Preferential depletion of CD2(low) plasmacytoid dendritic cells in HIV-infected subjects

Plasmacytoid dendritic cells (pDCs) are decreased in number and are functionally impaired in HIV act reasons for pDCs depletion are still unknown. It was recently reported that pDCs can be divided into two functionally distinct populations based on their CD2 expression level. To determine how the CD2(high) and CD2(low) populations are affected by HIV infection, we analyzed their frequencies in the peripheral blood of HIV-infected subjects and healthy controls. We found that the CD2(low) pDC subset was preferentially depleted in infected individuals. The frequency of CD2(low) pDCs correlated with the CD4(+) T-cell count but not with the plasma viral load. This finding furthers our understanding of the causes and consequences of pDC depletion during HIV infection.     

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.     

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

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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.     

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.     

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.     

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.     

Role of plasmacytoid dendritic cell subsets in allergic asthma

Plasmacytoid dendritic cells (pDCs) are major type‐I interferon‐producing cells that play important roles in antiviral immunity and tolerance induction. These cells share a common DC progenitor with conventional DCs, and Fms‐like tyrosine kinase‐3 ligand is essential for their development. Several subsets of pDCs have been identified to date including CCR9⁺, CD9⁺, and CD2⁺ pDCs. Recently, three subsets of pDCs were described, namely CD8α⁻β⁻, CD8α⁺β⁻, and CD8α⁺β⁺ subsets. Interestingly, CD8α⁺β⁻ and CD8α⁺β⁺ but not CD8α⁻β⁻ pDCs were shown to have tolerogenic effects in experimentally induced allergic asthma. These tolerogenic effects were shown to be mediated by the generation of FOXP3⁺ regulatory T cells through retinoic acid and the induction of retinaldehyde dehydrogenase enzymes. These newly described subsets of pDCs show high potentials for novel therapeutic approaches for the treatment of allergic diseases. In this review, we will address the new progress in our understanding of pDC biology with respect to allergic disease, in particular allergic asthma.     

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.     

CD49d/CD29‐integrin controls the accumulation of plasmacytoid dendritic cells into the CNS during neuroinflammation

Plasmacytoid dendritic cells (pDCs) are found in the CNS during neuroinflammation and have been reported to exert regulatory functions in multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE). However, the mechanisms of entry of pDCs into the CNS as well as their phenotype and innate functional properties, once recruited into the CNS, have not been thoroughly examined. Herein, we show that pDCs rapidly accumulate into the brain and spinal cord during the acute phase of EAE, and maintain the expression of numerous phenotypic markers typical of peripheral pDCs. Functionally, CNS‐pDCs constitutively expressed IRF7 and were able to rapidly produce type I IFNs and IL‐12p40 upon ex vivo TLR‐9 stimulation. Using adoptive transfer experiments, we provide evidence that CNS‐pDC are recruited from the blood and accumulate into the CNS during the acute phase of EAE. Accumulation of pDCs into the CNS was strongly inhibited in the absence of CD29, but not CD18, suggesting a major role for ß1 but not ß2 integrins. Indeed, blocking the CD49d α4‐integrins during acute EAE drastically diminished CNS‐pDC numbers. Together, our results demonstrate that circulating pDCs are actively recruited into the CNS during acute EAE through a mechanism largely dependent on CD49d/CD29‐integrins.     

Primary cutaneous blastic plasmacytoid dendritic cell neoplasm without extracutaneous manifestation: Case report and review of the literature

Blastic plasmacytoid dendritic cell (BPDC) neoplasm is a rare, highly aggressive hematopoietic malignancy with involvement of bone marrow and peripheral blood. We present 2 cases of primary cutaneous BPDC neoplasm without extracutaneous manifestation during the course of disease. A 36-year-old and a 51-year-old male presented with erythematous patches, purple plaques, and nodules on the head, trunk, and extremities. Skin biopsies revealed that the lesions of both cases were composed of diffusely medium-sized monomorphic blastoid cells infiltrating into the dermis and subcutis. The neoplastic cells were strongly positive for CD4, CD56, CD123, and TdT, whereas other T-cell markers and EBV markers were not expressed. The patients underwent polychemotherapy with hyper-CVAD regimen and obtained a remarkable clinical response with regression of skin lesions. No sign of recurrence and extracutaneous manifestation was found during the period of follow-up. We presume that the favorable prognosis of our cases might result from the presentation only with a skin lesion, diffuse TdT expression in tumor cells, and aggressive chemotherapy with hyper-CVAD regimens. Laboratory examination for blood and bone marrow should be performed every 3-6 months during the first period of follow-up to monitor the progression of disease even if the patients had complete remission at initial chemotherapy.     

Tacrolimus treatment of plasmacytoid dendritic cells inhibits dinucleotide (CpG-)-induced tumour necrosis factor-alpha secretion

Tacrolimus is a widely used immunosuppressive agent. Although T cells are the main targets of these pharmacological drugs, antigen presentation may also be affected. Among antigen-presenting cells, plasmacytoid dendritic cells (PDCs) are the main source of type I interferons upon microbial challenge, and are involved in several diseases and autoimmune disorders. The aim of this study was to evaluate whether tacrolimus can modulate the function of PDCs in vitro. Maturation and function of PDCs was determined using flow cytometry, enzyme-linked immunosorbent assay and cytometry bead arrays. The effect of tacrolimus on PDCs was observed mainly when the cells were pretreated with the immunosuppressive agent before activation. Upon dinucleotide-oligodeoxynucleotide (CpG-ODN) activation, tacrolimus pretreated PDCs showed a significant reduction in the surface expression of co-stimulatory molecules and human leucocyte antigen D-related (HLA-DR) and secreted reduced levels of tumour necrosis factor (TNF)-alpha. These results show that tacrolimus treatment of PDCs impairs CpG-induced activation, which could affect the outcome of the immune response.     

Cytologic features and frequency of plasmacytoid dendritic cells in the lymph nodes of patients with histiocytic necrotizing lymphadenitis (Kikuchi‐Fujimoto disease)

Histiocytic necrotizing lymphadenitis (HNL), also known as Kikuchi‐Fujimoto disease, is a benign and self‐limiting disease. It is histologically characterized by nodal lesions that show the infiltration of histiocytes, lymphoid cells, myeloid dendritic cells (mDCs), and plasmacytoid dendritic cells (pDCs), along with either apoptotic or karyorrhexic nuclear debris. pDCs have been proposed to be lymphoid early‐committed immature DCs which are positive for CD123, CD303, CD68, and HLA‐DR but negative for fascin, a mature DC marker, as well as CD13 and CD33,which are mDC markers. In the present study, we analyzed the cytomorphologic features and frequency of pDCs in the lymph nodes of HNL patients. Because the cytologic apprearance of pDCs with Papanicolau staining was quite similar to that of large lymphocytes, immunocytochemistry against CD123 was necessary for the distinction of pDCs. Counting the number of CD123‐positive pDCs in the HNL lymph nodes revealed that pDCs more frequently infiltrated the lymph nodes in the setting of HNL than in either reactive lymphadenitis or T and B cell lymphoma. In addition, interestingly, the numberof pDCs did not depend on the age of the HNL lesion, thus suggesting that pDCs are excellent indicators for the cytologic diagnosis of HNL. Diagn. Cytopathol. 2010. © 2009 Wiley‐Liss, Inc.     

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.     

HIV-infected cells are major inducers of plasmacytoid dendritic cell interferon production, maturation, and migration

Plasmacytoid dendritic cells (PDC), natural type-1 interferon (IFN) producing cells, could play a role in the innate anti-HIV immune response. Previous reports indicated that PDC IFN production is induced by HIV. Our results show a more robust IFN induction when purified PDC (>95%) were exposed to HIV-infected cells. This effect was not observed with non-viable cells, DNA, and RNA extracted from infected cells, and viral proteins. The response was blocked by anti-CD4 and neutralizing anti-gp120 antibodies as well as soluble CD4. IFN induction by HIV-infected cells was also prevented by low-dose chloroquine, which inhibits endosomal acidification. PDC IFN release resulted in reduced HIV production by infected CD4+ cells, supporting an anti-HIV activity of PDC. Stimulated CD4+ cells induced PDC activation and maturation; markers for PDC migration (CCR7) were enhanced by HIV-infected CD4+ cells only. This latter finding could explain the decline in circulating PDC in HIV-infected individuals.