Involvement of plasmacytoid dendritic cells in human diseases

In vitro studies have reported that plasmacytoid dendritic cells (PDCs) exert multiple functions, including production of interferon (IFN)-alpha as effector cells and regulation of T-cell responses as mature DCs. Here we review recent data obtained in situ showing that PDCs accumulate in lesions of type I IFN-related disorders (virus infections and lupus erythematosus), Th2 cell-dominated allergic reactions, and ovarian carcinoma. These results demonstrate that PDCs do migrate to peripheral tissues during inflammation, which lends further support to the view that PDCs most likely are important players in innate and adaptive immunity in vivo. Future research should aim at defining the exact pathogenic or defense roles of PDCs in such disorders and determine whether these cells are potential targets for therapeutic intervention in microbial infections, allergy, autoimmunity, or cancer.     

Murine thymic plasmacytoid dendritic cells

We report herein heterogeneous murine thymic cell subsets expressing CD11c and B220 (CD45R). The CD11c(+)B220(+) subset expresses Ly6C(high) and MHC class II(low) in contrast with previously described thymic DC (CD11c(+)B220(-) cells). Freshly isolated thymic CD11c(+)B220(+) cells show typical plasmacytoid morphology which differentiates to mature DC, in vitro with CpG oligodeoxynucleotides (ODN) 2216; we term this subset thymic plasmacytoid DC (pDC). These thymic pDC are highly sensitive to spontaneous apoptosis in vitro and induce low T cell allo-proliferation activity. Thymic pDC express low TLR2, TLR3 and TLR4 mRNA, normally found on human immature DC, and high TLR7 and TLR9 mRNA, normally found on human pDC. Thymic pDC also produce high amounts of IFN-alpha following culture with CpG ODN 2216 (TLR9 ligands) as compared with the previously defined thymic DC lineage which expresses low TLR9 mRNA and produce high IL-12 (p40) with CpG ODN 2216. These results indicate that thymic pDC are similar to IFN-producing cells as well as human pDC. The TLR and cytokine production profiles are consistent with a nomenclature of pDC. The repertoire of this cell lineage to TLR9 ligands demonstrate that such responses are determined not only by the quantity of expression, but also cell lineage.     

Recruitment of immature plasmacytoid dendritic cells (plasmacytoid monocytes) and myeloid dendritic cells in primary cutaneous melanomas

The present study has analysed the distribution and phenotype of dendritic cells (DCs) in primary cutaneous melanomas and sentinel lymph nodes by immunohistochemistry. In primary melanomas, an increase of DCs was found in the epidermis and the peritumoural area. Intraepidermal DCs were mostly CD1a⁺/Langerin⁺ Langerhans cells. Peritumoural DCs included a large population of DC‐SIGN⁺/mannose‐receptor⁺/CD1a^? DCs, a small subset of CD1a⁺ DCs, and, remarkably, plasmacytoid monocytes/plasmacytoid DCs (PM/PDCs). The PM/PDCs, most likely recruited by SDF‐1 secreted by melanoma cells, produced type I interferon (IFN‐I), but the expression of the IFN‐α inducible protein MxA was extremely variable and very limited in the majority of cases. All DC subsets were predominantly immature. The peritumoural area also contained a minor subset of mature CD1a⁺ DCs. However, the small amount of local interleukin (IL)‐12 p40 mRNA and the naïve phenotype of 20–50% of peritumoural T‐lymphocytes are consistent with poor T‐cell stimulation or erroneous recruitment. In sentinel lymph nodes, notable expansion of mature CD1a⁺/Langerin⁺ DCs was observed. The paucity of intratumoural DCs and the predominant immature phenotype of peritumoural dermal DCs indicate defective maturation of primary cutaneous melanoma‐associated DCs, resulting in lack of T‐cell priming. These results may explain why melanoma cells grow despite the presence of infiltrating immune cells. Copyright © 2003 John Wiley & Sons, Ltd.     

Origin and differentiation of dendritic cells

Despite extensive, recent research on the development of dendritic cells (DCs), their origin is a controversial issue in immunology, with important implications regarding their use in cancer immunotherapy. Although, under defined experimental conditions, DCs can be generated from myeloid or lymphoid precursors, the differentiation pathways that generate DCs in vivo remain unknown largely. Indeed, experimental results suggest that the in vivo differentiation of a particular DC subpopulation could be unrelated to its possible experimental generation. Nevertheless, the analysis of DC differentiation by in vivo and in vitro experimental systems could provide important insights into the control of the physiological development of DCs and constitutes the basis of a model of common DC differentiation that we propose.     

Plasmacytoid dendritic cells promote acute kidney injury by producing interferon-α

Acute kidney injury (AKI) is a common clinical complication associated with high mortality in patients. Immune cells and cytokines have recently been described to play essential roles in AKI pathogenesis. Plasmacytoid dendritic cells (pDCs) are a unique DC subset that specializes in type I interferon (IFN) production. Here, we showed that pDCs rapidly infiltrated the kidney in response to AKI and contributed to kidney damage by producing IFN-α. Deletion of pDCs using DTR^BDCA2 transgenic (Tg) mice suppressed cisplatin-induced AKI, accompanied by marked reductions in proinflammatory cytokine production, immune cell infiltration and apoptosis in the kidney. In contrast, adoptive transfer of pDCs during AKI exacerbated kidney damage. We further identified IFN-α as the key factor that mediated the functions of pDCs during AKI, as IFN-α neutralization significantly attenuated kidney injury. Furthermore, IFN-α produced by pDCs directly induced the apoptosis of renal tubular epithelial cells (TECs) in vitro. In addition, our data demonstrated that apoptotic TECs induced the activation of pDCs, which was inhibited in the presence of an apoptosis inhibitor. Furthermore, similar deleterious effects of pDCs were observed in an ischemia reperfusion (IR)-induced AKI model. Clinically, increased expression of IFN-α in kidney biopsies was observed in kidney transplants with AKI. Taken together, the results of our study reveal that pDCs play a detrimental role in AKI via IFN-α.     

Circulating myeloid and plasmacytoid dendritic cells after allergen inhalation in asthmatic subjects

BACKGROUND: Dendritic cells are key contributors to initiation and maintenance of T-cell immunity to inhaled allergen. The purpose of this study was to enumerate the changes in peripheral blood myeloid (mDCs) and plasmacytoid dendritic cells (pDCs), the DCs expressing chemokine receptor 6 (CCR6) and chemokine receptor 7 (CCR7), following diluent and allergen inhalation in asthmatic subjects. METHODS: Peripheral blood was obtained from 16 allergic asthmatic subjects before and at 0.5, 1, 2, 3, 4, 6, 24, and 48 h after inhaled diluent and allergen challenges. Dendritic cells were enumerated using flow cytometry. RESULTS: Allergen inhalation significantly reduced mDCs at 6 h (21.3 +/- 2.0 vs 15.0 +/- 1.8/microl blood; P < 0.05) and 24 h (21.5 +/- 3.4 vs 16.4 +/- 2.4/microl blood; P < 0.05) after challenge. Circulating pDCs were significantly lower than baseline up to 24 h after both allergen and diluent challenges. There was a significant efflux of CCR6(+) mDCs from peripheral blood at 6 h and CCR6(+) pDCs at 4 h after allergen challenge, when compared with diluent. There was no difference in the number of circulating CCR7(+) mDCs or pDCs after diluent or allergen challenges. CONCLUSIONS: Peripheral blood mDCs and CCR6(+) mDCs, but not pDCs, are reduced up to 24 h after allergen inhalation. Thus, allergen inhalation causes trafficking of immature CCR6(+) DCs from blood into the airway, while that of the trafficking of the mature CCR7(+) DCs from the airways into the regional lymph nodes probably occurs through the lymphatic system.     

Rapamycin has suppressive and stimulatory effects on human plasmacytoid dendritic cell functions

Plasmacytoid dendritic cells (PDC) are involved in innate immunity by interferon (IFN)-α production, and in adaptive immunity by stimulating T cells and inducing generation of regulatory T cells (T_reg). In this study we studied the effects of mammalian target of rapamycin (mTOR) inhibition by rapamycin, a commonly used immunosuppressive and anti-cancer drug, on innate and adaptive immune functions of human PDC. A clinically relevant concentration of rapamycin inhibited Toll-like receptor (TLR)-7-induced IFN-α secretion potently (−64%) but TLR-9-induced IFN-α secretion only slightly (−20%), while the same concentration suppressed proinflammatory cytokine production by TLR-7-activated and TLR-9-activated PDC with similar efficacy. Rapamycin inhibited the ability of both TLR-7-activated and TLR-9-activated PDC to stimulate production of IFN-γ and interleukin (IL)-10 by allogeneic T cells. Surprisingly, mTOR-inhibition enhanced the capacity of TLR-7-activated PDC to stimulate naive and memory T helper cell proliferation, which was caused by rapamycin-induced up-regulation of CD80 expression on PDC. Finally, rapamycin treatment of TLR-7-activated PDC enhanced their capacity to induce CD4⁺forkhead box protein 3 (FoxP3)⁺ regulatory T cells, but did not affect the generation of suppressive CD8⁺CD38⁺lymphocyte activation gene (LAG)-3⁺ T_reg. In general, rapamycin inhibits innate and adaptive immune functions of TLR-stimulated human PDC, but enhances the ability of TLR-7-stimulated PDC to stimulate CD4⁺ T cell proliferation and induce CD4⁺FoxP3⁺ regulatory T cell generation.     

The multifaceted murine plasmacytoid dendritic cell

Plasmacytoid dendritic cells (PDCs) or natural interferon-producing cells, function as the body’s innate defense against viral infections. As discussed here, they may play additional roles in response to bacterial pathogens and may have the capacity to induce different type of T-cell responses depending on what signals they receive. The discovery of murine PDCs will allow for the design of models to study viral immunobiology in vivo and to determine their function in various diseases that involve plasmacytoid dendritic cells, such as selected leukemias, lymphomas, allergies, different autoimmune conditions, and their possible role in inducing and maintaining tolerance.     

Sequence independent interferon‐α induction by multimerized phosphodiester DNA depends on spatial regulation of Toll‐like receptor‐9 activation in plasmacytoid dendritic cells

Single‐stranded versus multimeric phosphorothioate‐modified CpG oligodeoxynucleotides (ODNs) undergo differential endosomal trafficking upon uptake into plasmacytoid dendritic cells (pDCs), correlating with Toll‐like receptor‐9‐dependent pDC maturation/activation (single‐stranded B‐type CpG ODN) or interferon‐α (IFN‐α) induction (multimeric A‐type CpG ODN), respectively. As was recently shown, IFN‐α production, other than by CpG ODNs, can also be induced in a sequence‐independent manner by phosphodiester (PD) ODNs multimerized by 3′ poly‐guanosine (poly‐G) tails. We investigate here the type of endosomal trafficking responsible for IFN‐α induction by natural PD ODN ligands. We show that 3′ extension with poly‐G tails leads to multimerization of single‐stranded PD ODNs and to enhanced cellular uptake into pDCs. While monomeric PD ODNs, which induce CpG‐dependent Toll‐like receptor‐9 stimulation and pDC maturation/activation, localized to late endosomal/lysosomal compartments, the poly‐G multimerized PD ODNs, which induce CpG‐independent IFN‐α production, located to vesicles with a distinct, ‘early’ endosomal phenotype. We conclude that poly‐G‐mediated multimerization of natural PD ODNs allows for sequence‐independent, Toll‐like receptor‐9‐dependent IFN‐α induction in pDCs by combining three distinct effects: relative protection of sensitive PD ODNs from extracellular and intracellular DNase degradation, enhanced cellular uptake and preferential early endosomal compartmentation.     

Dexamethasone preferentially suppresses plasmacytoid dendritic cell differentiation and enhances their apoptotic death

Plasmacytoid dendritic cells (pDC) are an important source of type-1 interferon (IFN) following microbial infection and also play key roles in the induction of innate and adaptive immune responses. Here, we show that the glucocorticoid (GC) dexamethasone (Dex) strikingly reduces pDC (and myeloid DC) numbers in secondary lymphoid tissue and liver of normal and hematopoietic growth factor-mobilized mice and suppresses pDC differentiation from bone marrow precursors in vitro. Moreover, the apoptotic death of pDC in vitro was enhanced by exposure to Dex. Notably, however, Toll-like receptor 9 expression and virally induced IFNalpha production by residual pDC from Dex-treated animals were unaffected. Thus, whereas marked reduction in absolute numbers of pDC by GC may predispose to viral infection, often associated with GC-mediated immunosuppression, reductions in pDC and IFNalpha production may contribute to the beneficial effects on GC observed in systemic autoimmune disease, in which that both pDC and IFNalpha have been implicated.     

Clonal lineage tracing reveals shared origin of conventional and plasmacytoid dendritic cells

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Recruitment of dendritic cells in oral lichen planus

Using immunohistochemistry the presence of different dendritic cell (DC) subsets was analysed in 16 biopsies from patients with oral lichen planus (OLP). A significant increase of CD1a+/Langerin+ Langerhans cells, DC-SIGN+ DC and CD123+/BDCA2+ plasmacytoid DCs (PDCs) was found in the epithelium and in the stroma of OLP biopsies compared to normal oral mucosa. A proportion of DCs were mature DC-LAMP+ and expressed S100 or CD11c, typically found in the interdigitating DCs of nodal T-cell areas. Double staining revealed that mature DCs co-expressed CCR7, thus indicating the development of a nodal migratory phenotype upon maturation. Significant recruitment of PDCs producing IFN-alpha was demonstrated by the expression of MxA within the lichenoid inflammatory infiltrate and close cell-to-cell contacts between PDCs and mature DCs were observed, with a significant correlation between the numbers of these two populations. Moreover, PDCs were also found to contain Granzyme-B, an associated-cytotoxic granule protein, inducing target cell apoptosis. Taken together, these results suggest that PDCs may promote maturation of DCs and amplify the cytotoxicity of lymphoid cells. Finally, the recruitment of different subtypes of DC, such as Langerhans cells, stromal DC-SIGN+ DCs and PDCs, associated with a significant proportion of mature DCs, acquiring a CCR7+ 'migratory' phenotype, indicate that they may play a pivotal role in the development of the lichenoid inflammatory infiltrate that occurs typically in OLP.     

Prostaglandin E2 is a negative regulator on human plasmacytoid dendritic cells

Prostaglandin E2 (PGE2), a major lipid derived from the metabolism of arachidonic acid, is an environmentally bioactive substance produced by inflammatory processes and acts as a cAMP up-regulator that plays an important role in immune responses. It has been reported that PGE2 has the ability to inhibit the production of interleukin-12 by myeloid dendritic cells (MDCs) and macrophages, and then induce preferential T helper type 2 (Th2) cell responses. However, little is known of the function of PGE2 for plasmacytoid dendritic cells (PDCs), which may contribute to the innate and adaptive immune response to viral infection, allergy and autoimmune diseases. In the present study, we compared the biological effect of PGE2 on human PDCs and MDCs. PGE2 caused the death of PDCs but MDCs survived. Furthermore, we found that, whereas PGE2 inhibited interferon-alpha production by PDCs in response to virus or cytosine-phosphate-guanosine, it inhibited interleukin-12 production by MDCs in response to lipopolysaccharide (LPS) or poly(I:C). Although both virus-stimulated PDCs and LPS-stimulated MDCs preferentially induced the development of interferon-gamma-producing Th1 cells, pretreatment with PGE2 led both DC subsets to attenuate their Th1-inducing capacity. These findings suggest that PGE2 represents a negative regulator on not only MDCs but also PDCs.     

Tumorous proliferations of plasmacytoid dendritic cells and Langerhans cells associated with acute myeloid leukaemia

Song H‐L, Huang W‐Y, Chen Y‐P & Chang K‐C
(2012) Histopathology  61, 974–983 Tumorous proliferations of plasmacytoid dendritic cells and Langerhans cells associated with acute myeloid leukaemia Aims: Proliferation of plasmacytoid dendritic cells (PDCs) occurs in both reactive lymphoid hyperplasia and myeloproliferative disorders, especially chronic myelomonocytic leukaemia. PDCs in the former appear reactive, but in the latter are reported to be clonally related to the underlying myeloid neoplasm. Langerhans cells (LCs), another type of dendritic cell, also proliferate in both reactive dermatoses and, rarely, myeloproliferative disorders, such as acute leukaemia. Methods and results: We report a rare case of tumorous proliferation of PDCs and LCs in the systemic lymph nodes in a 55‐year‐old man with acute myeloid leukaemia. A microsatellite instability assay showed identical patterns of short tandem repeats in both microdissected PDC and LC components, along with blood blasts. Conclusions: We hypothesize that the combined proliferations of PDCs and LCs derive from the same haematopoietic stem cells, but that they differentiate divergently under the effect of different microenvironments.     

Immune functions and recruitment of plasmacytoid dendritic cells in psoriasis

Psoriasis is one of the most common chronic T cell-mediated diseases in humans. Among the most proximal event in the innate immunity cascade driving psoriatic inflammation is the secretion of type I IFN by activated plasmacytoid dendritic cells (pDC), a special DC subset strategically positioned in pre-psoriatic symptomless skin. There is an IFN-α signature in primary psoriatic plaques, and blocking of type I IFN signalling can prevent the expansion of pathogenetic T cells and development of psoriatic phenotype. Recently, we have demonstrated that pDC infiltration in psoriatic skin correlates with the expression of markers typical of early phases of psoriasis, whereas it is almost absent in long-lasting lesions. Importantly, pDC recruitment in psoriatic skin is strictly associated with the chemerin/ChemR23 axis, and is temporally active during psoriatic plaque development. Pro-chemerin is produced primarily by dermal fibroblasts, but also by mast cells and endothelial cells. Once secreted, it can be activated by enzymes produced by neutrophils and mast cells, which infiltrate early psoriasis lesions. These findings propose the chemerin/ChemR23 axis as a potential novel therapeutic target in psoriasis.     

Role of natural interferon-producing cells and T lymphocytes in porcine monocyte-derived dendritic cell maturation

Maturation of dendritic cells (DC) is a key immunological process regulating immune responses to pathogens and vaccines, as well as tolerance and autoimmune processes. Consequently, the regulation of DC maturation should reflect these multifaceted immunological processes. In the present study, we have defined the role of particular cytokines, Toll-like receptor (TLR) ligands and T lymphocytes in the porcine monocyte-derived DC (MoDC). Interferon-alpha (IFN-alpha) alone was a poor inducer of MoDC maturation, but in association with tumour necrosis factor-alpha (TNF-alpha), or TLR ligands such as lipopolysaccharide and polyinosinic-polycytidylic acid I:C, an up-regulation of major histocompatibility complex II and CD80/86 expression was noted, along with reduced endocytic activity. In contrast, TNF-alpha alone or in combination with the TLR ligands was a poor inducer of DC maturation, but co-operated with T-lymphocytes in the presence of antigen to induce DC maturation. Natural interferon producing cells (NIPC, or plasmacytoid DCs) represent a danger-recognition system of the immune defences, and can respond to viruses not otherwise recognized as posing a danger. Indeed, MoDC did not respond to transmissible gastroenteritis virus (TGEV), whereas NIPC produced high levels of IFN-alpha and TNF-alpha after TGEV stimulation. Moreover, supernatants from the stimulated NIPC induced maturation in MoDCs. These matured MoDCs displayed an enhanced ability to present antigen to and thus stimulate T cells. Taken together, the present work demonstrates that maturation of MoDC not only results from TLR signalling, but can require co-operation with various cell types--principally NIPC and activated T cells--which would reflect the particular immunological situation.     

Altered innate immune response of plasmacytoid dendritic cells in multiple sclerosis

Plasmacytoid dendritic cells (pDCs) are of crucial importance in immune regulation and response to microbial factors. In multiple sclerosis (MS), pDCs from peripheral blood showed an immature phenotype, but its role in susceptibility to MS is not determined. Because infectious diseases are established triggers of exacerbations in MS, in this study we have characterized the expression of Toll‐like receptors (TLR) and the maturation and functional properties of peripheral blood pDCs from clinically stable, untreated MS patients in response to signals of innate immunity. After stimulation of TLR‐9, interferon (IFN)‐α production by pDCs was significantly lower in MS (n = 12) compared to healthy controls (n = 9). In an allogenic two‐step co‐culture assay we found an impaired effect of TLR‐9 stimulation on IFN‐γ expression of autologous naive T cells in MS patients (n = 4). In peripheral blood mononuclear cells, TLR‐9 stimulation with type A CpG ODN resulted in a higher expression of TLR‐1, ‐2, ‐4, ‐5 and ‐8 in MS patients (n = 7) compared with healthy controls (n = 11). These findings suggest an altered innate immune response to microbial stimuli in MS patients and may help understanding of why common infectious agents trigger MS attacks.