritic cell population for efficient CTL priming.
      ).
      Because culture methods change the surface cellular phenotype, the purest phenotypic classification of dermal DCs is best performed in situ, followed by ex vivo functional verification of antigen-presenting capacity. Unfortunately, there is no single or specific marker for these cells, although the integrin CD11c is probably the best tool we currently have to identify them. For many years, antibodies to Factor XIIIA clotting factor were used to identify a dermal population of cells that have multiple dendritic processes protruding from a stellate-shaped cell body, and were thus called “dermal dendrocytes” (
      • Headington J.T.
      The dermal dendrocyte.
      ). In 1993,
      • Meunier L.
      • Gonzalez-Ramos A.
      • Cooper K.D.
      Heterogeneous populations of class II MHC+ cells in human dermal cell suspensions. Identification of a small subset responsible for potent dermal antigen-presenting cell activity with features analogous to Langerhans cells.
      described a small population of HLA-DR+CD11c+CD1c+FXIIIA+ cells from cultured normal human dermis that had the capacity to stimulate T cells in a mixed leukocyte reaction. In addition,
      • Nestle F.O.
      • Turka L.A.
      • Nickoloff B.J.
      Characterization of dermal dendritic cells in psoriasis. Autostimulation of T lymphocytes and induction of Th1 type cytokines.
      ) showed that immunostimulatory dermal DC populations were present from psoriatic skin. However, it has recently been demonstrated that factor XIIIA is induced with culture and is actually a macrophage marker, rather than a specific DC marker (
      • Töröcsik D.
      • Bardos H.
      • Nagy L.
      • Adany R.
      Identification of factor XIII-A as a marker of alternative macrophage activation.
      ;
      • Zaba L.C.
      • Fuentes-Duculan J.
      • Steinman R.M.
      • Krueger J.G.
      • Lowes M.A.
      Normal human dermis contains distinct populations of CD11c+BDCA-1+ dendritic cells and CD163+FXIIIA+ macrophages.
      ). Thus, more work needs to be performed to reevaluate the body of literature classifying dermal antigen-presenting cells as FXIIIA+.

      Resident dermal DCs

      To understand dermal DCs and to develop working models to study these cells, we and others have developed the concept that there is a resident population of dermal DCs, as well as an additional group of DCs that appear or develop during inflammation (“inflammatory” dermal DCs) (
      • Shortman K.
      • Naik S.H.
      Steady-state and inflammatory dendritic-cell development.
      ). A proportion of resident murine steady-state dermal DCs (CD11c+) appear to be able to proliferate in situ to maintain the baseline population (
      • Bogunovic M.
      • Ginhoux F.
      • Wagers A.
      • Loubeau M.
      • Isola L.M.
      • Lubrano L.
      • et al.
      Identification of a radio-resistant and cycling dermal dendritic cell population in mice and men.
      ). The major resident population in normal dermis is identified phenotypically with a single monoclonal antibody, CD1c, which is also known as blood dendritic cell antigen (BDCA)-1 (Figure 2). Anti-BDCA antibodies-1 (CD1c), -2 (CD303), -3 (CD141), and -4 (CD304/neuropilin-1) recognize proteins that were first used to identify circulating DCs (
      • Dzionek A.
      • Fuchs A.
      • Schmidt P.
      • Cremer S.
      • Zysk M.
      • Miltenyi S.
      • et al.
      BDCA-2, BDCA-3, and BDCA-4: three markers for distinct subsets of dendritic cells in human peripheral blood.
      ;
      • MacDonald K.P.
      • Munster D.J.
      • Clark G.J.
      • Dzionek A.
      • Schmitz J.
      • Hart D.N.
      Characterization of human blood dendritic cell subsets.
      ). In steady state, CD1c+ (BDCA-1) DCs are relatively immature with modest T-cell stimulatory ability, but their immunostimulatory capacity can be greatly increased with DC maturing stimuli (
      • Zaba L.C.
      • Fuentes-Duculan J.
      • Steinman R.M.
      • Krueger J.G.
      • Lowes M.A.
      Normal human dermis contains distinct populations of CD11c+BDCA-1+ dendritic cells and CD163+FXIIIA+ macrophages.
      ). These CD1c+ (BDCA-1) DCs are also CD11c+HLA-DR+CD45+CD14-, are mostly DC-specific ICAM-3-grabbing nonintegrin/CD209+, and by flow cytometric analysis are approximately 50% low level CD1a+ (unpublished data). CD1c+CD14-CD1a+ dermal DCs from normal skin are also CCR7+ and are responsive to the lymph node chemokine CCL19, suggesting that these cells can migrate to draining lymph nodes for antigen presentation (
      • Angel C.E.
      • George E.
      • Brooks A.E.
      • Ostrovsky L.L.
      • Brown T.L.
      • Dunbar P.R.
      Cutting edge: CD1a+ antigen-presenting cells in human dermis respond rapidly to CCR7 ligands.
      ). Before these experiments, it had been previously shown that dermal DCs associating with T cells in normal skin display an activated phenotype (
      • Pope M.
      • Betjes M.G.
      • Hirmand H.
      • Hoffman L.
      • Steinman R.M.
      Both dendritic cells and memory T lymphocytes emigrate from organ cultures of human skin and form distinctive dendritic-T-cell conjugates.
      ;
      • McLellan A.D.
      • Heiser A.
      • Hart D.N.
      Induction of dendritic cell costimulator molecule expression is suppressed by T cells in the absence of antigen-specific signalling: role of cluster formation, CD40 and HLA-class II for dendritic cell activation.
      ). It is possible that these immature CD1c+ (BDCA-1) resident DCs are tolerogenic in steady state, analogous to epidermal LCs.
      CD1a has also been used to specifically identify immunostimulatory dermal DCs in normal skin (
      • Lenz A.
      • Heine M.
      • Schuler G.
      • Romani N.
      Human and murine dermis contain dendritic cells. Isolation by means of a novel method and phenotypical and functional characterization.
      ;
      • Nestle F.O.
      • Zheng X.G.
      • Thompson C.B.
      • Turka L.A.
      • Nickoloff B.J.
      Characterization of dermal dendritic cells obtained from normal human skin reveals phenotypic and functionally distinctive subsets.
      ;
      • Angel C.E.
      • George E.
      • Brooks A.E.
      • Ostrovsky L.L.
      • Brown T.L.
      • Dunbar P.R.
      Cutting edge: CD1a+ antigen-presenting cells in human dermis respond rapidly to CCR7 ligands.
      ,
      • Angel C.E.
      • Lala A.
      • Chen C.J.
      • Edgar S.G.
      • Ostrovsky L.L.
      • Dunbar P.R.
      CD14+ antigen-presenting cells in human dermis are less mature than their CD1a+ counterparts.
      ) and in psoriasis (
      • Nestle F.O.
      • Turka L.A.
      • Nickoloff B.J.
      Characterization of dermal dendritic cells in psoriasis. Autostimulation of T lymphocytes and induction of Th1 type cytokines.
      ). In normal skin, dermal CD1a+ cells appear to be CD1c+ (BDCA-1) in situ and also in single cell suspensions, although CD1a stains dermal cells at lower intensity compared to epidermal Langerhans cells (unpublished data). This suggests that dermal CD1a+ cells may be a subset of the resident myeloid DCs, but CD1c+ (BDCA-1+) may be a more useful marker of these cells as it co-localizes with nearly all the CD11c+ cells. Second, there are reports of an additional population of dermal antigen-presenting cells identified by CD14+ (
      • Morelli A.E.
      • Rubin J.P.
      • Erdos G.
      • Tkacheva O.A.
      • Mathers A.R.
      • Zahorchak A.F.
      • et al.
      CD4+ T cell responses elicited by different subsets of human skin migratory dendritic cells.
      ;
      • Angel C.E.
      • Lala A.
      • Chen C.J.
      • Edgar S.G.
      • Ostrovsky L.L.
      • Dunbar P.R.
      CD14+ antigen-presenting cells in human dermis are less mature than their CD1a+ counterparts.
      ). In our studies, there are few CD14+ cells in normal skin in situ (unpublished data) and it is not yet clear if these are indeed dermal residents. When the skin is cultured to produce dermal single cell suspensions, it is possible that there are contaminating monocytes. Future studies are required to clarify the CD14+ dermal population and the role of the CD1a+CD1c+ dermal DC subset.
      Although most of these CD1c+ (BDCA-1) cells are relatively immature, there is a small subgroup (∼5%) expressing mature DC markers (
      • Zaba L.C.
      • Fuentes-Duculan J.
      • Steinman R.M.
      • Krueger J.G.
      • Lowes M.A.
      Normal human dermis contains distinct populations of CD11c+BDCA-1+ dendritic cells and CD163+FXIIIA+ macrophages.
      ). This includes DC-lysosomal-associated membrane protein/CD208, and endocytic receptor DEC-205/CD205 that is present on immature DCs, but markedly upregulated on maturation (
      • Guo M.
      • Gong S.
      • Maric S.
      • Misulovin Z.
      • Pack M.
      • Mahnke K.
      • et al.
      A monoclonal antibody to the DEC-205 endocytosis receptor on human dendritic cells.
      ;
      • Butler M.
      • Morel A.S.
      • Jordan W.J.
      • Eren E.
      • Hue S.
      • Shrimpton R.E.
      • et al.
      Altered expression and endocytic function of CD205 in human dendritic cells, and detection of a CD205-DCL-1 fusion protein upon dendritic cell maturation.
      ). These rare, phenotypically mature cells often aggregate together in dermal clusters, but their scarcity prevents detailed functional analysis. Perhaps normal skin requires a small population of mature DCs for fast antigen presentation to local T cells, or for ongoing “micro” immune responses.
      In normal skin, there is also a population of dermal DCs identified by CD141 (BDCA-3). These CD141+ (BDCA-3) cells constitute approximately 10% of all CD11c+ dermal DCs and do not overlap with CD1c+ (BDCA-1) DCs (
      • Zaba L.C.
      • Fuentes-Duculan J.
      • Steinman R.M.
      • Krueger J.G.
      • Lowes M.A.
      Normal human dermis contains distinct populations of CD11c+BDCA-1+ dendritic cells and CD163+FXIIIA+ macrophages.
      ). Again, functional analysis has not been performed on dermal CD141+ (BDCA-3) cells due to their low frequency. However, it has been established that CD141+ (BDCA-3) DCs in blood are nonoverlapping with blood CD1c+ (BDCA-1) DCs and are the least immunostimulatory myeloid blood DC population (
      • MacDonald K.P.
      • Munster D.J.
      • Clark G.J.
      • Dzionek A.
      • Schmitz J.
      • Hart D.N.
      Characterization of human blood dendritic cell subsets.
      ).

      “Inflammatory” dermal DCs

      Psoriatic inflammation induces dramatic changes in dermal DC populations, most obviously a 30-fold increase in CD11c+ DCs in the dermis (approximately equal to T-cell numbers) (
      • Zaba L.C.
      • Cardinale I.
      • Gilleaudeau P.
      • Sullivan-Whalen M.
      • Suarez Farinas M.
      • Fuentes-Duculan J.
      • et al.
      Amelioration of epidermal hyperplasia by TNF inhibition is associated with reduced Th17 responses.
      ) (Figure 2). These DCs return to normal or nonlesional levels with effective treatment (
      • Lowes M.A.
      • Turton J.A.
      • Krueger J.G.
      • Barnetson R.S.
      Psoriasis vulgaris flare during efalizumab therapy does not preclude future use: a case series.
      ;
      • Zaba L.C.
      • Fuentes-Duculan J.
      • Eungdamrong N.J.
      • Abello M.V.
      • Novitskaya I.
      • Pierson K.
      • et al.
      Psoriasis is characterized by accumulation of immunostimulatory and Th1/Th17 cell polarizing myeloid dendritic cells.
      ). Characterization of these cells during inflammation is not yet complete, but our preliminary studies suggest that they are not CD1c+ (BDCA-1), that is, these “inflammatory” myeloid dermal DCs are CD11c+CD1c-. This indicates that they may be derived from circulating DC precursors migrating into the skin due to inflammatory and chemotactic signals. Potential precursors include circulating hematopoietic precursor cells (
      • Svensson M.
      • Kaye P.M.
      Stromal-cell regulation of dendritic-cell differentiation and function.
      ;
      • Massberg S.
      • Schaerli P.
      • Knezevic-Maramica I.
      • Kollnberger M.
      • Tubo N.
      • Moseman E.A.
      • et al.
      Immunosurveillance by hematopoietic progenitor cells trafficking through blood, lymph, and peripheral tissues.
      ), circulating “pre-DCs” (CD11c+ HLA-DRhi, CD16+) (
      • Randolph G.J.
      • Sanchez-Schmitz G.
      • Liebman R.M.
      • Schakel K.
      The CD16(+) (FcgammaRIII(+)) subset of human monocytes preferentially becomes migratory dendritic cells in a model tissue setting.
      ;
      • Tacke F.
      • Randolph G.J.
      Migratory fate and differentiation of blood monocyte subsets.
      ;
      • Piccioli D.
      • Tavarini S.
      • Borgogni E.
      • Steri V.
      • Nuti S.
      • Sammicheli C.
      • et al.
      Functional specialization of human circulating CD16 and CD1c myeloid dendritic-cell subsets.
      ), monocytes (
      • Serbina N.V.
      • Salazar-Mather T.P.
      • Biron C.A.
      • Kuziel W.A.
      • Pamer E.G.
      TNF/iNOS-producing dendritic cells mediate innate immune defense against bacterial infection.
      ), or resident DCs.
      In psoriasis, we have been able to determine that dermal DCs produce mediators, such as tumor necrosis factor and intracellular nitric oxide synthase, which have been termed tumor necrosis factor and inducible nitric oxide synthase-producing DCs (Tip-DCs) (
      • Lowes M.A.
      • Chamian F.
      • Abello M.V.
      • Fuentes-Duculan J.
      • Lin S.L.
      • Nussbaum R.
      • et al.
      Increase in TNF-alpha and inducible nitric oxide synthase-expressing dendritic cells in psoriasis and reduction with efalizumab (anti-CD11a).
      ). It is likely that these Tip-DCs are contained within the CD11c+CD1c- population of “inflammatory” myeloid DCs in psoriasis lesions (
      • Zaba L.C.
      • Fuentes-Duculan J.
      • Eungdamrong N.J.
      • Abello M.V.
      • Novitskaya I.
      • Pierson K.
      • et al.
      Psoriasis is characterized by accumulation of immunostimulatory and Th1/Th17 cell polarizing myeloid dendritic cells.
      ). Tip-DCs were first described in a murine model of Listeria monocytogenes infection (
      • Serbina N.V.
      • Salazar-Mather T.P.
      • Biron C.A.
      • Kuziel W.A.
      • Pamer E.G.
      TNF/iNOS-producing dendritic cells mediate innate immune defense against bacterial infection.
      ) and have also been found in murine Escherichia coli bladder infection (
      • Engel D.
      • Dobrindt U.
      • Tittel A.
      • Peters P.
      • Maurer J.
      • Gutgemann I.
      • et al.
      Tumor necrosis factor alpha- and inducible nitric oxide synthase-producing dendritic cells are rapidly recruited to the bladder in urinary tract infection but are dispensable for bacterial clearance.
      ). In humans, the location and functions of Tip-DCs are emerging: they are present in the lamina propria of the gut where they may be important for immunoglobulin A production (
      • Tezuka H.
      • Abe Y.
      • Iwata M.
      • Takeuchi H.
      • Ishikawa H.
      • Matsushita M.
      • et al.
      Regulation of IgA production by naturally occurring TNF/iNOS-producing dendritic cells.
      ), and they appear to be induced by topical imiquimod treatment of basal cell carcinoma (
      • Stary G.
      • Bangert C.
      • Tauber M.
      • Strohal R.
      • Kopp T.
      • Stingl G.
      Tumoricidal activity of TLR7/8-activated inflammatory dendritic cells.
      ), so they may participate in tumor rejection. Pathogenicity of these Tip-DCs in psoriasis is suggested by the rapid downmodulation of Tip-DC products tumor necrosis factor, inducible nitric oxide synthase, IL-20, and IL-23 during treatment with effective therapies (
      • Zaba L.C.
      • Cardinale I.
      • Gilleaudeau P.
      • Sullivan-Whalen M.
      • Suarez Farinas M.
      • Fuentes-Duculan J.
      • et al.
      Amelioration of epidermal hyperplasia by TNF inhibition is associated with reduced Th17 responses.
      ;
      • Haider A.S.
      • Lowes M.A.
      • Suarez-Farinas M.
      • Zaba L.C.
      • Cardinale I.
      • Khatcherian A.
      • et al.
      Identification of cellular pathways of “Type 1,” Th17 T cells, and TNF- and inducible nitric oxide synthase-producing dendritic cells in autoimmune inflammation through pharmacogenomic study of cyclosporine A in psoriasis.
      ). Tip-DCs can also stimulate the differentiation and activation of Th17 T cells, which are a new set of T cells associated with autoimmune inflammation in many disease models (
      • Zaba L.C.
      • Fuentes-Duculan J.
      • Eungdamrong N.J.
      • Abello M.V.
      • Novitskaya I.
      • Pierson K.
      • et al.
      Psoriasis is characterized by accumulation of immunostimulatory and Th1/Th17 cell polarizing myeloid dendritic cells.
      ). The potential role of these DCs as sources of inflammatory mediators is in contrast to the classic role of DCs as antigen-presenting cells, and warrants further attention. Because these DCs may actually be the key target of a variety of anti-inflammatory therapies, and may be broadly involved in “autoimmune” inflammation of many different human diseases, we need to better understand the development and activation of these cells.
      In another common skin disease, atopic dermatitis, a population of inflammatory DCs have also been described. These cells were initially termed inflammatory dendritic epidermal cells based on flow cytometric analysis of cells from epidermal cell suspensions (
      • Wollenberg A.
      • Kraft S.
      • Hanau D.
      • Bieber T.
      Immunomorphological and ultrastructural characterization of Langerhans cells and a novel, inflammatory dendritic epidermal cell (IDEC) population in lesional skin of atopic eczema.
      ,
      • Wollenberg A.
      • Mommaas M.
      • Oppel T.
      • Schottdorf E.M.
      • Gunther S.
      • Moderer M.
      Expression and function of the mannose receptor CD206 on epidermal dendritic cells in inflammatory skin diseases.
      ;
      • Novak N.
      • Bieber T.
      The role of dendritic cell subtypes in the pathophysiology of atopic dermatitis.
      ). Inflammatory dendritic epidermal cells were defined by the following: HLA-DR+Lin-CD11c+CD1a+ and these DCs co-express CD206/macrophage mannose receptor, CD36, FceRI, immunoglobulin E, CD1b/c, CD11b, as well as DC-specific ICAM-3-grabbing nonintegrin/CD209 (
      • Guttman-Yassky E.
      • Lowes M.A.
      • Fuentes-Duculan J.
      • Whynot J.
      • Novitskaya I.
      • Cardinale I.
      • et al.
      Major differences in inflammatory dendritic cells and their products distinguish atopic dermatitis from psoriasis.
      ). There is now appreciation that these DCs are also located in the dermis and appear to produce a different array of cytokines and chemokines (Th2 chemokines CCL17 and CCL18) than do psoriatic inflammatory DCs, and do not have an inducible nitric oxide synthase signature (
      • Guttman-Yassky E.
      • Lowes M.A.
      • Fuentes-Duculan J.
      • Whynot J.
      • Novitskaya I.
      • Cardinale I.
      • et al.
      Major differences in inflammatory dendritic cells and their products distinguish atopic dermatitis from psoriasis.
      ). Thus the cutaneous inflammatory millieu may drive the differentiation of different types of inflammatory DCs that contribute specifically to the disease process and even clinical phenotype.

      Plasmacytoid Dcs

      PDCs are an additional unique population of resident cutaneous DCs initially described by their morphology, which is similar to a plasma cell (
      • Corcoran L.
      • Ferrero I.
      • Vremec D.
      • Lucas K.
      • Waithman J.
      • O’Keeffe M.
      • et al.
      The lymphoid past of mouse plasmacytoid cells and thymic dendritic cells.
      ). There are considerable phenotypic and functional differences of PDCs in humans and mice, which may contribute to the confusion in the literature as to their precise role in immune responses (
      • Valladeau J.
      • Saeland S.
      Cutaneous dendritic cells.
      ). PDCs share many characteristics with B cells, including dependence on a B-cell transcription factor (SPI-B), and immunoglobulin gene rearrangements. It now appears that both PDCs and myeloid DCs may actually arise from a bone marrow-derived common DC precursor (
      • Naik S.H.
      • Sathe P.
      • Park H.Y.
      • Metcalf D.
      • Proietto A.I.
      • Dakic A.
      • et al.
      Development of plasmacytoid and conventional dendritic cell subtypes from single precursor cells derived in vitro and in vivo.
      ;
      • Onai N.
      • Obata-Onai A.
      • Schmid M.A.
      • Ohteki T.
      • Jarrossay D.
      • Manz M.G.
      Identification of clonogenic common Flt3+M-CSFR+ plasmacytoid and conventional dendritic cell progenitors in mouse bone marrow.
      ). Although both myeloid and pDCs express high levels of HLA-DR and have the capacity to present antigen, pDCs are characterized by their ability to produce large amounts of type 1 interferon (IFN) (IFN-α, β, ω) during viral infection—10,000 fold more IFN than any other cell type (
      • Kadowaki N.
      • Antonenko S.
      • Lau J.Y.
      • Liu Y.J.
      Natural interferon alpha/beta-producing cells link innate and adaptive immunity.
      ;
      • Ito T.
      • Amakawa R.
      • Inaba M.
      • Hori T.
      • Ota M.
      • Nakamura K.
      • et al.
      Plasmacytoid dendritic cells regulate Th cell responses through OX40 ligand and type I IFNs.
      ). This potent IFN production is induced by viral RNA and DNA containing repeated unmethylated CG nucleotide (CpG) binding to Toll-like receptor 7 and Toll-like receptor 9 endosomal receptors, and the CpG class determines the level of IFN produced (
      • Rothenfusser S.
      • Tuma E.
      • Endres S.
      • Hartmann G.
      Plasmacytoid dendritic cells: the key to CpG.
      ). IFN-α, the most studied of the Type I IFNs, modulates development and maturation of many immune cells, including T cells and myeloid DCs, by binding to abundantly expressed IFN receptor (
      • Theofilopoulos A.N.
      • Baccala R.
      • Beutler B.
      • Kono D.H.
      Type I interferons (alpha/beta) in immunity and autoimmunity.
      ). In addition, different stimulation conditions (for example, influenza virus and CpG) may induce distinct activation states in pDC (
      • Iparraguirre A.
      • Tobias J.W.
      • Hensley S.E.
      • Masek K.S.
      • Cavanagh L.L.
      • Rendl M.
      • et al.
      Two distinct activation states of plasmacytoid dendritic cells induced by influenza virus and CpG 1826 oligonucleotide.
      ). The pleiotropic effects of pDC activation are complicated and not fully understood.
      Monoclonal antibodies for pDC identification are well developed and include CD123/IL-3R, BDCA-2, and BDCA-4. BDCA-2 is the only marker that is exclusive to pDCs, as myeloid DCs can express low levels of CD123 and BDCA-4 (
      • Liu Y.J.
      IPC: professional type 1 interferon-producing cells and plasmacytoid dendritic cell precursors.
      ). Thus, a common phenotypic definition of blood and tissue pDCs is HLA-DR+CD11c-CD123hiBDCA-2+. Research on the function of human pDCs during steady state and disease is limited by low frequency and transitory expression of IFNα (
      • Nestle F.O.
      • Gilliet M.
      Defining upstream elements of psoriasis pathogenesis: an emerging role for interferon alpha.
      ).
      In studies of normal skin, there are a small number of pDCs (
      • Ebner S.
      • Ehammer Z.
      • Holzmann S.
      • Schwingshackl P.
      • Forstner M.
      • Stoitzner P.
      • et al.
      Expression of C-type lectin receptors by subsets of dendritic cells in human skin.
      ;
      • Zaba L.C.
      • Fuentes-Duculan J.
      • Steinman R.M.
      • Krueger J.G.
      • Lowes M.A.
      Normal human dermis contains distinct populations of CD11c+BDCA-1+ dendritic cells and CD163+FXIIIA+ macrophages.
      ), and there does not appear to be any marked increase in the frequency of these cells in chronic large plaque psoriasis (
      • Guttman-Yassky E.
      • Lowes M.A.
      • Fuentes-Duculan J.
      • Whynot J.
      • Novitskaya I.
      • Cardinale I.
      • et al.
      Major differences in inflammatory dendritic cells and their products distinguish atopic dermatitis from psoriasis.
      ), although others have found an increase of these cells in psoriasis (
      • Nestle F.O.
      • Conrad C.
      • Tun-Kyi A.
      • Homey B.
      • Gombert M.
      • Boyman O.
      • et al.
      Plasmacytoid predendritic cells initiate psoriasis through interferon-alpha production.
      ). However, two recent observations support a role for pDCs during the initiation phase of psoriasis. First, in xenotransplant experiments of nonlesional skin from patients with psoriasis grafted onto immunosuppressed mice, the stress of transplantation is sufficient for psoriasis to develop spontaneously in the graft (
      • Nestle F.O.
      • Nickoloff B.J.
      From classical mouse models of psoriasis to a spontaneous xenograft model featuring use of AGR mice.
      ). Blockade of IFN-α prevented development of psoriasis, implicating pDCs as they are the primary source of IFN-α in the skin. Second, keratinocyte peptide LL37 (also known as cathelicidin or cathelicidin antimicrobial peptide (cyclic AMP)) binds to self-DNA and Toll-like receptor 9 in pDCs, and induces IFN-α (
      • Lande R.
      • Gregorio J.
      • Facchinetti V.
      • Chatterjee B.
      • Wang Y.H.
      • Homey B.
      • et al.
      Plasmacytoid dendritic cells sense self-DNA coupled with antimicrobial peptide.
      ). Expression of this antimicrobial peptide is increased during inflammation such as psoriasis, and downstream effects of this increased IFN-α production may be activation of myeloid DCs and initiation of psoriasis (
      • Nestle F.O.
      • Gilliet M.
      Defining upstream elements of psoriasis pathogenesis: an emerging role for interferon alpha.
      ). Patients with psoriasis may have pDCs that are particularly sensitive to LL37 and respond in an exaggerated manner with increased IFN-α induction, thus setting in motion psoriatic inflammation.

      Summary

      DC heterogeneity and complexity has made them difficult to understand, but we are currently developing better tools and models to study these cells. DCs are central orchestrators of innate and cellular immune responses, either by secretion of bioactive cytokines or inflammatory mediators that modulate stromal and local cutaneous immunocytes, or by their ability to directly activate T cells. Currently, we do not know the relative contribution or temporal involvement of DC subsets, T cells, and keratinocytes in initiating and maintaining skin inflammation. The data summarized here indicate that DCs are important in cutaneous homeostasis and are likely central to pathogenic processes in the skin. This information from the skin may also be applicable to other organs, systems, and diseases. Further studies on cutaneous DCs are essential if we are to tap into the enormous therapeutic potential of these fascinating cells.

      ACKNOWLEDGMENTS

      Research was supported by NIH grants UL1 RR024143. MAL is supported by 1 K23 AR052404-01A1 and LZ is supported by NIH MSTP grant GM07739. We thank Dr Ralph Steinman for his continued support and inspiration.

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