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Sample records for gluconate-induced dendritic cell

  1. Vitamin D Can Ameliorate Chlorhexidine Gluconate-Induced Peritoneal Fibrosis and Functional Deterioration through the Inhibition of Epithelial-to-Mesenchymal Transition of Mesothelial Cells

    PubMed Central

    Lee, Yi-Che; Hung, Shih-Yuan; Liou, Hung-Hsiang; Lin, Tsun-Mei; Tsai, Chu-Hung; Lin, Sheng-Hsiang; Tsai, Yau-Sheng; Chang, Min-Yu; Wang, Hsi-Hao; Ho, Li-Chun; Chen, Yi-Ting; Wu, Ching-Fang; Chen, Ho-Ching; Chen, Hsin-Pao; Liu, Kuang-Wen; Chen, Chih-I.; She, Kuan Min; Wang, Hao-Kuang; Lin, Chi-Wei; Chiou, Yuan-Yow

    2015-01-01

    Background. Peritoneal dialysis (PD) can induce fibrosis and functional alterations in PD patients' peritoneal membranes, due to long-term unphysiological dialysate exposure, partially occurring via triggering of epithelial-to-mesenchymal transition (EMT) in peritoneal mesothelial cells (MCs). Vitamin D can ameliorate these negative effects; however, the mechanism remains unexplored. Therefore, we investigated its possible links to MCs EMT inhibition. Methods. Peritoneal fibrosis was established in Sprague-Dawley rats by chlorhexidine gluconate (CG) intraperitoneal injection for 21 days, with and without 1α,25(OH)2D3 treatment. Morphological and functional evaluation and western blot analysis of EMT marker were performed upon peritoneum tissue. In vitro study was also performed in a primary human peritoneal MC culture system; MCs were incubated with transforming growth factor-β1 (TGF-β1) in the absence or presence of 1α,25(OH)2D3. EMT marker expression, migration activities, and cytoskeleton redistribution of MCs were determined. Results. 1α,25(OH)2D3 ameliorated CG-induced morphological and functional deterioration in animal model, along with CG-induced upregulation of α-SMA and downregulation of E-cadherin expression. Meanwhile, 1α,25(OH)2D3 also ameliorated TGF-β1-induced decrease in E-cadherin expression, increase in Snai1 and α-SMA expression, intracellular F-actin redistribution, and migration activity in vitro. Conclusion. 1α,25(OH)2D3 can ameliorate CG-induced peritoneal fibrosis and attenuate functional deterioration through inhibiting MC EMT. PMID:26495304

  2. Follicular Dendritic Cell Sarcoma

    PubMed Central

    Udayakumar, Achandira M.; Al-Bahri, Maiya; Burney, Ikram A.; Al-Haddabi, Ibrahim

    2015-01-01

    Follicular dendritic cell sarcoma (FDCS) is a rare neoplasm with a non-specific and insidious presentation further complicated by the difficult diagnostic and therapeutic assessment. It has a low to intermediate risk of recurrence and metastasis. Unlike other soft tissue sarcomas or histiocytic and dendritic cell neoplasms, cytogenetic studies are very limited in FDCS cases. Although no specific chromosomal marker has yet been established, complex aberrations and different ploidy types have been documented. We report the case of a 39-year-old woman with FDCS who presented to the Sultan Qaboos University Hospital in Muscat, Oman, in February 2013. Ultrastructural, immunophenotypical and histological findings are reported. In addition, karyotypic findings showed deletions of the chromosomes 1p, 3q, 6q, 7q, 8q and 11q. To the best of the authors’ knowledge, these have not been reported previously in this tumour. Techniques such as spectral karyotyping may help to better characterise chromosomal abnormalities in this type of tumour. PMID:26355964

  3. Dendritic cells in asthma.

    PubMed

    van Helden, Mary J; Lambrecht, Bart N

    2013-12-01

    The lungs are constantly exposed to antigens, most of which are non-pathogenic and do not require the induction of an immune response. Dendritic cells (DCs) are situated at the basolateral site of the lungs and continuously scan the environment to detect the presence of pathogens and subsequently initiate an immune response. They are a heterogeneous population of antigen-presenting cells that exert specific functions. Compelling evidence is now provided that DCs are both sufficient and necessary to induce allergic responses against several inhaled harmless allergens. How various DC subsets exactly contribute to the induction of allergic asthma is currently a subject of intense investigation. We here review the current progress in this field. PMID:24455765

  4. Can dendritic cells see light?

    NASA Astrophysics Data System (ADS)

    Chen, Aaron C.-H.; Huang, Ying-Ying; Sharma, Sulbha K.; Hamblin, Michael R.

    2010-02-01

    There are many reports showing that low-level light/laser therapy (LLLT) can enhance wound healing, upregulate cell proliferation and has anti-apoptotic effects by activating intracellular protective genes. In the field of immune response study, it is not known with any certainty whether light/laser is proinflammatory or anti-inflammatory. Increasingly in recent times dendritic cells have been found to play an important role in inflammation and the immunological response. In this study, we try to look at the impact of low level near infrared light (810-nm) on murine bone-marrow derived dendritic cells. Changes in surface markers, including MHC II, CD80 and CD11c and the secretion of interleukins induced by light may provide additional evidence to reveal the mystery of how light affects the maturation of dendritic cells as well how these light-induced mature dendritic cells would affect the activation of adaptive immune response.

  5. Dendritic Cell-Targeted Vaccines

    PubMed Central

    Cohn, Lillian; Delamarre, Lélia

    2014-01-01

    Despite significant effort, the development of effective vaccines inducing strong and durable T-cell responses against intracellular pathogens and cancer cells has remained a challenge. The initiation of effector CD8+ T-cell responses requires the presentation of peptides derived from internalized antigen on class I major histocompatibility complex molecules by dendritic cells (DCs) in a process called cross-presentation. A current strategy to enhance the effectiveness of vaccination is to deliver antigens directly to DCs. This is done via selective targeting of antigen using monoclonal antibodies directed against endocytic receptors on the surface of the DCs. In this review, we will discuss considerations relevant to the design of such vaccines: the existence of DC subsets with specialized functions, the impact of the antigen intracellular trafficking on cross-presentation, and the influence of maturation signals received by DCs on the outcome of the immune response. PMID:24910635

  6. Fate Mapping of Dendritic Cells

    PubMed Central

    Poltorak, Mateusz Pawel; Schraml, Barbara Ursula

    2015-01-01

    Dendritic cells (DCs) are a heterogeneous group of mononuclear phagocytes with versatile roles in immunity. They are classified predominantly based on phenotypic and functional properties, namely their stellate morphology, expression of the integrin CD11c, and major histocompatibility class II molecules, as well as their superior capacity to migrate to secondary lymphoid organs and stimulate naïve T cells. However, these attributes are not exclusive to DCs and often change within inflammatory or infectious environments. This led to debates over cell identification and questioned even the mere existence of DCs as distinct leukocyte lineage. Here, we review experimental approaches taken to fate map DCs and discuss how these have shaped our understanding of DC ontogeny and lineage affiliation. Considering the ontogenetic properties of DCs will help to overcome the inherent shortcomings of purely phenotypic- and function-based approaches to cell definition and will yield a more robust way of DC classification. PMID:25999945

  7. Dendritic cells in lung immunopathology.

    PubMed

    Cook, Peter C; MacDonald, Andrew S

    2016-07-01

    Dendritic cells (DCs) lie at the heart of the innate immune system, specialised at recognising danger signals in many forms including foreign material, infection or tissue damage and initiating powerful adaptive immune and inflammatory responses. In barrier sites such as the lung, the instrumental role that DCs play at the interface between the environment and the host places them in a pivotal position in determining the severity of inflammatory disease. The past few years has seen a significant increase in our fundamental understanding of the subsets of DCs involved in pulmonary immunity, as well as the mechanisms by which they are activated and which they may use to coordinate downstream inflammation and pathology. In this review, we will summarise current understanding of the multi-faceted role that DCs play in the induction, maintenance and regulation of lung immunopathology, with an emphasis on allergic pulmonary disease. PMID:27256370

  8. Dendritic cells in autoimmune thyroid disease.

    PubMed

    Kabel, P J; Voorbij, H A; van der Gaag, R D; Wiersinga, W M; de Haan, M; Drexhage, H A

    1987-01-01

    Dendritic cells form a morphologically distinct class of cells characterized by shape, reniform nucleus, absent to weak acid-phosphatase activity and strong Class II MHC determinant positivity. Functionally they are the most efficient cells in antigen presentation to T-lymphocytes which indicates their role in the initiation of an immune response. Using immunehistochemical techniques we studied the presence of dendritic cells in normal Wistar rat and human thyroids, in thyroids of BBW rats developing thyroid autoimmunity and in Graves' goitres. Dendritic cells could be identified in all thyroids studied and were positioned underneath the thyrocytes in between the follicles. Skin dendritic cells travel via lymphatics to draining lymph nodes, thus forming an antigen presenting cell system. It is likely that a similar cell system exists on the level of the thyroid for dendritic cells have also been detected in thyroid draining lymph nodes. In normal thyroid tissue of both human and rat dendritic cells were relatively scarce. During the initial phases of the thyroid autoimmune response in the BBW rat (before the appearance of Tg-antibodies in the circulation) numbers of thyroid dendritic cells increased. Intrathyroidal T-helper cells, B-cells or plasma cells could not be found. The thyroid draining lymph node contained large numbers of plasma cells. During the later stages of the thyroid autoimmune response in the BB/W rat (after the appearance of Tg-antibodies in the circulation) and in Graves' goitres dendritic cells were not only present in high number, but 20-30% were seen in contact with now-present intrathyroidal T-helper lymphocytes.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:3475920

  9. Podosomes of dendritic cells facilitate antigen sampling

    PubMed Central

    Reinieren-Beeren, Inge; Cambi, Alessandra; Figdor, Carl G.; van den Bogaart, Geert

    2014-01-01

    Summary Dendritic cells sample the environment for antigens and play an important role in establishing the link between innate and acquired immunity. Dendritic cells contain mechanosensitive adhesive structures called podosomes that consist of an actin-rich core surrounded by integrins, adaptor proteins and actin network filaments. They facilitate cell migration via localized degradation of extracellular matrix. Here we show that podosomes of human dendritic cells locate to spots of low physical resistance in the substrate (soft spots) where they can evolve into protrusive structures. Pathogen recognition receptors locate to these protrusive structures where they can trigger localized antigen uptake, processing and presentation to activate T-cells. Our data demonstrate a novel role in antigen sampling for podosomes of dendritic cells. PMID:24424029

  10. Plasmacytoid Dendritic Cells in Atherosclerosis

    PubMed Central

    Döring, Yvonne; Zernecke, Alma

    2012-01-01

    Atherosclerosis, a chronic inflammatory disease of the vessel wall and the underlying cause of cardiovascular disease, is initiated and maintained by innate and adaptive immunity. Accumulating evidence suggests an important contribution of autoimmune responses to this disease. Plasmacytoid dendritic cells (pDCs), a specialized cell type known to produce large amounts of type I interferons (IFNs) in response to bacterial and viral infections, have recently been revealed to play important roles in atherosclerosis. For example, the development of autoimmune complexes consisting of self-DNA and antimicrobial peptides, which trigger chronic type I IFN production by pDCs, promote early atherosclerotic lesion formation. pDCs and pDC-derived type I IFNs can also induce the maturation of conventional DCs and macrophages, and the development of autoreactive B cells and antibody production. These mechanisms, known to play a role in the pathogenesis of other autoimmune diseases such as systemic lupus erythematosus and psoriasis, may also affect the development and progression of atherosclerotic lesion formation. This review discusses emerging evidence showing a contribution of pDCs in the onset and progression of atherosclerosis. PMID:22754539

  11. Regulation of Th2 Cell Immunity by Dendritic Cells

    PubMed Central

    Na, Hyeongjin

    2016-01-01

    Th2 cell immunity is required for host defense against helminths, but it is detrimental in allergic diseases in humans. Unlike Th1 cell and Th17 cell subsets, the mechanism by which dendritic cells modulate Th2 cell responses has been obscure, in part because of the inability of dendritic cells to provide IL-4, which is indispensable for Th2 cell lineage commitment. In this regard, immune cells other than dendritic cells, such as basophils and innate lymphoid cells, have been suggested as Th2 cell inducers. More recently, multiple independent researchers have shown that specialized subsets of dendritic cells mediate Th2 cell responses. This review will discuss the current understanding related to the regulation of Th2 cell responses by dendritic cells and other immune cells. PMID:26937227

  12. Dendritic Cells Stimulated by Cationic Liposomes.

    PubMed

    Vitor, Micaela Tamara; Bergami-Santos, Patrícia Cruz; Cruz, Karen Steponavicius Piedade; Pinho, Mariana Pereira; Barbuto, José Alexandre Marzagão; De La Torre, Lucimara Gaziola

    2016-01-01

    Immunotherapy of cancer aims to harness the immune system to detect and destroy cancer cells. To induce an immune response against cancer, activated dendritic cells (DCs) must present tumor antigens to T lymphocytes of patients. However, cancer patients' DCs are frequently defective, therefore, they are prone to induce rather tolerance than immune responses. In this context, loading tumor antigens into DCs and, at the same time, activating these cells, is a tempting goal within the field. Thus, we investigated the effects of cationic liposomes on the DCs differentiation/maturation, evaluating their surface phenotype and ability to stimulate T lymphocytes proliferation in vitro. The cationic liposomes composed by egg phosphatidylcholine, 1,2-dioleoyl-3-trimethylammonium propane and 1,2-dioleoylphosphatidylethanolamine (50/25/25% molar) were prepared by the thin film method followed by extrusion (65 nm, polydispersity of 0.13) and by the dehydration-rehydration method (95% of the population 107 nm, polydispersity of 0.52). The phenotypic analysis of dendritic cells and the analysis of T lymphocyte proliferation were performed by flow cytometry and showed that both cationic liposomes were incorporated and activated dendritic cells. Extruded liposomes were better incorporated and induced higher CD86 expression for dendritic cells than dehydrated-rehydrated vesicles. Furthermore, dendritic cells which internalized extruded liposomes also provided stronger T lymphocyte stimulation. Thus, cationic liposomes with a smaller size and polydispersity seem to be better incorporated by dendritic cells. Hence, these cationic liposomes could be used as a potential tool in further cancer immunotherapy strategies and contribute to new strategies in immunotherapy. PMID:27398454

  13. ISOLATION OF CHICKEN FOLLICULAR DENDRITIC CELLS

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The aim of the present study was to isolate chicken follicular dendritic cells (FDC). A combination of methods involving panning, iodixanol density gradient centrifugation, and magnetic cell separation technology made it possible to obtain functional FDC from the cecal tonsils from chickens, which h...

  14. The multifaceted biology of plasmacytoid dendritic cells

    PubMed Central

    Swiecki, Melissa; Colonna, Marco

    2015-01-01

    Plasmacytoid dendritic cells (pDCs) are a unique dendritic cell subset that specializes in the production of type I interferons (IFNs). pDCs promote antiviral immune responses and have been implicated in the pathogenesis of autoimmune diseases characterized by a type I IFN signature. However, pDCs can also induce tolerogenic immune responses. Here, we review recent progress from the field of pDC biology, focusing on: the molecular mechanisms that regulate pDC development and functions; the pathways involved in their sensing of pathogens and endogenous nucleic acids; the function of pDCs at mucosal sites; and their roles in infections, autoimmunity and cancer. PMID:26160613

  15. Suppression of zinc dendrites in zinc electrode power cells

    NASA Technical Reports Server (NTRS)

    Damjanovic, A.; Diggle, J. W.

    1970-01-01

    Addition of various tetraalkyl quarternary ammonium salts, to alkaline zincate electrolyte of cell, prevents formation of zinc dendrites during charging of zinc electrode. Electrode capacity is not impaired and elimination of dendrites prolongs cell life.

  16. [Application of dendritic cells in clinical tumor therapy].

    PubMed

    Li, Yan; Xian, Li-jian

    2002-04-01

    The active immunotherapy of dendritic cells is hot in tumor therapy research area. This article is a review of the source of dendritic cells, loading antigen, immunotherapy pathway, clinical application, choice of patients, and so on. It makes preparation for further research of dendritic cells. PMID:12452029

  17. Detecting Danger: The Dendritic Cell Algorithm

    NASA Astrophysics Data System (ADS)

    Greensmith, Julie; Aickelin, Uwe; Cayzer, Steve

    The "Dendritic Cell Algorithm" (DCA) is inspired by the function of the dendritic cells of the human immune system. In nature, dendritic cells are the intrusion detection agents of the human body, policing the tissue and organs for potential invaders in the form of pathogens. In this research, an abstract model of dendritic cell (DC) behavior is developed and subsequently used to form an algorithm—the DCA. The abstraction process was facilitated through close collaboration with laboratory-based immunologists, who performed bespoke experiments, the results of which are used as an integral part of this algorithm. The DCA is a population-based algorithm, with each agent in the system represented as an "artificial DC". Each DC has the ability to combine multiple data streams and can add context to data suspected as anomalous. In this chapter, the abstraction process and details of the resultant algorithm are given. The algorithm is applied to numerous intrusion detection problems in computer security including the detection of port scans and botnets, where it has produced impressive results with relatively low rates of false positives.

  18. Characterization of chicken dendritic cell markers

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Animal and Natural Resources Institute, ARS-USDA, Beltsville, MD, USA. New mouse monoclonal antibodies which detect CD80 and CD83 were developed to characterize chicken dendritic cells (DCs). The characteristics of these molecules have been studied in human, swine, ovine, feline, and canine but not ...

  19. Follicular dendritic cell sarcoma of the tonsil

    PubMed Central

    Kara, Tuba; Serinsoz, Ebru; Arpaci, Rabia Bozdogan; Vayisoglu, Yusuf

    2013-01-01

    Follicular dendritic cell sarcoma (FDCS) is an uncommon tumour within the spectrum of histiocytic and dendritic cell neoplasms that can occur at nodal and extra-nodal sites. Besides being rare, these tumours are difficult to diagnose. A 72-year-old man with a painless mass in the right tonsil was admitted to the Mersin University Hospital. Tonsillectomy was performed. Microscopically, the tumour consisted of spindle-shaped cells with large oval to polygonal nuclei. Lymphocytes were scattered among the tumour cells. Immunohistochemically, the cells were positive for CD23 and vimentin. The tumour was diagnosed as FDCS with histological and immunohistochemical findings. Recognition of extranodal FDCS requires knowledge of this entity and to consider it during the diagnosis. Confirmatory immunohistochemical staining is essential for diagnosis. Correct characterisation of this neoplasm is important because of its potential for recurrence and metastasis. PMID:23365157

  20. Sensitivity of Dendritic Cells to Microenvironment Signals

    PubMed Central

    Motta, Juliana Maria; Rumjanek, Vivian Mary

    2016-01-01

    Dendritic cells are antigen-presenting cells capable of either activating the immune response or inducing and maintaining immune tolerance. They do this by integrating stimuli from the environment and changing their functional status as a result of plasticity. The modifications suffered by these cells have consequences in the way the organism may respond. In the present work two opposing situations known to affect dendritic cells are analyzed: tumor growth, leading to a microenvironment that favors the induction of a tolerogenic profile, and organ transplantation, which leads to a proinflammatory profile. Lessons learned from these situations may help to understand the mechanisms of modulation resulting not only from the above circumstances, but also from other pathologies. PMID:27088097

  1. Plasmacytoid dendritic cell role in cutaneous malignancies.

    PubMed

    Saadeh, Dana; Kurban, Mazen; Abbas, Ossama

    2016-07-01

    Plasmacytoid dendritic cells (pDCs) correspond to a specialized dendritic cell population that exhibit plasma cell morphology, express CD4, CD123, HLA-DR, blood-derived dendritic cell antigen-2 (BDCA-2), and Toll-like receptor (TLR)7 and TLR9 within endosomal compartments. Through their production of type I interferons (IFNs) and other pro-inflammatory cytokines, pDCs provide anti-viral resistance and link the innate and adaptive immunity by controlling the function of myeloid DCs, lymphocytes, and natural killer (NK) cells. While lacking from normal skin, pDCs are usually recruited to the skin in several cutaneous pathologies where they appear to be involved in the pathogenesis of several infectious, inflammatory/autoimmune, and neoplastic entities. Among the latter group, pDCs have the potential to induce anti-tumour immunity; however, the complex interaction of pDCs with tumor cells and their micro-environment appears to contribute to immunologic tolerance. In this review, we aim at highlighting the role played by pDCs in cutaneous malignancies with special emphasis on the underlying mechanisms. PMID:27236509

  2. Dendritic Cells in Systemic Lupus Erythematosus

    PubMed Central

    Seitz, Heather M.; Matsushima, Glenn K.

    2010-01-01

    Systemic lupus erythematosus (SLE) persists as a chronic inflammatory autoimmune disease and is characterized by the production of autoantibodies and immune complexes that affects multiple organs. The underlying mechanism that triggers and sustain disease are complex and involves certain susceptibility genes and environmental factors. There have been several immune mediators linked to SLE including cytokines and chemokines that have been reviewed elsewhere(1–3). A number of articles have reviewed the role of B cells and T cells in SLE(4–10). Here, we focus on role of dendritic cells (DC) and innate immune factors that may regulate autoreactive B cells. PMID:20367140

  3. Role of Dendritic Cells in Immune Dysfunction

    NASA Technical Reports Server (NTRS)

    Savary, Cherylyn A.

    1997-01-01

    Specific aims include: (1) Application of the bioreactor to enhance cytokine-regulated proliferation and maturation of dendritic cells (DC); (2) Based on clues from spaceflight: compare the frequency and function of DC in normal donors and immunocompromised cancer patients; and (3) Initiate studies on the efficiency of cytokine therapy and DC-assisted immunotherapy (using bioreactor-expanded DC) in animal models of experimental fungal infections.

  4. Dendritic cell-based cancer therapeutic vaccines

    PubMed Central

    Palucka, Karolina; Banchereau, Jacques

    2013-01-01

    The past decade has seen tremendous developments in novel cancer therapies, through targeting of tumor cell-intrinsic pathways whose activity is linked to genetic alterations, as well as the targeting of tumor cell-extrinsic factors such as growth factors. Furthermore, immunotherapies are entering the clinic at an unprecedented speed following the demonstration that T cells can efficiently reject tumors and that their anti-tumor activity can be enhanced with antibodies against immune regulatory molecules (checkpoints blockade). Current immunotherapy strategies include monoclonal antibodies against tumor cells or immune regulatory molecules, cell-based therapies such as adoptive transfer of ex vivo activated T cells and natural killer (NK) cells, and cancer vaccines. Herein, we discuss the immunological basis for therapeutic cancer vaccines and how the current understanding of dendritic cell (DC) and T cell biology might enable development of next-generation curative therapies for patients with cancer. PMID:23890062

  5. Galectin-1 Regulates Tissue Exit of Specific Dendritic Cell Populations*

    PubMed Central

    Thiemann, Sandra; Man, Jeanette H.; Chang, Margaret H.; Lee, Benhur; Baum, Linda G.

    2015-01-01

    During inflammation, dendritic cells emigrate from inflamed tissue across the lymphatic endothelium into the lymphatic vasculature and travel to regional lymph nodes to initiate immune responses. However, the processes that regulate dendritic cell tissue egress and migration across the lymphatic endothelium are not well defined. The mammalian lectin galectin-1 is highly expressed by vascular endothelial cells in inflamed tissue and has been shown to regulate immune cell tissue entry into inflamed tissue. Here, we show that galectin-1 is also highly expressed by human lymphatic endothelial cells, and deposition of galectin-1 in extracellular matrix selectively regulates migration of specific human dendritic cell subsets. The presence of galectin-1 inhibits migration of immunogenic dendritic cells through the extracellular matrix and across lymphatic endothelial cells, but it has no effect on migration of tolerogenic dendritic cells. The major galectin-1 counter-receptor on both dendritic cell populations is the cell surface mucin CD43; differential core 2 O-glycosylation of CD43 between immunogenic dendritic cells and tolerogenic dendritic cells appears to contribute to the differential effect of galectin-1 on migration. Binding of galectin-1 to immunogenic dendritic cells reduces phosphorylation and activity of the protein-tyrosine kinase Pyk2, an effect that may also contribute to reduced migration of this subset. In a murine lymphedema model, galectin-1−/− animals had increased numbers of migratory dendritic cells in draining lymph nodes, specifically dendritic cells with an immunogenic phenotype. These findings define a novel role for galectin-1 in inhibiting tissue emigration of immunogenic, but not tolerogenic, dendritic cells, providing an additional mechanism by which galectin-1 can dampen immune responses. PMID:26216879

  6. Mucosal dendritic cells shape mucosal immunity

    PubMed Central

    Chang, Sun-Young; Ko, Hyun-Jeong; Kweon, Mi-Na

    2014-01-01

    Dendritic cells (DCs) are key modulators that shape the immune system. In mucosal tissues, DCs act as surveillance systems to sense infection and also function as professional antigen-presenting cells that stimulate the differentiation of naive T and B cells. On the basis of their molecular expression, DCs can be divided into several subsets with unique functions. In this review, we focus on intestinal DC subsets and their function in bridging the innate signaling and adaptive immune systems to maintain the homeostasis of the intestinal immune environment. We also review the current strategies for manipulating mucosal DCs for the development of efficient mucosal vaccines to protect against infectious diseases. PMID:24626170

  7. Generation of regulatory dendritic cells after treatment with paeoniflorin.

    PubMed

    Chen, Dan; Li, Yingxi; Wang, Xiaodong; Li, Keqiu; Jing, Yaqing; He, Jinghua; Qiang, Zhaoyan; Tong, Jingzhi; Sun, Ke; Ding, Wen; Kang, Yi; Li, Guang

    2016-08-01

    Regulatory dendritic cells are a potential therapeutic tool for assessing a variety of immune overreaction diseases. Paeoniflorin, a bioactive glucoside extracted from the Chinese herb white paeony root, has been shown to be effective at inhibiting the maturation and immunostimulatory function of murine bone marrow-derived dendritic cells. However, whether paeoniflorin can program conventional dendritic cells toward regulatory dendritic cells and the underlying mechanism remain unknown. Here, our study demonstrates that paeoniflorin can induce the production of regulatory dendritic cells from human peripheral blood monocyte-derived immature dendritic cells in the absence or presence of lipopolysaccharide (LPS) but not from mature dendritic cells, thereby demonstrating the potential of paeoniflorin as a specific immunosuppressive drug with fewer complications and side effects. These regulatory dendritic cells treated with paeoniflorin exhibited high CD11b/c and low CD80, CD86 and CD40 expression levels as well as enhanced abilities to capture antigen and promote the proliferation of CD4(+)CD25(+) T cells and reduced abilities to migrate and promote the proliferation of CD4(+) T cells, which is associated with the upregulation of endogenous transforming growth factor (TGF)-β-mediated indoleamine 2,3-dioxygenase (IDO) expression. Collectively, paeoniflorin could program immature dendritic cells (imDCs) and imDCs stimulated with LPS toward a regulatory DC fate by upregulating the endogenous TGF-β-mediated IDO expression level, thereby demonstrating its potential as a specific immunosuppressive drug. PMID:26721806

  8. Immunometabolism governs dendritic cell and macrophage function

    PubMed Central

    2016-01-01

    Recent studies on intracellular metabolism in dendritic cells (DCs) and macrophages provide new insights on the functioning of these critical controllers of innate and adaptive immunity. Both cell types undergo profound metabolic reprogramming in response to environmental cues, such as hypoxia or nutrient alterations, but importantly also in response to danger signals and cytokines. Metabolites such as succinate and citrate have a direct impact on the functioning of macrophages. Immunogenicity and tolerogenicity of DCs is also determined by anabolic and catabolic processes, respectively. These findings provide new prospects for therapeutic manipulation in inflammatory diseases and cancer. PMID:26694970

  9. [Dendritic cells in cancer immunotherapy].

    PubMed

    Gato, M; Liechtenstein, T; Blanco-Luquín, I; Zudaire, M I; Kochan, G; Escors, D

    2015-01-01

    Since the beginning of the 20th century, biomedical scientists have tried to take advantage of the natural anti-cancer activities of the immune system. However, all the scientific and medical efforts dedicated to this have not resulted in the expected success. In fact, classical antineoplastic treatments such as surgery, radio and chemotherapy are still first line treatments. Even so, there is a quantity of experimental evidence demonstrating that cancer cells are immunogenic. However, the effective activation of anti-cancer T cell responses closely depends on an efficient antigen presentation carried out by professional antigen presenting cells such as DC. Although there are a number of strategies to strengthen antigen presentation by DC, anti-cancer immunotherapy is not as effective as we would expect according to preclinical data accumulated in recent decades. We do not aim to make an exhaustive review of DC immunotherapy here, which is an extensive research subject already dealt with in many specialised reviews. Instead, we present the experimental approaches undertaken by our group over the last decade, by modifying DC to improve their anti-tumour capacities. PMID:26486534

  10. Reduced Purkinje cell dendritic arborization and loss of dendritic spines in essential tremor.

    PubMed

    Louis, Elan D; Lee, Michelle; Babij, Rachel; Ma, Karen; Cortés, Etty; Vonsattel, Jean-Paul G; Faust, Phyllis L

    2014-12-01

    Based on accumulating post-mortem evidence of abnormalities in Purkinje cell biology in essential tremor, we hypothesized that regressive changes in dendritic morphology would be apparent in the Purkinje cell population in essential tremor cases versus age-matched controls. Cerebellar cortical tissue from 27 cases with essential tremor and 27 age-matched control subjects was processed by the Golgi-Kopsch method. Purkinje cell dendritic anatomy was quantified using a Neurolucida microscopic system interfaced with a motorized stage. In all measures, essential tremor cases demonstrated significant reductions in dendritic complexity compared with controls. Median values in essential tremor cases versus controls were: 5712.1 versus 10 403.2 µm (total dendrite length, P=0.01), 465.9 versus 592.5 µm (branch length, P=0.01), 22.5 versus 29.0 (maximum branch order, P=0.001), and 165.3 versus 311.7 (number of terminations, P=0.008). Furthermore, the dendritic spine density was reduced in essential tremor cases (medians=0.82 versus 1.02 µm(-1), P=0.03). Our demonstration of regressive changes in Purkinje cell dendritic architecture and spines in essential tremor relative to control brains provides additional evidence of a pervasive abnormality of Purkinje cell biology in this disease, which affects multiple neuronal cellular compartments including their axon, cell body, dendrites and spines. PMID:25367027

  11. Immune Monitoring Using mRNA-Transfected Dendritic Cells.

    PubMed

    Borch, Troels Holz; Svane, Inge Marie; Met, Özcan

    2016-01-01

    Dendritic cells are known to be the most potent antigen presenting cell in the immune system and are used as cellular adjuvants in therapeutic anticancer vaccines using various tumor-associated antigens or their derivatives. One way of loading antigen into the dendritic cells is by mRNA electroporation, ensuring presentation of antigen through major histocompatibility complex I and potentially activating T cells, enabling them to kill the tumor cells. Despite extensive research in the field, only one dendritic cell-based vaccine has been approved. There is therefore a great need to elucidate and understand the immunological impact of dendritic cell vaccination in order to improve clinical benefit. In this chapter, we describe a method for performing immune monitoring using peripheral blood mononuclear cells and autologous dendritic cells transfected with tumor-associated antigen-encoding mRNA. PMID:27236804

  12. Dendritic cells as therapeutic targets in neuroinflammation.

    PubMed

    Lüssi, Felix; Zipp, Frauke; Witsch, Esther

    2016-07-01

    Multiple sclerosis (MS) is the most common chronic inflammatory demyelinating disorder of the central nervous system characterized by infiltration of immune cells and progressive damage to myelin sheaths and neurons. There is still no cure for the disease, but drug regimens can reduce the frequency of relapses and slightly delay progression. Myeloid cells or antigen-presenting cells (APCs) such as dendritic cells (DC), macrophages, and resident microglia, are key players in both mediating immune responses and inducing immune tolerance. Mounting evidence indicates a contribution of these myeloid cells to the pathogenesis of multiple sclerosis and to the effects of treatment, the understanding of which might provide strategies for more potent novel therapeutic interventions. Here, we review recent insights into the role of APCs, with specific focus on DCs in the modulation of neuroinflammation in MS. PMID:26970979

  13. Probiotics, dendritic cells and bladder cancer.

    PubMed

    Feyisetan, Oladapo; Tracey, Christopher; Hellawell, Giles O

    2012-06-01

    What's known on the subject? and What does the study add? The suppressor effect of probiotics on superficial bladder cancer is an observed phenomenon but the specific mechanism is poorly understood. The evidence strongly suggests natural killer (NK) cells are the anti-tumour effector cells involved and NK cell activity correlates with the observed anti-tumour effect in mice. It is also known that dendritic cells (DC) cells are responsible for the recruitment and mobilization of NK cells so therefore it may be inferred that DC cells are most likely to be the interphase point at which probiotics act. In support of this, purification of NK cells was associated with a decrease in NK cells activity. The current use of intravesical bacille Calmette-Guérin in the management of superficial bladder cancer is based on the effect of a localised immune response. In the same way, understanding the mechanism of action of probiotics and the role of DC may potentially offer another avenue via which the immune system may be manipulated to resist bladder cancer. Probiotic foods have been available in the UK since 1996 with the arrival of the fermented milk drink (Yakult) from Japan. The presence of live bacterial ingredients (usually lactobacilli species) may confer health benefits when present in sufficient numbers. The role of probiotics in colo-rectal cancer may be related in part to the suppression of harmful colonic bacteria but other immune mechanisms are involved. Anti-cancer effects outside the colon were suggested by a Japanese report of altered rates of bladder tumour recurrence after ingestion of a particular probiotic. Dendritic cells play a central role to the general regulation of the immune response that may be modified by probiotics. The addition of probiotics to the diet may confer benefit by altering rates of bladder tumour recurrence and also alter the response to immune mechanisms involved with the application of intravesical treatments (bacille Calmette

  14. Transcriptional control of dendritic cell differentiation.

    PubMed

    Sasaki, Izumi; Kaisho, Tsuneyasu

    2014-01-01

    Dendritic cells (DCs) are professional antigen presenting cells involved critically not only in provoking innate immune responses but also in establishing adaptive immune responses. Dendritic cells are heterogenous and divided into several subsets, including plasmactyoid DCs (pDCs) and several types of conventional DCs (cDCs), which show subset-specific functions. Plasmactyoid DCs are featured by their ability to produce large amounts of type I interferons (IFNs) in response to nucleic acid sensors, TLR7 and TLR9 and involved in anti-viral immunity and pathogenesis of certain autoimmune disorders such as psoriasis. Conventional DCs include the DC subsets with high crosspresentation activity, which contributes to anti-viral and anti-tumor immunity. These subsets are generated from hematopoietic stem cells (HSCs) via several intermediate progenitors and the development is regulated by the transcriptional mechanisms in which subset-specific transcription factors play major roles. We have recently found that an Ets family transcription factor, SPI-B, which is abundantly expressed in pDCs among DC subsets, plays critical roles in functions and late stage development of pDCs. SPI-B functions in cooperation with other transcription factors, especially, interferon regulatory factor (IRF) family members. Here we review the transcription factor-based molecular mechanisms for generation and functions of DCs, mainly by focusing on the roles of SPI-B and its relatives. PMID:24875951

  15. Regulation of Dendritic Cell Function in Inflammation

    PubMed Central

    Said, André; Weindl, Günther

    2015-01-01

    Dendritic cells (DC) are professional antigen presenting cells and link the innate and adaptive immune system. During steady state immune surveillance in skin, DC act as sentinels against commensals and invading pathogens. Under pathological skin conditions, inflammatory cytokines, secreted by surrounding keratinocytes, dermal fibroblasts, and immune cells, influence the activation and maturation of different DC populations including Langerhans cells (LC) and dermal DC. In this review we address critical differences in human DC subtypes during inflammatory settings compared to steady state. We also highlight the functional characteristics of human DC subsets in inflammatory skin environments and skin diseases including psoriasis and atopic dermatitis. Understanding the complex immunoregulatory role of distinct DC subsets in inflamed human skin will be a key element in developing novel strategies in anti-inflammatory therapy. PMID:26229971

  16. Comparative dendritic cell biology of veterinary mammals.

    PubMed

    Summerfield, Artur; Auray, Gael; Ricklin, Meret

    2015-01-01

    Dendritic cells (DC) have a main function in innate immunity in that they sense infections and environmental antigens at the skin and mucosal surfaces and thereby critically influence decisions about immune activation or tolerance. As professional antigen-presenting cells, they are essential for induction of adaptive immune responses. Consequently, knowledge on this cell type is required to understand the immune systems of veterinary mammals, including cattle, sheep, pigs, dogs, cats, and horses. Recent ontogenic studies define bona fide DC as an independent lineage of hematopoietic cells originating from a common precursor. Distinct transcription factors control the development into the two subsets of classical DC and plasmacytoid DC. These DC subsets express a distinguishable transcriptome, which differs from that of monocyte-derived DC. Using a comparative approach based on phenotype and function, this review attempts to classify DC of veterinary mammals and to describe important knowledge gaps. PMID:25387110

  17. Functions of fascin in dendritic cells.

    PubMed

    Yamashiro, Shigeko

    2012-01-01

    Fascin-1 is an actin-bundling protein that shares no homology with other actin-bundling proteins. It is greatly induced upon maturation of dendritic cells (DCs). However, fascin-1 is not expressed in other primary blood cells, including macrophages and neutrophils, indicating a unique role of fascin-1 in the function of DCs upon maturation. An increasing body of evidence has shown that fascin-1 plays critical roles in maturation-associated DC functions, including dynamic assembly of veil-like membrane protrusions, disassembly of podosomes, migration to lymph nodes, and the assembly of the immunological synapse. Pathological analyses of fascin-1 expression revealed that fascin-1 is a useful marker of diseases of immune cells, including Langerhans cell histiocytosis and Hodgkin diseases. Furthermore, attempts have been made to explore the use of a fascin-1 promoter for DNA vaccination because it is strong and specific to DCs. PMID:22428853

  18. Developmental mechanisms that regulate retinal ganglion cell dendritic morphology

    PubMed Central

    Tian, Ning

    2011-01-01

    One of the fundamental features of retinal ganglion cells (RGCs) is that dendrites of individual RGCs are confined to one or a few narrow strata within the inner plexiform layer (IPL), and each RGC synapses only with a small group of presynaptic bipolar and amacrine cells with axons/dendrites ramified in the same strata to process distinct visual features. The underlying mechanisms which control the development of this laminar-restricted distribution pattern of RGC dendrites have been extensively studied, and it is still an open question whether the dendritic pattern of RGCs is determined by molecular cues or by activity-dependent refinement. Accumulating evidence suggests that both molecular cues and activity-dependent refinement might regulate RGC dendrites in a cell subtype-specific manner. However, identification of morphological subtypes of RGCs before they have achieved their mature dendritic pattern is a major challenge in the study of RGC dendritic development. This problem is now being circumvented through the use of molecular markers in genetically engineered mouse lines to identify RGC subsets early during development. Another unanswered fundamental question in the study of activity-dependent refinement of RGC dendrites is how changes in synaptic activity lead to the changes in dendritic morphology. Recent studies have started to shed light on the molecular basis of activity-dependent dendritic refinement of RGCs by showing that some molecular cascades control the cytoskeleton reorganization of RGCs. PMID:21542137

  19. Measles Virus Induces Functional TRAIL Production by Human Dendritic Cells

    PubMed Central

    Vidalain, Pierre-Olivier; Azocar, Olga; Lamouille, Barbara; Astier, Anne; Rabourdin-Combe, Chantal; Servet-Delprat, Christine

    2000-01-01

    Measles virus infection induces a profound immunosuppression that can lead to serious secondary infections. Here we demonstrate that measles virus induces tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) mRNA and protein expression in human monocyte-derived dendritic cells. Moreover, measles virus-infected dendritic cells are shown to be cytotoxic via the TRAIL pathway. PMID:10590149

  20. Dendritic web silicon photovoltaic cell research

    SciTech Connect

    Easoz, J.A.; Rosey, R.; Campbell, R.B.; Rupnik, R.; Sprecace, R.P.; Piotrowski, P.A. . Advanced Energy Systems Div.); McHugh, J.P.; Seidensticker, R.G. . Science and Technology Center)

    1990-05-01

    This report summarizes the evaluation of a checkpoint demonstration of the throughout capability of the silicon dendritic web growth process as of January 1989. The demonstrated throughput of about 20,000 sq.cm/furnace/week was less than desired for a commercial production facility, however the results clearly indicated that the desired 35,000 sq.cm/furnace/week would be reached with continuous melt replenishment during growth. Improvements in seeding and increase in crystal length would increase the throughput even more. Solar cells subsequently fabricated on the material grown during the demonstration had average efficiency levels (14%) equivalent to cells fabricated on web produced prior to the demonstration run. Finally, a business analysis based on the present results gave estimated photovoltaic module costs in agreement with potential commercial viability. 5 figs., 8 tabs.

  1. Dendritic cell control of tolerogenic responses

    PubMed Central

    Manicassamy, Santhakumar; Pulendran, Bali

    2011-01-01

    Summary One of the most fundamental problems in immunology is the seemingly schizophrenic ability of the immune system to launch robust immunity against pathogens, while acquiring and maintaining a state of tolerance to the body’s own tissues and the trillions of commensal microorganisms and food antigens that confront it every day. A fundamental role for the innate immune system, particularly dendritic cells (DCs), in orchestrating immunological tolerance has been appreciated, but emerging studies have highlighted the nature of the innate receptors and the signaling pathways that program DCs to a tolerogenic state. Furthermore, several studies have emphasized the major role played by cellular interactions, and the microenvironment in programming tolerogenic DCs. Here we review these studies and suggest that the innate control of tolerogenic responses can be viewed as different hierarchies of organization, in which DCs, their innate receptors and signaling networks, and their interactions with other cells and local microenvironments represent different levels of the hierarchy. PMID:21488899

  2. Dendritic cell defects in the colorectal cancer

    PubMed Central

    Legitimo, Annalisa; Consolini, Rita; Failli, Alessandra; Orsini, Giulia; Spisni, Roberto

    2014-01-01

    Colorectal cancer (CRC) results from the accumulation of both genetic and epigenetic alterations of the genome. However, also the formation of an inflammatory milieu plays a pivotal role in tumor development and progression. Dendritic cells (DCs) play a relevant role in tumor by exerting differential pro-tumorigenic and anti-tumorigenic functions, depending on the local milieu. Quantitative and functional impairments of DCs have been widely observed in several types of cancer, including CRC, representing a tumor-escape mechanism employed by cancer cells to elude host immunosurveillance. Understanding the interactions between DCs and tumors is important for comprehending the mechanisms of tumor immune surveillance and escape, and provides novel approaches to therapy of cancer. This review summarizes updated information on the role of the DCs in colon cancer development and/or progression. PMID:25483675

  3. Alarmins Link Neutrophils and Dendritic Cells

    PubMed Central

    Yang, De; de la Rosa, Gonzalo; Tewary, Poonam; Oppenheim, Joost J.

    2009-01-01

    Neutrophils are the first major population of leukocyte to infiltrate infected or injured tissues and are crucial for initiating host innate defense and adaptive immunity. Although the contribution of neutrophils to innate immune defense is mediated predominantly by phagocytosis and killing of microorganisms, neutrophils also participate in the induction of adaptive immune responses. At sites of infection and/or injury, neutrophils release numerous mediators upon degranulation or death, among these are alarmins which have a characteristic dual capacity to mobilize and activate antigen-presenting cells. We describe here how alarmins released by neutrophil degranulation and/or death can link neutrophils to dendritic cells by promoting their recruitment and activation, resulting in the augmentation of innate and adaptive immune responses. PMID:19699678

  4. Follicular dendritic cells in health and disease

    PubMed Central

    El Shikh, Mohey Eldin M.; Pitzalis, Costantino

    2012-01-01

    Follicular dendritic cells (FDCs) are unique immune cells that contribute to the regulation of humoral immune responses. These cells are located in the B-cell follicles of secondary lymphoid tissues where they trap and retain antigens (Ags) in the form of highly immunogenic immune complexes (ICs) consisting of Ag plus specific antibody (Ab) and/or complement proteins. FDCs multimerize Ags and present them polyvalently to B-cells in periodically arranged arrays that extensively crosslink the B-cell receptors for Ag (BCRs). FDC-FcγRIIB mediates IC periodicity, and FDC-Ag presentation combined with other soluble and membrane bound signals contributed by FDCs, like FDC-BAFF, -IL-6, and -C4bBP, are essential for the induction of the germinal center (GC) reaction, the maintenance of serological memory, and the remarkable ability of FDC-Ags to induce specific Ab responses in the absence of cognate T-cell help. On the other hand, FDCs play a negative role in several disease conditions including chronic inflammatory diseases, autoimmune diseases, HIV/AIDS, prion diseases, and follicular lymphomas. Compared to other accessory immune cells, FDCs have received little attention, and their functions have not been fully elucidated. This review gives an overview of FDC structure, and recapitulates our current knowledge on the immunoregulatory functions of FDCs in health and disease. A better understanding of FDCs should permit better regulation of Ab responses to suit the therapeutic manipulation of regulated and dysregulated immune responses. PMID:23049531

  5. Follicular dendritic cells in health and disease.

    PubMed

    El Shikh, Mohey Eldin M; Pitzalis, Costantino

    2012-01-01

    Follicular dendritic cells (FDCs) are unique immune cells that contribute to the regulation of humoral immune responses. These cells are located in the B-cell follicles of secondary lymphoid tissues where they trap and retain antigens (Ags) in the form of highly immunogenic immune complexes (ICs) consisting of Ag plus specific antibody (Ab) and/or complement proteins. FDCs multimerize Ags and present them polyvalently to B-cells in periodically arranged arrays that extensively crosslink the B-cell receptors for Ag (BCRs). FDC-FcγRIIB mediates IC periodicity, and FDC-Ag presentation combined with other soluble and membrane bound signals contributed by FDCs, like FDC-BAFF, -IL-6, and -C4bBP, are essential for the induction of the germinal center (GC) reaction, the maintenance of serological memory, and the remarkable ability of FDC-Ags to induce specific Ab responses in the absence of cognate T-cell help. On the other hand, FDCs play a negative role in several disease conditions including chronic inflammatory diseases, autoimmune diseases, HIV/AIDS, prion diseases, and follicular lymphomas. Compared to other accessory immune cells, FDCs have received little attention, and their functions have not been fully elucidated. This review gives an overview of FDC structure, and recapitulates our current knowledge on the immunoregulatory functions of FDCs in health and disease. A better understanding of FDCs should permit better regulation of Ab responses to suit the therapeutic manipulation of regulated and dysregulated immune responses. PMID:23049531

  6. GATA2 regulates dendritic cell differentiation.

    PubMed

    Onodera, Koichi; Fujiwara, Tohru; Onishi, Yasushi; Itoh-Nakadai, Ari; Okitsu, Yoko; Fukuhara, Noriko; Ishizawa, Kenichi; Shimizu, Ritsuko; Yamamoto, Masayuki; Harigae, Hideo

    2016-07-28

    Dendritic cells (DCs) are critical immune response regulators; however, the mechanism of DC differentiation is not fully understood. Heterozygous germ line GATA2 mutations induce GATA2-deficiency syndrome, characterized by monocytopenia, a predisposition to myelodysplasia/acute myeloid leukemia, and a profoundly reduced DC population, which is associated with increased susceptibility to viral infections, impaired phagocytosis, and decreased cytokine production. To define the role of GATA2 in DC differentiation and function, we studied Gata2 conditional knockout and haploinsufficient mice. Gata2 conditional deficiency significantly reduced the DC count, whereas Gata2 haploinsufficiency did not affect this population. GATA2 was required for the in vitro generation of DCs from Lin(-)Sca-1(+)Kit(+) cells, common myeloid-restricted progenitors, and common dendritic cell precursors, but not common lymphoid-restricted progenitors or granulocyte-macrophage progenitors, suggesting that GATA2 functions in the myeloid pathway of DC differentiation. Moreover, expression profiling demonstrated reduced expression of myeloid-related genes, including mafb, and increased expression of T-lymphocyte-related genes, including Gata3 and Tcf7, in Gata2-deficient DC progenitors. In addition, GATA2 was found to bind an enhancer element 190-kb downstream region of Gata3, and a reporter assay exhibited significantly reduced luciferase activity after adding this enhancer region to the Gata3 promoter, which was recovered by GATA sequence deletion within Gata3 +190. These results suggest that GATA2 plays an important role in cell-fate specification toward the myeloid vs T-lymphocyte lineage by regulating lineage-specific transcription factors in DC progenitors, thereby contributing to DC differentiation. PMID:27259979

  7. Strategies to reduce dendritic cell activation through functional biomaterial design

    PubMed Central

    Hume, Patrick S.; He, Jing; Haskins, Kathryn; Anseth, Kristi S.

    2012-01-01

    Dendritic cells play a key role in determining adaptive immunity, and there is growing interest in characterizing and manipulating the interactions between dendritic cells and biomaterial surfaces. Contact with several common biomaterials can induce the maturation of immature dendritic cells, but substrates that reduce dendritic cell maturation are of particular interest within the field of cell-based therapeutics where the goal is to reduce the immune response to cell-laden material carriers. In this study, we use a materials-based strategy to functionalize poly(ethylene glycol) hydrogels with immobilized immunosuppressive factors (TGF-β1 and IL-10) to reduce the maturation of immature dendritic cells. TGF-β1 and IL-10 are commonly employed as soluble factors to program dendritic cells in vitro, and we demonstrate that these proteins retain bioactivity towards dendritic cells when immobilized on hydrogel surfaces. Following stimulation with lipopolysaccharide (LPS) and/or cytokines, a dendritic cell line interacting with the surfaces of immunosuppressive hydrogels expressed reduced markers of maturation, including IL-12 and MHCII. The bioactivity of these immunomodulatory hydrogels was further confirmed with primary bone marrow dendritic cells (BMDCs) isolated from non-obese diabetic (NOD) mice, as quantified by a decrease in activation markers and a significantly reduced capacity to activate T cells. Furthermore, by introducing a second signal to promote BMDC-material interactions combined with the presentation of tolerizing signals, the mulitfunctional PEG hydrogels were found to further increase signaling towards BMDCs, as evidenced by greater reductions in maturation markers. PMID:22361099

  8. DEX-1 and DYF-7 establish sensory dendrite length by anchoring dendritic tips during cell migration.

    PubMed

    Heiman, Maxwell G; Shaham, Shai

    2009-04-17

    Cells are devices whose structures delimit function. For example, in the nervous system, neuronal and glial shapes dictate paths of information flow. To understand how cells acquire their shapes, we examined the formation of a sense organ in C. elegans. Using time-lapse imaging, we found that sensory dendrites form by stationary anchoring of dendritic tips during cell-body migration. A genetic screen identified DEX-1 and DYF-7, extracellular proteins required for dendritic tip anchoring, which act cooperatively at the time and place of anchoring. DEX-1 and DYF-7 contain, respectively, zonadhesin and zona pellucida domains, and DYF-7 self-associates into multimers important for anchoring. Thus, unlike other dendrites, amphid dendritic tips are positioned by DEX-1 and DYF-7 without the need for long-range guidance cues. In sequence and function, DEX-1 and DYF-7 resemble tectorins, which anchor stereocilia in the inner ear, suggesting that a sensory dendrite anchor may have evolved into part of a mechanosensor. PMID:19344940

  9. Magnetic Nanoparticles for Imaging Dendritic Cells

    PubMed Central

    Kobukai, Saho; Baheza, Richard; Cobb, Jared G.; Virostko, Jack; Xie, Jingping; Gillman, Amelie; Koktysh, Dmitry; Kerns, Denny; Does, Mark; Gore, John C.; Pham, Wellington

    2015-01-01

    We report the development of superparamagnetic iron oxide (SPIOs) nanoparticles and investigate the migration of SPIO-labeled dendritic cells (DCs) in a syngeneic mouse model using magnetic resonance (MR) imaging. The size of the dextran-coated SPIO is roughly 30 nm, and the DCs are capable of independent uptake of these particles, although not at levels comparable to particle uptake in the presence of a transfecting reagent. On average, with the assistance of polylysine, the particles were efficiently delivered inside DCs within one hour of incubation. The SPIO particles occupy approximately 0.35% of cell surface and are equivalent to 34.6 pg of iron per cell. In vivo imaging demonstrated that the labeled cells migrated from the injection site in the footpad to the corresponding popliteal lymph node. The homing of labeled cells in the lymph nodes resulted in a signal drop of up to 79%. Furthermore, labeling DCs with SPIO particles did not compromise cell function, we demonstrated that SPIO-enhanced MR imaging can be used to track the migration of DCs effectively in vivo. Magn Reson Med 63:1383–1390, 2010. PMID:20432309

  10. Role of Dendritic Cells in Immune Dysfunction

    NASA Technical Reports Server (NTRS)

    Savary, Cherylyn A.

    1998-01-01

    The specific aims of the project were: (1) Application of the NASA bioreactor to enhance cytokine-regulated proliferation and maturation of dendritic cells (DC). (2) Compare the frequency and function of DC in normal donors and immunocompromised cancer patients. (3) Analyze the effectiveness of cytokine therapy and DC-assisted immunotherapy (using bioreactor-expanded DC) in a murine model of experimental fungal disease. Our investigations have provided new insight into DC immunobiology and have led to the development of methodology to evaluate DC in blood of normal donors and patients. Information gained from these studies has broadened our understanding of possible mechanisms involved in the immune dysfunction of space travelers and earth-bound cancer patients, and could contribute to the design of novel therapies to restore/preserve immunity in these individuals. Several new avenues of investigation were also revealed. The results of studies completed during Round 2 are summarized.

  11. Dendritic Cells in the Cancer Microenvironment

    PubMed Central

    Ma, Yang; Shurin, Galina V.; Peiyuan, Zhu; Shurin, Michael R.

    2013-01-01

    The complexity of the tumor immunoenvironment is underscored by the emergence and discovery of different subsets of immune effectors and regulatory cells. Tumor-induced polarization of immune cell differentiation and function makes this unique environment even more intricate and variable. Dendritic cells (DCs) represent a special group of cells that display different phenotype and activity at the tumor site and exhibit differential pro-tumorigenic and anti-tumorigenic functions. DCs play a key role in inducing and maintaining the antitumor immunity, but in the tumor environment their antigen-presenting function may be lost or inefficient. DCs might be also polarized into immunosuppressive/tolerogenic regulatory DCs, which limit activity of effector T cells and support tumor growth and progression. Although various factors and signaling pathways have been described to be responsible for abnormal functioning of DCs in cancer, there are still no feasible therapeutic modalities available for preventing or reversing DC malfunction in tumor-bearing hosts. Thus, better understanding of DC immunobiology in cancer is pivotal for designing novel or improved therapeutic approaches that will allow proper functioning of DCs in patients with cancer. PMID:23386903

  12. Metabolism Is Central to Tolerogenic Dendritic Cell Function

    PubMed Central

    Sim, Wen Jing; Ahl, Patricia Jennifer; Connolly, John Edward

    2016-01-01

    Immunological tolerance is a fundamental tenant of immune homeostasis and overall health. Self-tolerance is a critical component of the immune system that allows for the recognition of self, resulting in hyporeactivity instead of immunogenicity. Dendritic cells are central to the establishment of dominant immune tolerance through the secretion of immunosuppressive cytokines and regulatory polarization of T cells. Cellular metabolism holds the key to determining DC immunogenic or tolerogenic cell fate. Recent studies have demonstrated that dendritic cell maturation leads to a shift toward a glycolytic metabolic state and preferred use of glucose as a carbon source. In contrast, tolerogenic dendritic cells favor oxidative phosphorylation and fatty acid oxidation. This dichotomous metabolic reprogramming of dendritic cells drives differential cellular function and plays a role in pathologies, such as autoimmune disease. Pharmacological alterations in metabolism have promising therapeutic potential. PMID:26980944

  13. Brain dendritic cells: biology and pathology.

    PubMed

    D'Agostino, Paul M; Gottfried-Blackmore, Andres; Anandasabapathy, Niroshana; Bulloch, Karen

    2012-11-01

    Dendritic cells (DC) are the professional antigen-presenting cells of the immune system. In their quiescent and mature form, the presentation of self-antigens by DC leads to tolerance; whereas, antigen presentation by mature DC, after stimulation by pathogen-associated molecular patterns, leads to the onset of antigen-specific immunity. DC have been found in many of the major organs in mammals (e.g. skin, heart, lungs, intestines and spleen); while the brain has long been considered devoid of DC in the absence of neuroinflammation. Consequently, microglia, the resident immune cell of the brain, have been charged with many functional attributes commonly ascribed to DC. Recent evidence has challenged the notion that DC are either absent or minimal players in brain immune surveillance. This review will discuss the recent literature examining DC involvement within both the young and aged steady-state brain. We will also examine DC contributions during various forms of neuroinflammation resulting from neurodegenerative autoimmune disease, injury, and CNS infections. This review also touches upon DC trafficking between the central nervous system and peripheral immune compartments during viral infections, the new molecular technologies that could be employed to enhance our current understanding of brain DC ontogeny, and some potential therapeutic uses of DC within the CNS. PMID:22825593

  14. Phenotype and function of nasal dendritic cells

    PubMed Central

    Lee, Haekyung; Ruane, Darren; Law, Kenneth; Ho, Yan; Garg, Aakash; Rahman, Adeeb; Esterházy, Daria; Cheong, Cheolho; Goljo, Erden; Sikora, Andrew G.; Mucida, Daniel; Chen, Benjamin; Govindraj, Satish; Breton, Gaëlle; Mehandru, Saurabh

    2015-01-01

    Intranasal vaccination generates immunity across local, regional and distant sites. However, nasal dendritic cells (DC), pivotal for the induction of intranasal vaccine- induced immune responses, have not been studied in detail. Here, using a variety of parameters, we define nasal DCs in mice and humans. Distinct subsets of “classical” DCs, dependent on the transcription factor zbtb46 were identified in the murine nose. The murine nasal DCs were FLT3 ligand-responsive and displayed unique phenotypic and functional characteristics including the ability to present antigen, induce an allogeneic T cell response and migrate in response to LPS or live bacterial pathogens. Importantly, in a cohort of human volunteers, BDCA-1+ DCs were observed to be the dominant nasal DC population at steady state. During chronic inflammation, the frequency of both BDCA-1+ and BDCA-3hi DCs was reduced in the nasal tissue, associating the loss of these immune sentinels with chronic nasal inflammation. The present study is the first detailed description of the phenotypic, ontogenetic and functional properties of nasal DCs and will inform the design of preventative immunization strategies as well as therapeutic modalities against chronic rhinosinusitis. PMID:25669151

  15. Transcriptional Regulation of Dendritic Cell Diversity

    PubMed Central

    Chopin, Michaël; Allan, Rhys S.; Belz, Gabrielle T.

    2012-01-01

    Dendritic cells (DCs) are specialized antigen presenting cells that are exquisitely adapted to sense pathogens and induce the development of adaptive immune responses. They form a complex network of phenotypically and functionally distinct subsets. Within this network, individual DC subsets display highly specific roles in local immunosurveillance, migration, and antigen presentation. This division of labor amongst DCs offers great potential to tune the immune response by harnessing subset-specific attributes of DCs in the clinical setting. Until recently, our understanding of DC subsets has been limited and paralleled by poor clinical translation and efficacy. We have now begun to unravel how different DC subsets develop within a complex multilayered system. These findings open up exciting possibilities for targeted manipulation of DC subsets. Furthermore, ground-breaking developments overcoming a major translational obstacle – identification of similar DC populations in mouse and man – now sets the stage for significant advances in the field. Here we explore the determinants that underpin cellular and transcriptional heterogeneity within the DC network, how these influence DC distribution and localization at steady-state, and the capacity of DCs to present antigens via direct or cross-presentation during pathogen infection. PMID:22566910

  16. Mechanisms regulating dendritic cell specification and development

    PubMed Central

    Watowich, Stephanie S.; Liu, Yong-Jun

    2010-01-01

    Summary Understanding the diversification of dendritic cell (DC) lineages is one of the last frontiers in mapping the developmental hierarchy of the hematopoietic system. DCs are a vital link between the innate and adaptive immune responses, thus elucidating their developmental pathways is crucial for insight into the generation of natural immunity and for learning how to regulate DCs in clinical settings. DCs arise from hematopoietic stem cells through specialized progenitor subsets under the direction of FMS-like tyrosine kinase 3 ligand (Flt3L) and Flt3L receptor (Flt3) signaling. Recent studies have revealed important contributions from granulocyte-macrophage colony-stimulating factor (GM-CSF) and type I interferons (IFNs) in vivo. Furthermore, DC development is guided by lineage-restricted transcription factors such as IRF8, E2-2, and Batf3. A critical question centers on how cytokines and lineage-restricted transcription factors operate molecularly to direct DC diversification. Here we review recent findings that provide new insight into the DC developmental process. PMID:20969586

  17. Dendritic cell interactions with Histoplasma and Paracoccidioides.

    PubMed

    Thind, Sharanjeet K; Taborda, Carlos P; Nosanchuk, Joshua D

    2015-01-01

    Fungi are among the most common microbes encountered by humans. More than 100, 000 fungal species have been described in the environment to date, however only a few species cause disease in humans. Fungal infections are of particular importance to immunocompromised hosts in whom disease is often more severe, especially in those with impaired cell-mediated immunity such as individuals with HIV infection, hematologic malignancies, or those receiving TNF-α inhibitors. Nevertheless, environmental disturbances through natural processes or as a consequence of deforestation or construction can expose immunologically competent people to a large number of fungal spores resulting in asymptomatic acquisition to life-threatening disease. In recent decades, the significance of the innate immune system and more importantly the role of dendritic cells (DC) have been found to play a fundamental role in the resolution of fungal infections, such as in dimorphic fungi like Histoplasma and Paracoccidioides. In this review article the general role of DCs will be illustrated as the bridge between the innate and adaptive immune systems, as well as their specific interactions with these 2 dimorphic fungi. PMID:25933034

  18. Select forms of tumor cell apoptosis induce dendritic cell maturation.

    PubMed

    Demaria, Sandra; Santori, Fabio R; Ng, Bruce; Liebes, Leonard; Formenti, Silvia C; Vukmanovic, Stanislav

    2005-03-01

    Dendritic cells (DC) play a crucial role in initiating immune responses to tumors. DC can efficiently present antigens from apoptotic tumor cells, but apoptotic cells are thought to lack the inflammatory signals required to induce DC maturation. Here, we show that apoptosis of 67NR mouse carcinoma cells via the Fas (CD95) pathway or induced by the anticancer drug bortezomib (PS-341) but not by ultraviolet irradiation is associated with the production of maturation signals for DC. These data have important implications for the effects of chemotherapy on antitumor immunity in solid and hematologic malignancies. PMID:15569694

  19. Dendritic cell reprogramming by the hypoxic environment.

    PubMed

    Bosco, Maria Carla; Varesio, Luigi

    2012-12-01

    Myeloid dendritic cells (DCs) are professional antigen-presenting cells central to the orchestration of innate and acquired immunity and the maintenance of self-tolerance. The local microenvironment contributes to the regulation of DC development and functions, and deregulated DC responses may result in amplification of inflammation, loss of tolerance, or establishment of immune escape mechanisms. DC generation from monocytic precursors recruited at sites of inflammation, tissue damage, or neoplasia occurs under condition of low partial oxygen pressure (pO(2), hypoxia). We reviewed the literature addressing the phenotypic and functional changes triggered by hypoxia in monocyte-derived immature (i) and mature (m) DCs. The discussion will revolve around in vitro studies of gene expression profile, which give a comprehensive representation of the complexity of response of these cells to low pO(2). The gene expression pattern of hypoxic DC will be discussed to address the question of the relationship with a specific maturation stage. We will summarize data relative to the regulation of the chemotactic network, which points to a role for hypoxia in promoting a migratory phenotype in iDCs and a highly proinflammatory state in mDCs. Current knowledge of the strict regulatory control exerted by hypoxia on the expression of immune-related cell surface receptors will also be addressed, with a particular focus on a newly identified marker of hypoxic DCs endowed with proinflammatory properties. Furthermore, we discuss the literature on the transcription mechanisms underlying hypoxia-regulated gene expression in DCs, which support a major role for the HIF/HRE pathway. Finally, recent advances shedding light on the in vivo influence of the local hypoxic microenvironment on DCs infiltrating the inflamed joints of juvenile idiopathic arthritis patients are outlined. PMID:22901977

  20. Follicular dendritic cell function and murine AIDS.

    PubMed Central

    Masuda, A; Burton, G F; Fuchs, B A; Bhogal, B S; Rupper, R; Szakal, A K; Tew, J G

    1994-01-01

    Infection of mice with LP-BM5 elicits an immunodeficiency state referred to as murine acquired immune deficiency syndrome (MAIDS). Shortly after infection, retrovirus particles become associated with follicular dendritic cells (FDC) and this study was undertaken to determine whether retroviruses alter FDC functions. The FDC functions examined included the ability to: (1) retain antigen (Ag) trapped prior to infection; (2) trap new Ag after infection; (3) maintain specific IgG responses; and (4) provide co-stimulatory signals to B cells. Mice were infected with LP-BM5 and the ability of their FDC to trap and retain 125I-Ag (HSA) was assessed. Serum anti-HSA levels were monitored and FDC co-stimulatory activity was indicated by increased B-cell proliferation. HSA trapped on FDC prior to infection began to disappear by 3 weeks and was practically gone by 6 weeks. Serum anti-HSA titres were maintained normally for about 3 weeks after infection and then declined precipitously. The ability of FDC to trap new Ag began to disappear around the second and third week of infection and was markedly depressed by the fourth week. However, FDC recovered from infected mice retained their ability to co-stimulate anti-mu- and interleukin-4 (IL-4)-activated B cells throughout a 5-week period. In short, the ability of FDC to trap and retain specific Ag and maintain specific antibody levels was markedly depressed after retrovirus infection. However, FDC from infected mice continued to provide co-stimulatory signals and these signals may contribute to the lymphadenopathy and splenomegaly characteristic of MAIDS. Images Figure 4 PMID:8132218

  1. Dendritic cell-based therapy for mantle cell lymphoma.

    PubMed

    Munger, Corey M; Vose, Julie M; Joshi, Shantaram S

    2006-06-01

    Mantle cell lymphoma (MCL) is a B cell malignancy that is resistant to conventional therapies. High-dose therapy (HDT) followed by stem cell transplantation is effective in inducing remission. However, residual lymphoma cells are eventually responsible for the subsequent relapse. Effective therapeutic strategies to eliminate the residual lymphoma is required. In this study, we have examined the in vitro and in vivo anti-lymphoma effects of MCL-specific cytotoxic T lymphocytes (CTLs) that were generated using dendritic cells (DCs) fused with MCL cells for immunostimulation. Dendritic cells were generated in vitro using dendritic cell-specific medium, cytomorphology, immunophenotypes and functional capabilities of the generated DCs were studied. Such DCs were then used for the preparation of DC-MCL hybrids and the DC-MCL hybrids were used to generate CTLs against MCL cells and tested for their MCL-specific cytotoxicity in vitro and in vivo. The CTLs demonstrated MCL-specific cytotoxicity in vitro against GRANT-519, a human MCL cell line. These CTLs did not show significant effect against an irrelevant target. To test the in vivo therapeutic effect of DC-MCL hybrid-stimulated CTLs, a preclinical model consisting of NOD-SCID mice bearing Granta 519 was developed. The NOD-SCID mice bearing Granta-519 MCL tumors were treated with DC-MCL hybrids and the same donor T lymphocytes. There was an increase in survival (60% in mice treated with DC-MCL hybrid approach compared to 20% in the untreated group). Histological analysis of liver from control and treated mice displayed a decrease in the number of the tumor nodules in the treatment group. These results indicate the potential of DC-based therapy for the treatment of MCL. PMID:16685434

  2. Dendritic polymers: Universal glue for cells

    NASA Astrophysics Data System (ADS)

    Frey, Holger

    2012-05-01

    A dendritic polymer consisting of inversely oriented lipid head groups on a polyvalent polyglycerol scaffold makes an effective reversible biomembrane adhesive that may find use as a tissue sealant and a drug-delivery vehicle.

  3. Dendritic cells in inflammatory sinonasal diseases.

    PubMed

    Cao, P-P; Shi, L-L; Xu, K; Yao, Y; Liu, Z

    2016-07-01

    Dendritic cells (DCs) are critical in linking the innate and adaptive immune responses, which have been implicated in the pathogenesis of many immune and inflammatory diseases as well as the development of tumours. The role of DCs in the pathophysiology of lung diseases has been widely studied. However, the phenotype, subset and function of DCs in upper airways under physiological or pathological conditions remain largely undefined. Allergic rhinitis (AR) and chronic rhinosinusitis (CRS) are two important upper airway diseases with a high worldwide prevalence. Aberrant innate and adaptive immune responses have been considered to play an important role in the pathogenesis of AR and CRS. To this end, understanding the function of DCs in shaping the immune responses in sinonasal mucosa is critical in exploring the pathogenic mechanisms underlying AR and CRS as well as in developing novel therapeutic strategies. This review summarizes the phenotype, subset, function and regulation of DCs in sinonasal mucosa, particularly in the setting of AR and CRS. Furthermore, this review discusses the perspectives for future research and potential clinical utility focusing on DC pathways in the context of AR and CRS. PMID:27159777

  4. Ion channels modulating mouse dendritic cell functions.

    PubMed

    Matzner, Nicole; Zemtsova, Irina M; Nguyen, Thi Xuan; Duszenko, Michael; Shumilina, Ekaterina; Lang, Florian

    2008-11-15

    Ca(2+)-mediated signal transduction pathways play a central regulatory role in dendritic cell (DC) responses to diverse Ags. However, the mechanisms leading to increased [Ca(2+)](i) upon DC activation remained ill-defined. In the present study, LPS treatment (100 ng/ml) of mouse DCs resulted in a rapid increase in [Ca(2+)](i), which was due to Ca(2+) release from intracellular stores and influx of extracellular Ca(2+) across the cell membrane. In whole-cell voltage-clamp experiments, LPS-induced currents exhibited properties similar to the currents through the Ca(2+) release-activated Ca(2+) channels (CRAC). These currents were highly selective for Ca(2+), exhibited a prominent inward rectification of the current-voltage relationship, and showed an anomalous mole fraction and a fast Ca(2+)-dependent inactivation. In addition, the LPS-induced increase of [Ca(2+)](i) was sensitive to margatoxin and ICAGEN-4, both inhibitors of voltage-gated K(+) (Kv) channels Kv1.3 and Kv1.5, respectively. MHC class II expression, CCL21-dependent migration, and TNF-alpha and IL-6 production decreased, whereas phagocytic capacity increased in LPS-stimulated DCs in the presence of both Kv channel inhibitors as well as the I(CRAC) inhibitor SKF-96365. Taken together, our results demonstrate that Ca(2+) influx in LPS-stimulated DCs occurs via Ca(2+) release-activated Ca(2+) channels, is sensitive to Kv channel activity, and is in turn critically important for DC maturation and functions. PMID:18981098

  5. The effect of dendritic cells on the retinal cell transplantation

    SciTech Connect

    Oishi, Akio; Nagai, Takayuki; Mandai, Michiko Takahashi, Masayo; Yoshimura, Nagahisa

    2007-11-16

    The potential of bone marrow cell-derived immature dendritic cells (myeloid iDCs) in modulating the efficacy of retinal cell transplantation therapy was investigated. (1) In vitro, myeloid iDCs but not BMCs enhanced the survival and proliferation of embryonic retinal cells, and the expression of various neurotrophic factors by myeloid iDCs was confirmed with RT-PCR. (2) In subretinal transplantation, neonatal retinal cells co-transplanted with myeloid iDCs showed higher survival rate compared to those transplanted without myeloid iDCs. (3) CD8 T-cells reactive against donor retinal cells were significantly increased in the mice with transplantation of retinal cells alone. These results suggested the beneficial effects of the use of myeloid iDCs in retinal cell transplantation therapy.

  6. In vivo imaging of dendritic pruning in dentate granule cells.

    PubMed

    Gonçalves, J Tiago; Bloyd, Cooper W; Shtrahman, Matthew; Johnston, Stephen T; Schafer, Simon T; Parylak, Sarah L; Tran, Thanh; Chang, Tina; Gage, Fred H

    2016-06-01

    We longitudinally imaged the developing dendrites of adult-born mouse dentate granule cells (DGCs) in vivo and found that they underwent over-branching and pruning. Exposure to an enriched environment and constraint of dendritic growth by disrupting Wnt signaling led to increased branch addition and accelerated growth, which were, however, counteracted by earlier and more extensive pruning. Our results indicate that pruning is regulated in a homeostatic fashion to oppose excessive branching and promote a similar dendrite structure in DGCs. PMID:27135217

  7. Dendritic Cell-Nerve Clusters Are Sites of T Cell Proliferation in Allergic Airway Inflammation

    PubMed Central

    Veres, Tibor Z.; Shevchenko, Marina; Krasteva, Gabriela; Spies, Emma; Prenzler, Frauke; Rochlitzer, Sabine; Tschernig, Thomas; Krug, Norbert; Kummer, Wolfgang; Braun, Armin

    2009-01-01

    Interactions between T cells and dendritic cells in the airway mucosa precede secondary immune responses to inhaled antigen. The purpose of this study was to identify the anatomical locations where dendritic cell–T cell interactions occur, resulting in T cells activation by dendritic cells. In a mouse model of allergic airway inflammation, we applied whole-mount immunohistology and confocal microscopy to visualize dendritic cells and T cells together with nerves, epithelium, and smooth muscle in three dimensions. Proliferating T cells were identified by the detection of the incorporation of the nucleotide analogue 5-ethynyl-2′-deoxyuridine into the DNA. We developed a novel quantification method that enabled the accurate determination of cell–cell contacts in a semi-automated fashion. Dendritic cell–T cell interactions occurred beneath the smooth muscle layer, but not in the epithelium. Approximately 10% of the dendritic cells were contacted by nerves, and up to 4% of T cells formed clusters with these dendritic cells. T cells that were clustered with nerve-contacting dendritic cells proliferated only in the airways of mice with allergic inflammation but not in the airways of negative controls. Taken together, these results suggest that during the secondary immune response, sensory nerves influence dendritic cell-driven T cell activation in the airway mucosa. PMID:19179611

  8. Immunity and Tolerance Induced by Intestinal Mucosal Dendritic Cells.

    PubMed

    Aliberti, Julio

    2016-01-01

    Dendritic cells present in the digestive tract are constantly exposed to environmental antigens, commensal flora, and invading pathogens. Under steady-state conditions, these cells have high tolerogenic potential, triggering differentiation of regulatory T cells to protect the host from unwanted proinflammatory immune responses to innocuous antigens or commensals. On the other hand, these cells must discriminate between commensal flora and invading pathogens and mount powerful immune response against pathogens. A potential result of unbalanced tolerogenic versus proinflammatory responses mediated by dendritic cells is associated with chronic inflammatory conditions, such as Crohn's disease, ulcerative colitis, food allergies, and celiac disease. Herein, we review the dendritic cell population involved in mediating tolerance and immunity in mucosal surfaces, the progress in unveiling their development in vivo, and factors that can influence their functions. PMID:27034589

  9. A Model of Dendritic Cell Therapy for Melanoma

    PubMed Central

    DePillis, Lisette; Gallegos, Angela; Radunskaya, Ami

    2013-01-01

    Dendritic cells are a promising immunotherapy tool for boosting an individual’s antigen-specific immune response to cancer. We develop a mathematical model using differential and delay-differential equations to describe the interactions between dendritic cells, effector-immune cells, and tumor cells. We account for the trafficking of immune cells between lymph, blood, and tumor compartments. Our model reflects experimental results both for dendritic cell trafficking and for immune suppression of tumor growth in mice. In addition, in silico experiments suggest more effective immunotherapy treatment protocols can be achieved by modifying dose location and schedule. A sensitivity analysis of the model reveals which patient-specific parameters have the greatest impact on treatment efficacy. PMID:23516248

  10. Immunity and Tolerance Induced by Intestinal Mucosal Dendritic Cells

    PubMed Central

    Aliberti, Julio

    2016-01-01

    Dendritic cells present in the digestive tract are constantly exposed to environmental antigens, commensal flora, and invading pathogens. Under steady-state conditions, these cells have high tolerogenic potential, triggering differentiation of regulatory T cells to protect the host from unwanted proinflammatory immune responses to innocuous antigens or commensals. On the other hand, these cells must discriminate between commensal flora and invading pathogens and mount powerful immune response against pathogens. A potential result of unbalanced tolerogenic versus proinflammatory responses mediated by dendritic cells is associated with chronic inflammatory conditions, such as Crohn's disease, ulcerative colitis, food allergies, and celiac disease. Herein, we review the dendritic cell population involved in mediating tolerance and immunity in mucosal surfaces, the progress in unveiling their development in vivo, and factors that can influence their functions. PMID:27034589

  11. Activation of B cells by antigens on follicular dendritic cells

    PubMed Central

    El Shikh, Mohey Eldin M.; El Sayed, Rania M.; Sukumar, Selvakumar; Szakal, Andras K.; Tew, John G.

    2010-01-01

    A need for antigen-processing and presentation to B cells is not widely appreciated. However, cross-linking of multiple B cell receptors (BCRs) by T-independent antigens delivers a potent signal that induces antibody responses. Such BCR cross-linking also occurs in germinal centers where follicular dendritic cells (FDCs) present multimerized antigens as periodically arranged antigen-antibody complexes (ICs). Unlike T cells that recognize antigens as peptide-MHC complexes, optimal B cell-responses are induced by multimerized FDC-ICs that simultaneously engage multiple BCRs. FDC-FcγRIIB mediates IC-periodicity and FDC-BAFF, -IL-6 and -C4bBP are co-stimulators. Remarkably, specific antibody responses can be induced by FDC-ICs in the absence of T cells, opening up the exciting possibility that people with T cell insufficiencies may be immunized with T-dependent vaccines via FDC-ICs. PMID:20418164

  12. How Follicular Dendritic Cells Shape the B-Cell Antigenome

    PubMed Central

    Kranich, Jan; Krautler, Nike Julia

    2016-01-01

    Follicular dendritic cells (FDCs) are stromal cells residing in primary follicles and in germinal centers of secondary and tertiary lymphoid organs (SLOs and TLOs). There, they play a crucial role in B-cell activation and affinity maturation of antibodies. FDCs have the unique capacity to bind and retain native antigen in B-cell follicles for long periods of time. Therefore, FDCs shape the B-cell antigenome (the sum of all B-cell antigens) in SLOs and TLOs. In this review, we discuss recent findings that explain how this stromal cell type can arise in almost any tissue during TLO formation and, furthermore, focus on the mechanisms of antigen capture and retention involved in the generation of long-lasting antigen depots displayed on FDCs. PMID:27446069

  13. Avian dendritic cells: Phenotype and ontogeny in lymphoid organs.

    PubMed

    Nagy, Nándor; Bódi, Ildikó; Oláh, Imre

    2016-05-01

    Dendritic cells (DC) are critically important accessory cells in the innate and adaptive immune systems. Avian DCs were originally identified in primary and secondary lymphoid organs by their typical morphology, displaying long cell processes with cytoplasmic granules. Several subtypes are known. Bursal secretory dendritic cells (BSDC) are elongated cells which express vimentin intermediate filaments, MHC II molecules, macrophage colony-stimulating factor 1 receptor (CSF1R), and produce 74.3+ secretory granules. Avian follicular dendritic cells (FDC) highly resemble BSDC, express the CD83, 74.3 and CSF1R molecules, and present antigen in germinal centers. Thymic dendritic cells (TDC), which express 74.3 and CD83, are concentrated in thymic medulla while interdigitating DC are found in T cell-rich areas of secondary lymphoid organs. Avian Langerhans cells are a specialized 74.3-/MHC II+ cell population found in stratified squamous epithelium and are capable of differentiating into 74.3+ migratory DCs. During organogenesis hematopoietic precursors of DC colonize the developing lymphoid organ primordia prior to immigration of lymphoid precursor cells. This review summarizes our current understanding of the ontogeny, cytoarchitecture, and immunophenotype of avian DC, and offers an antibody panel for the in vitro and in vivo identification of these heterogeneous cell types. PMID:26751596

  14. Plasmacytoid dendritic cells migrate in afferent skin lymph.

    PubMed

    Pascale, Florentina; Pascale, Florentia; Contreras, Vanessa; Bonneau, Michel; Courbet, Alexandre; Chilmonczyk, Stefan; Bevilacqua, Claudia; Epardaud, Mathieu; Eparaud, Mathieu; Niborski, Violeta; Riffault, Sabine; Balazuc, Anne-Marie; Foulon, Eliane; Guzylack-Piriou, Laurence; Riteau, Beatrice; Hope, Jayne; Bertho, Nicolas; Charley, Bernard; Schwartz-Cornil, Isabelle

    2008-05-01

    Conventional dendritic cells enter lymph nodes by migrating from peripheral tissues via the lymphatic route, whereas plasmacytoid dendritic cells (pDC), also called IFN-producing cells (IPC), are described to gain nodes from blood via the high endothelial venules. We demonstrate here that IPC/pDC migrate in the afferent lymph of two large mammals. In sheep, injection of type A CpG oligodinucleotide (ODN) induced lymph cells to produce type I IFN. Furthermore, low-density lymph cells collected at steady state produced type I IFN after stimulation with type A CpG ODN and enveloped viruses. Sheep lymph IPC were found within a minor B(neg)CD11c(neg) subset expressing CD45RB. They presented a plasmacytoid morphology, expressed high levels of TLR-7, TLR-9, and IFN regulatory factor 7 mRNA, induced IFN-gamma production in allogeneic CD4(pos) T cells, and differentiated into dendritic cell-like cells under viral stimulation, thus fulfilling criteria of bona fide pDC. In mini-pig, a CD4(pos)SIRP(pos) subset in afferent lymph cells, corresponding to pDC homologs, produced type I IFN after type A CpG-ODN triggering. Thus, pDC can link innate and acquired immunity by migrating from tissue to draining node via lymph, similarly to conventional dendritic cells. PMID:18424716

  15. Manipulation of dendritic cell functions by human cytomegalovirus.

    PubMed

    Sinclair, John

    2008-01-01

    Dendritic cells are the most potent antigen-presenting cells of the mammalian immune system and are central to the initiation and maintenance of the adaptive immune response. They are crucial for the presentation of antigen to T cells and B cells, as well as the induction of chemokines and proinflammatory cytokines, which orchestrate the balance of the cell-mediated (Th1) and antibody (Th2) response. This ability of dendritic cells to present antigen and release chemokines and cytokines also bridges the innate and adaptive immune responses by driving T cell activation. These cells thus possess key immunological functions that make them the front line of defence for the targeting and clearance of any invading pathogen and, as such, they underpin the host immune response to infection. For efficient infection, invading pathogens often need to overcome these sentinel immune functions. It is therefore not surprising that pathogens have evolved numerous mechanisms to target dendritic cell functions directly or indirectly during infection, and at least one herpesvirus--human cytomegalovirus--has evolved a life cycle that hijacks dendritic cells for its long-term persistence in the infected host. PMID:19025715

  16. Regulatory multitasking of tolerogenic dendritic cells - lessons taken from vitamin d3-treated tolerogenic dendritic cells.

    PubMed

    Nikolic, Tatjana; Roep, Bart O

    2013-01-01

    Tolerogenic dendritic cells (DCs) work through silencing of differentiated antigen-specific T cells, activation and expansion of naturally occurring T regulatory cells (Tregs), transfer of regulatory properties to T cells, and the differentiation of naïve T cells into Tregs. Due to an operational definition based on T cell activation assays, the identity of tolerogenic DCs has been a matter of debate and it need not represent a specialized DC subset. Human tolerogenic DCs generated in vitro using inhibitory cytokines, growth factors, natural immunomodulators, or genetic manipulation have been effective and several of these tolerogenic DCs are currently being tested for clinical use. Ex vivo generated tolerogenic DCs reduce activation of naïve T cells using various means, promote a variety of regulatory T cells and most importantly, frequently show stable inhibitory phenotypes upon repetitive maturation with inflammatory factors. Yet, tolerogenic DCs differ with respect to the phenotype or the number of regulatory mechanisms they employ to modulate the immune system. In our experience, tolerogenic DCs generated using the biologically active form of vitamin D (VD3-DCs), alone, or combined with dexamethasone are proficient in their immunoregulatory functions. These tolerogenic DCs show a stable maturation-resistant semi-mature phenotype with low expression of activating co-stimulatory molecules, no production of the IL-12 family of cytokines and high expression of inhibitory molecules and IL-10. VD3-DCs induce increased apoptosis of effector T cells and induce antigen-specific regulatory T cells, which work through linked suppression ensuring infectious tolerance. Lessons learned on VD3-DCs help understanding the contribution of different pattern-recognition receptors (PRRs) and secondary signals to the tolerogenic function and how a cross-talk between DCs and T cells translates into immune regulation. PMID:23717310

  17. Regulation of Dendritic Cell Function by Vitamin D

    PubMed Central

    Barragan, Myriam; Good, Misty; Kolls, Jay K.

    2015-01-01

    Studies over the last two decades have revealed profound immunomodulatory aspects of vitamin D on various aspects of the immune system. This review will provide an overview of Vitamin D metabolism, a description of dendritic cell subsets, and highlight recent advances on the effects of vitamin D on dendritic cell function, maturation, cytokine production and antigen presentation. The active form of vitamin D, 1,25(OH)2D3, has important immunoregulatory and anti-inflammatory effects. Specifically, the 1,25(OH)2D3-Vitamin D3 complex can affect the maturation and migration of many dendritic cell subsets, conferring a special immunoregulatory role as well as tolerogenic properties affecting cytokine and chemokine production. Furthermore, there have been many recent studies demonstrating the effects of Vitamin D on allergic disease and autoimmunity. A clear understanding of the effects of the various forms of Vitamin D will provide new opportunities to improve human health. PMID:26402698

  18. Programmed Cell Death of Dendritic Cells in Immune Regulation

    PubMed Central

    Chen, Min; Wang, Jin

    2010-01-01

    Summary Programmed cell death is essential for the maintenance of lymphocyte homeostasis and immune tolerance. Dendritic cells (DCs), the most efficient antigen presenting cells, represent a small cell population in the immune system. However, DCs play major roles in the regulation of both innate and adaptive immune responses. Programmed cell death in DCs is essential for regulating DC homeostasis and consequently, the scope of immune responses. Interestingly, different DC subsets show varied turnover rates in vivo. The conventional DCs are relatively short-lived in most lymphoid organs, while plasmacytoid DCs are long-lived cells. Mitochondrion-dependent programmed cell death plays an important role in regulating spontaneous DC turnover. Antigen-specific T cells are also capable of killing DCs, thereby providing a mechanism for negative feedback regulation of immune responses. It has been shown that a surplus of DCs due to defects in programmed cell death leads to overactivation of lymphocytes and the onset of autoimmunity. Studying programmed cell death in DCs will shed light on the roles for DC turnover in the regulation of the duration and magnitude of immune responses in vivo, and in the maintenance of immune tolerance. PMID:20636805

  19. Human monocyte-derived dendritic cells turn into foamy dendritic cells with IL-17A.

    PubMed

    Salvatore, Giulia; Bernoud-Hubac, Nathalie; Bissay, Nathalie; Debard, Cyrille; Daira, Patricia; Meugnier, Emmanuelle; Proamer, Fabienne; Hanau, Daniel; Vidal, Hubert; Aricò, Maurizio; Delprat, Christine; Mahtouk, Karène

    2015-06-01

    Interleukin 17A (IL-17A) is a proinflammatory cytokine involved in the pathogenesis of chronic inflammatory diseases. In the field of immunometabolism, we have studied the impact of IL-17A on the lipid metabolism of human in vitro-generated monocyte-derived dendritic cells (DCs). Microarrays and lipidomic analysis revealed an intense remodeling of lipid metabolism induced by IL-17A in DCs. IL-17A increased 2-12 times the amounts of phospholipids, cholesterol, triglycerides, and cholesteryl esters in DCs. Palmitic (16:0), stearic (18:0), and oleic (18:ln-9c) acid were the main fatty acid chains present in DCs. They were strongly increased in response to IL-17A while their relative proportion remained unchanged. Capture of extracellular lipids was the major mechanism of lipid droplet accumulation, visualized by electron microscopy and Oil Red O staining. Besides this foamy phenotype, IL-17A induced a mixed macrophage-DC phenotype and expression of the nuclear receptor NR1H3/liver X receptor-α, previously identified in the context of atherosclerosis as the master regulator of cholesterol homeostasis in macrophages. These IL-17A-treated DCs were as competent as untreated DCs to stimulate allogeneic naive T-cell proliferation. Following this first characterization of lipid-rich DCs, we propose to call these IL-17A-dependent cells "foamy DCs" and discuss the possible existence of foamy DCs in atherosclerosis, a metabolic and inflammatory disorder involving IL-17A. PMID:25833686

  20. Imaging of plasmacytoid dendritic cell interactions with T cells.

    PubMed

    Mittelbrunn, María; Martínez del Hoyo, Gloria; López-Bravo, María; Martín-Cofreces, Noa B; Scholer, Alix; Hugues, Stéphanie; Fetler, Luc; Amigorena, Sebastián; Ardavín, Carlos; Sánchez-Madrid, Francisco

    2009-01-01

    Plasmacytoid dendritic cells (pDCs) efficiently produce type I interferon and participate in adaptive immune responses, although the molecular interactions between pDCs and antigen-specific T cells remain unknown. This study examines immune synapse (IS) formation between murine pDCs and CD4(+) T cells. Mature pDCs formed canonical ISs, involving relocation to the contact site of the microtubule-organizing center, F-actin, protein kinase C-, and pVav, and activation of early signaling molecules in T cells. However, immature pDCs were less efficient at forming conjugates with T cells and inducing IS formation, microtubule-organizing center translocation, and T-cell signaling and activation. Time-lapse videomicroscopy and 2-photon in vivo imaging of pDC-T-cell interactions revealed that immature pDCs preferentially mediated transient interactions, whereas mature pDCs promoted more stable contacts. Our data indicate that, under steady-state conditions, pDCs preferentially establish transient contacts with naive T cells and show a very modest immunogenic capability, whereas on maturation, pDCs are able to form long-lived contacts with T cells and significantly enhance their capacity to activate these lymphocytes. PMID:18818393

  1. T Cell Motility as Modulator of Interactions with Dendritic Cells

    PubMed Central

    Stein, Jens V.

    2015-01-01

    It is well established that the balance of costimulatory and inhibitory signals during interactions with dendritic cells (DCs) determines T cell transition from a naïve to an activated or tolerant/anergic status. Although many of these molecular interactions are well reproduced in reductionist in vitro assays, the highly dynamic motility of naïve T cells in lymphoid tissue acts as an additional lever to fine-tune their activation threshold. T cell detachment from DCs providing suboptimal stimulation allows them to search for DCs with higher levels of stimulatory signals, while storing a transient memory of short encounters. In turn, adhesion of weakly reactive T cells to DCs presenting peptides presented on major histocompatibility complex with low affinity is prevented by lipid mediators. Finally, controlled recruitment of CD8+ T cells to cognate DC–CD4+ T cell clusters shapes memory T cell formation and the quality of the immune response. Dynamic physiological lymphocyte motility therefore constitutes a mechanism to mitigate low avidity T cell activation and to improve the search for “optimal” DCs, while contributing to peripheral tolerance induction in the absence of inflammation. PMID:26579132

  2. Epidermal Viral Immunity Induced by CD8α+ Dendritic Cells But Not by Langerhans Cells

    NASA Astrophysics Data System (ADS)

    Allan, Rhys S.; Smith, Chris M.; Belz, Gabrielle T.; van Lint, Allison L.; Wakim, Linda M.; Heath, William R.; Carbone, Francis R.

    2003-09-01

    The classical paradigm for dendritic cell function derives from the study of Langerhans cells, which predominate within skin epidermis. After an encounter with foreign agents, Langerhans cells are thought to migrate to draining lymph nodes, where they initiate T cell priming. Contrary to this, we show here that infection of murine epidermis by herpes simplex virus did not result in the priming of virus-specific cytotoxic T lymphocytes by Langerhans cells. Rather, the priming response required a distinct CD8α+ dendritic cell subset. Thus, the traditional view of Langerhans cells in epidermal immunity needs to be revisited to accommodate a requirement for other dendritic cells in this response.

  3. Organ-derived dendritic cells have differential effects on alloreactive T cells

    PubMed Central

    Kim, Theo D.; Terwey, Theis H.; Zakrzewski, Johannes L.; Suh, David; Kochman, Adam A.; Chen, Megan E.; King, Chris G.; Borsotti, Chiara; Grubin, Jeremy; Smith, Odette M.; Heller, Glenn; Liu, Chen; Murphy, George F.; Alpdogan, Onder

    2008-01-01

    Dendritic cells (DCs) are considered critical for the induction of graft-versus-host disease (GVHD) after bone marrow transplantation (BMT). In addition to their priming function, dendritic cells have been shown to induce organ-tropism through induction of specific homing molecules on T cells. Using adoptive transfer of CFSE-labeled cells, we first demonstrated that alloreactive T cells differentially up-regulate specific homing molecules in vivo. Host-type dendritic cells from the GVHD target organs liver and spleen or skin- and gut-draining lymph nodes effectively primed naive allogeneic T cells in vitro with the exception of liver-derived dendritic cells, which showed less stimulatory capacity. Gut-derived dendritic cells induced alloreactive donor T cells with a gut-homing phenotype that caused increased GVHD mortality and morbidity compared with T cells stimulated with dendritic cells from spleen, liver, and peripheral lymph nodes in an MHC-mismatched murine BMT model. However, in vivo analysis demonstrated that the in vitro imprinting of homing molecules on alloreactive T cells was only transient. In conclusion, organ-derived dendritic cells can efficiently induce specific homing molecules on alloreactive T cells. A gut-homing phenotype correlates with increased GVHD mortality and morbidity after murine BMT, underlining the importance of the gut in the pathophysiology of GVHD. PMID:18178870

  4. Blastic plasmacytoid dendritic cell neoplasm (BPDCN): a rare entity.

    PubMed

    Lim, Ming Sheng; Lemmert, Karla; Enjeti, Anoop

    2016-01-01

    Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive haematological malignancy in the elderly, with a high frequency of cutaneous and bone marrow involvement and poor prognosis. We report a case of BPDCN with classic presentation and discuss its treatment and the value of different investigation tools used in diagnosis and response assessment. PMID:26791132

  5. Glucocorticoids Reduce Sepsis by Diminishing Dendritic Cell Responses.

    PubMed

    Robinson, Richard

    2015-10-01

    How does the body's immune system strike the delicate balance between under- and over-response? A new study shows that glucocorticoids limit the production of the proinflammatory cytokine interleukin-12 by dendritic cells in response to invading bacteria, thereby helping to avoid sepsis. Read the Research Article. PMID:26441144

  6. The role of human dendritic cells in HIV-1 infection.

    PubMed

    Ahmed, Zahra; Kawamura, Tatsuyoshi; Shimada, Shinji; Piguet, Vincent

    2015-05-01

    Dendritic cells (DCs) and their subsets have multifaceted roles in the early stages of HIV-1 transmission and infection. DC studies have led to remarkable discoveries, including identification of restriction factors, cellular structures promoting viral transmission including the infectious synapse or the interplay of the C-type lectins, Langerin on Langerhans cells (LCs), and dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin on other DC subsets, limiting or facilitating HIV transmission to CD4(+) T cells, respectively. LCs/DCs are also exposed to encountering HIV-1 and other sexually transmitted infections (herpes simplex virus-2, bacteria, fungi), which reprogram HIV-1 interaction with these cells. This review will summarize advances in the role of DCs during HIV-1 infection and discuss their potential involvement in the development of preventive strategies against HIV-1 and other sexually transmitted infections. PMID:25407434

  7. How tolerogenic dendritic cells induce regulatory T cells

    PubMed Central

    Maldonado, Roberto A.; von Andrian, Ulrich H.

    2010-01-01

    Since their discovery by Steinman and Cohn in 1973, dendritic cells (DCs) have become increasingly recognized for their crucial role as regulators of innate and adaptive immunity. DCs are exquisitely adept at acquiring, processing and presenting antigens to T cells. They also adjust the context (and hence the outcome) of antigen presentation in response to a plethora of environmental inputs that signal the occurence of pathogens or tissue damage. Such signals generally boost DC maturation, which promotes their migration from peripheral tissues into and within secondary lymphoid organs and their capacity to induce and regulate effector T cell responses. Conversely, more recent observations indicate that DCs are also crucial to ensure immunological peace. Indeed, DCs constantly present innocuous self and non-self antigens in a fashion that promotes tolerance, at least in part, through the control of regulatory T cells (Tregs). Tregs are specialized T cells that exert their immuno-suppressive function through a variety of mechanisms affecting both DCs and effector cells. Here, we review recent advances in our understanding of the relationship between tolerogenic DCs and Tregs. PMID:21056730

  8. Fascin1 promotes cell migration of mature dendritic cells.

    PubMed

    Yamakita, Yoshihiko; Matsumura, Fumio; Lipscomb, Michael W; Chou, Po-chien; Werlen, Guy; Burkhardt, Janis K; Yamashiro, Shigeko

    2011-03-01

    Dendritic cells (DCs) play central roles in innate and adaptive immunity. Upon maturation, DCs assemble numerous veil-like membrane protrusions, disassemble podosomes, and travel from the peripheral tissues to lymph nodes to present Ags to T cells. These alterations in morphology and motility are closely linked to the primary function of DCs, Ag presentation. However, it is unclear how and what cytoskeletal proteins control maturation-associated alterations, in particular, the change in cell migration. Fascin1, an actin-bundling protein, is specifically and greatly induced upon maturation, suggesting a unique role for fascin1 in mature DCs. To determine the physiological roles of fascin1, we characterized bone marrow-derived, mature DCs from fascin1 knockout mice. We found that fascin1 is critical for cell migration: fascin1-null DCs exhibit severely decreased membrane protrusive activity. Importantly, fascin1-null DCs have lower chemotactic activity toward CCL19 (a chemokine for mature DCs) in vitro, and in vivo, Langerhans cells show reduced emigration into draining lymph nodes. Morphologically, fascin1-null mature DCs are flatter and fail to disassemble podosomes, a specialized structure for cell-matrix adhesion. Expression of exogenous fascin1 in fascin1-null DCs rescues the defects in membrane protrusive activity, as well as in podosome disassembly. These results indicate that fascin1 positively regulates migration of mature DCs into lymph nodes, most likely by increasing dynamics of membrane protrusions, as well as by disassembling podosomes. PMID:21263068

  9. Interactions of bacterial pathogens with dendritic cells during invasion of mucosal surfaces.

    PubMed

    Granucci, Francesca; Ricciardi-Castagnoli, Paola

    2003-02-01

    Recent studies of mucosal immunity suggest a key role for dendritic cells in the regulation of gut immune responses, in both physiological and pathological conditions. Dendritic cells are widely distributed in the lamina propria of the gut and are involved in direct bacterial uptake across mucosal surfaces, which questions the role of dendritic cells in innate mucosal responses. Approximately 400 commensal microbial species are present in the gut lumen. So how do dendritic cells distinguish pathogens from luminal microflora? Are the cytokines and chemokines induced in dendritic cells tailored to the class of microbes being recognized? Several very important questions still need to be addressed. PMID:12615223

  10. A Comparison between Growth Morphology of "Eutectic" Cells/Dendrites and Single-Phase Cells/Dendrites

    NASA Technical Reports Server (NTRS)

    Tewari, S. N.; Raj, S. V.; Locci, I. E.

    2003-01-01

    Directionally solidified (DS) intermetallic and ceramic-based eutectic alloys with an in-situ composite microstructure containing finely distributed, long aspect ratio, fiber, or plate reinforcements are being seriously examined for several advanced aero-propulsion applications. In designing these alloys, additional solutes need to be added to the base eutectic composition in order to improve heir high-temperature strength, and provide for adequate toughness and resistance to environmental degradation. Solute addition, however, promotes instability at the planar liquid-solid interface resulting in the formation of two-phase eutectic "colonies." Because morphology of eutectic colonies is very similar to the single-phase cells and dendrites, the stability analysis of Mullins and Sekerka has been extended to describe their formation. Onset of their formation shows a good agreement with this approach; however, unlike the single-phase cells and dendrites, there is limited examination of their growth speed dependence of spacing, morphology, and spatial distribution. The purpose of this study is to compare the growth speed dependence of the morphology, spacing, and spatial distribution of eutectic cells and dendrites with that for the single-phase cells and dendrites.

  11. Tolerogenic Dendritic Cells for Regulatory T Cell Induction in Man

    PubMed Central

    Raker, Verena K.; Domogalla, Matthias P.; Steinbrink, Kerstin

    2015-01-01

    Dendritic cells (DCs) are highly specialized professional antigen-presenting cells that regulate immune responses, maintaining the balance between tolerance and immunity. Mechanisms via which they can promote central and peripheral tolerance include clonal deletion, the inhibition of memory T cell responses, T cell anergy, and induction of regulatory T cells (Tregs). These properties have led to the analysis of human tolerogenic DCs as a therapeutic strategy for the induction or re-establishment of tolerance. In recent years, numerous protocols for the generation of human tolerogenic DCs have been developed and their tolerogenic mechanisms, including induction of Tregs, are relatively well understood. Phase I trials have been conducted in autoimmune disease, with results that emphasize the feasibility and safety of treatments with tolerogenic DCs. Therefore, the scientific rationale for the use of tolerogenic DCs therapy in the fields of transplantation medicine and allergic and autoimmune diseases is strong. This review will give an overview on efforts and protocols to generate human tolerogenic DCs with focus on IL-10-modulated DCs as inducers of Tregs and discuss their clinical applications and challenges faced in further developing this form of immunotherapy. PMID:26617604

  12. Dendritic Cell Regulation by Cannabinoid-Based Drugs

    PubMed Central

    Svensson, Mattias; Chen, Puran; Hammarfjord, Oscar

    2010-01-01

    Cannabinoid pharmacology has made important advances in recent years after the cannabinoid system was discovered. Studies in experimental models and in humans have produced promising results using cannabinoid-based drugs for the treatment of obesity and cancer, as well as neuroinflammatory and chronic inflammatory diseases. Moreover, as we discuss here, additional studies also indicates that these drugs have immunosuppressive and anti-inflammatory properties including modulation of immune cell function. Thus, manipulation of the endocannabinoid system in vivo may provide novel therapeutic strategies against inflammatory disorders. At least two types of cannabinoid receptors, cannabinoid 1 and cannabinoid 2 receptors are expressed on immune cells such as dendritic cells (DC). Dendritic cells are recognized for their critical role in initiating and maintaining immune responses. Therefore, DC are potential targets for cannabinoid-mediated modulation. Here, we review the effects of cannabinoids on DC and provide some perspective concerning the therapeutic potential of cannabinoids for the treatment of human diseases involving aberrant inflammatory processes.

  13. Dendritic Kv3.3 potassium channels in cerebellar purkinje cells regulate generation and spatial dynamics of dendritic Ca2+ spikes.

    PubMed

    Zagha, Edward; Manita, Satoshi; Ross, William N; Rudy, Bernardo

    2010-06-01

    Purkinje cell dendrites are excitable structures with intrinsic and synaptic conductances contributing to the generation and propagation of electrical activity. Voltage-gated potassium channel subunit Kv3.3 is expressed in the distal dendrites of Purkinje cells. However, the functional relevance of this dendritic distribution is not understood. Moreover, mutations in Kv3.3 cause movement disorders in mice and cerebellar atrophy and ataxia in humans, emphasizing the importance of understanding the role of these channels. In this study, we explore functional implications of this dendritic channel expression and compare Purkinje cell dendritic excitability in wild-type and Kv3.3 knockout mice. We demonstrate enhanced excitability of Purkinje cell dendrites in Kv3.3 knockout mice, despite normal resting membrane properties. Combined data from local application pharmacology, voltage clamp analysis of ionic currents, and assessment of dendritic Ca(2+) spike threshold in Purkinje cells suggest a role for Kv3.3 channels in opposing Ca(2+) spike initiation. To study the physiological relevance of altered dendritic excitability, we measured [Ca(2+)](i) changes throughout the dendritic tree in response to climbing fiber activation. Ca(2+) signals were specifically enhanced in distal dendrites of Kv3.3 knockout Purkinje cells, suggesting a role for dendritic Kv3.3 channels in regulating propagation of electrical activity and Ca(2+) influx in distal dendrites. These findings characterize unique roles of Kv3.3 channels in dendrites, with implications for synaptic integration, plasticity, and human disease. PMID:20357073

  14. Variation of dorsal horn cell dendritic spread with map scale.

    PubMed

    Brown, P B; Millecchia, R; Culberson, J L; Gladfelter, W; Covalt-Dunning, D

    1996-10-21

    Cells in laminae III, IV, and V of cat dorsal horn were injected with horseradish peroxidase or neurobiotin. Dorsal views of the dendritic domains were constructed in order to measure their lengths, widths, areas, and length/width ratios in the horizontal plane (the plane of the somatotopic map). Dendritic domain width and area in the horizontal plane were negatively correlated with fractional distance between the medial and lateral edges of the dorsal horn. These results are consistent with the hypothesis that dendritic domain width varies with map scale, which is maximal in the medial dorsal horn. This is similar to the variation in widths of primary afferent bouton distributions. The parallel variation of dorsal horn cell dendritic domain width and primary afferent bouton distribution width with map scale suggests that there is a causal relation between morphology and map scale in the dorsal horn representation of the hindlimb. This variation of adult morphology with map scale must reflect mechanisms responsible for the assembly of receptive fields. PMID:8906504

  15. Self-Antigen Presentation by Dendritic Cells in Autoimmunity

    PubMed Central

    Hopp, Ann-Katrin; Rupp, Anne; Lukacs-Kornek, Veronika

    2014-01-01

    The operation of both central and peripheral tolerance ensures the prevention of autoimmune diseases. The maintenance of peripheral tolerance requires self-antigen presentation by professional antigen presenting cells (APCs). Dendritic cells (DCs) are considered as major APCs involved in this process. The current review discusses the role of DCs in autoimmune diseases, the various factors involved in the induction and maintenance of tolerogenic DC phenotype, and pinpoints their therapeutic capacity as well as potential novel targets for future clinical studies. PMID:24592266

  16. Mast Cells Condition Dendritic Cells to Mediate Allograft Tolerance

    PubMed Central

    de Vries, Victor C.; Pino-Lagos, Karina; Nowak, Elizabeth C.; Bennett, Kathy A.; Oliva, Carla; Noelle, Randolph J.

    2013-01-01

    SUMMARY Peripheral tolerance orchestrated by regulatory T cells, dendritic cells (DCs), and mast cells (MCs) has been studied in several models including skin allograft tolerance. We now define a role for MCs in controlling DC behavior (“conditioning”) to facilitate tolerance. Under tolerant conditions, we show that MCs mediated a marked increase in tumor necrosis factor (TNFα)-dependent accumulation of graft-derived DCs in the dLN compared to nontolerant conditions. This increase of DCs in the dLN is due to the local production of granulocyte macrophage colony-stimulating factor (GM-CSF) by MCs that induces a survival advantage of graft-derived DCs. DCs that migrated to the dLN from the tolerant allograft were tolerogenic; i.e., they dominantly suppress T cell responses and control regional immunity. This study underscores the importance of MCs in conditioning DCs to mediate peripheral tolerance and shows a functional impact of peripherally produced TNFα and GM-CSF on the migration and function of tolerogenic DCs. PMID:22035846

  17. Blastic plasmacytoid dendritic cell neoplasm: diagnostic criteria and therapeutical approaches.

    PubMed

    Pagano, Livio; Valentini, Caterina G; Grammatico, Sara; Pulsoni, Alessandro

    2016-07-01

    Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare haematological malignancy derived from the precursors of plamacytoid dendritic cells, with an aggressive clinical course and high frequency of cutaneous and bone marrow involvement. Neoplastic cells express CD4, CD43 (also termed SPN), CD45RA and CD56 (also termed NCAM1), as well as the plasmacytoid dendritic cell-associated antigens CD123 (also termed IL3RA), BDCA-2 (also termed CD303, CLEC4E) TCL1 and CTLA1 (also termed GZMB). The median survival is only a few months as the tumour exhibits a progressive course despite initial response to chemotherapy. The best modality of treatment remains to be defined. Generally, patients receive acute leukaemia-like induction, according to acute myeloid leukaemia (AML)-type or acute lymphoid leukaemia (ALL)-type regimens. The frequent neuromeningeal involvement indicates systematic pre-emptive intrathecal chemotherapy in addition to intensive chemotherapy. Allogeneic haematopoietic stem cell transplantation (HSCT), particularly when performed in first remission, may improve the survival. Preliminary data suggest a potential role for immunomodulatory agents and novel targeted drugs. Herein epidemiology, clinical manifestations, diagnosis and management of BPDCN will be presented. In detail, this review focuses on the therapeutic aspects of BPDCN, proposing a treatment algorithm for the management of the disease, including induction chemotherapy, allogeneic HSCT and intrathecal prophylaxis at different steps of treatment, according to compliance, biological and clinical characteristics of patients. PMID:27264021

  18. Intestinal immune homeostasis is regulated by the crosstalk between epithelial cells and dendritic cells.

    PubMed

    Rimoldi, Monica; Chieppa, Marcello; Salucci, Valentina; Avogadri, Francesca; Sonzogni, Angelica; Sampietro, Gianluca M; Nespoli, Angelo; Viale, Giuseppe; Allavena, Paola; Rescigno, Maria

    2005-05-01

    The control of damaging inflammation by the mucosal immune system in response to commensal and harmful ingested bacteria is unknown. Here we show epithelial cells conditioned mucosal dendritic cells through the constitutive release of thymic stromal lymphopoietin and other mediators, resulting in the induction of 'noninflammatory' dendritic cells. Epithelial cell-conditioned dendritic cells released interleukins 10 and 6 but not interleukin 12, and they promoted the polarization of T cells toward a 'classical' noninflammatory T helper type 2 response, even after exposure to a T helper type 1-inducing pathogen. This control of immune responses seemed to be lost in patients with Crohn disease. Thus, the intimate interplay between intestinal epithelial cells and dendritic cells may help to maintain gut immune homeostasis. PMID:15821737

  19. Large-Scale mRNA Transfection of Dendritic Cells by Electroporation in Continuous Flow Systems.

    PubMed

    Selmeczi, David; Hansen, Thomas Steen; Met, Özcan; Svane, Inge Marie; Larsen, Niels B

    2016-01-01

    Electroporation is well established for transient mRNA transfection of many mammalian cells, including immune cells such as dendritic cells used in cancer immunotherapy. Therapeutic application requires methods to efficiently electroporate and transfect millions of immune cells in a fast process with high cell survival. Continuous flow of suspended dendritic cells through a channel incorporating spatially separated microporous meshes with a synchronized electrical pulsing sequence can yield dendritic cell transfection rates of >75 % with survival rates of >90 %. This chapter describes the instrumentation and methods needed for the efficient transfection by electroporation of millions of dendritic cells in one continuous flow process. PMID:27236798

  20. Novel Murine Dendritic Cell Lines: A Powerful Auxiliary Tool for Dendritic Cell Research

    PubMed Central

    Fuertes Marraco, Silvia A.; Grosjean, Frédéric; Duval, Anaïs; Rosa, Muriel; Lavanchy, Christine; Ashok, Devika; Haller, Sergio; Otten, Luc A.; Steiner, Quynh-Giao; Descombes, Patrick; Luber, Christian A.; Meissner, Felix; Mann, Matthias; Szeles, Lajos; Reith, Walter; Acha-Orbea, Hans

    2012-01-01

    Research in vitro facilitates discovery, screening, and pilot experiments, often preceding research in vivo. Several technical difficulties render Dendritic Cell (DC) research particularly challenging, including the low frequency of DC in vivo, thorough isolation requirements, and the vulnerability of DC ex vivo. Critically, there is not as yet a widely accepted human or murine DC line and in vitro systems of DC research are limited. In this study, we report the generation of new murine DC lines, named MutuDC, originating from cultures of splenic CD8α conventional DC (cDC) tumors. By direct comparison to normal WT splenic cDC subsets, we describe the phenotypic and functional features of the MutuDC lines and show that they have retained all the major features of their natural counterpart in vivo, the splenic CD8α cDC. These features include expression of surface markers Clec9A, DEC205, and CD24, positive response to TLR3 and TLR9 but not TLR7 stimuli, secretion of cytokines, and chemokines upon activation, as well as cross-presentation capacity. In addition to the close resemblance to normal splenic CD8α cDC, a major advantage is the ease of derivation and maintenance of the MutuDC lines, using standard culture medium and conditions, importantly without adding supplementary growth factors or maturation-inducing stimuli to the medium. Furthermore, genetically modified MutuDC lines have been successfully obtained either by lentiviral transduction or by culture of DC tumors originating from genetically modified mice. In view of the current lack of stable and functional DC lines, these novel murine DC lines have the potential to serve as an important auxiliary tool for DC research. PMID:23162549

  1. Targeting Dendritic Cells in vivo for Cancer Therapy

    PubMed Central

    Caminschi, Irina; Maraskovsky, Eugene; Heath, William Ross

    2012-01-01

    Monoclonal antibodies that recognize cell surface molecules have been used deliver antigenic cargo to dendritic cells (DC) for induction of immune responses. The encouraging anti-tumor immunity elicited using this immunization strategy suggests its suitability for clinical trials. This review discusses the complex network of DC, the functional specialization of DC subsets, the immunological outcomes of targeting different DC subsets and their cell surface receptors, and the requirements for the induction of effective anti-tumor CD4 and CD8 T cell responses that can recognize tumor-specific antigens. Finally, we review preclinical experiments and the progress toward targeting human DC in vivo. PMID:22566899

  2. Dextromethorphan inhibits activations and functions in dendritic cells.

    PubMed

    Chen, Der-Yuan; Song, Pei-Shan; Hong, Jau-Shyong; Chu, Ching-Liang; Pan, I-Horng; Chen, Yi-Ming; Lin, Ching-Hsiung; Lin, Sheng-Hao; Lin, Chi-Chen

    2013-01-01

    Dendritic cells (DCs) play an important role in connecting innate and adaptive immunity. Thus, DCs have been regarded as a major target for the development of immunomodulators. In this study, we examined the effect of dextromethorphan (DXM), a common cough suppressant with a high safety profile, on the activation and function of DCs. In the presence of DXM, the LPS-induced expression of the costimulatory molecules in murine bone marrow-derived dendritic cells (BMDCs) was significantly suppressed. In addition, DXM treatment reduced the production of reactive oxygen species (ROS), proinflammatory cytokines, and chemokines in maturing BMDCs that were activated by LPS. Therefore, DXM abrogated the ability of LPS-stimulated DCs to induce Ag-specific T-cell activation, as determined by their decreased proliferation and IFN- γ secretion in mixed leukocyte cultures. Moreover, the inhibition of LPS-induced MAPK activation and NF- κ B translocation may contribute to the suppressive effect of DXM on BMDCs. Remarkably, DXM decreased the LPS-induced surface expression of CD80, CD83, and HLA-DR and the secretion of IL-6 and IL-12 in human monocyte-derived dendritic cells (MDDCs). These findings provide a new insight into the impact of DXM treatment on DCs and suggest that DXM has the potential to be used in treating DC-related acute and chronic diseases. PMID:23781253

  3. Dextromethorphan Inhibits Activations and Functions in Dendritic Cells

    PubMed Central

    Chen, Der-Yuan; Song, Pei-Shan; Hong, Jau-Shyong; Chu, Ching-Liang; Pan, I-Horng; Chen, Yi-Ming; Lin, Ching-Hsiung; Lin, Sheng-Hao; Lin, Chi-Chen

    2013-01-01

    Dendritic cells (DCs) play an important role in connecting innate and adaptive immunity. Thus, DCs have been regarded as a major target for the development of immunomodulators. In this study, we examined the effect of dextromethorphan (DXM), a common cough suppressant with a high safety profile, on the activation and function of DCs. In the presence of DXM, the LPS-induced expression of the costimulatory molecules in murine bone marrow-derived dendritic cells (BMDCs) was significantly suppressed. In addition, DXM treatment reduced the production of reactive oxygen species (ROS), proinflammatory cytokines, and chemokines in maturing BMDCs that were activated by LPS. Therefore, DXM abrogated the ability of LPS-stimulated DCs to induce Ag-specific T-cell activation, as determined by their decreased proliferation and IFN-γ secretion in mixed leukocyte cultures. Moreover, the inhibition of LPS-induced MAPK activation and NF-κB translocation may contribute to the suppressive effect of DXM on BMDCs. Remarkably, DXM decreased the LPS-induced surface expression of CD80, CD83, and HLA-DR and the secretion of IL-6 and IL-12 in human monocyte-derived dendritic cells (MDDCs). These findings provide a new insight into the impact of DXM treatment on DCs and suggest that DXM has the potential to be used in treating DC-related acute and chronic diseases. PMID:23781253

  4. Epidermal cells are the primary phagocytes in the fragmentation and clearance of degenerating dendrites in Drosophila

    PubMed Central

    Xiao, Hui; Wang, Denan; Franc, Nathalie C.; Jan, Lily Yeh; Jan, Yuh-Nung

    2014-01-01

    SUMMARY During developmental remodeling, neurites destined for pruning often degenerate on-site. Physical injury also induces degeneration of neurites distal to the injury site. Prompt clearance of degenerating neurites is important for maintaining tissue homeostasis and preventing inflammatory responses. Here we show that in both dendrite pruning and dendrite injury of Drosophila sensory neurons, epidermal cells rather than hemocytes are the primary phagocytes in clearing degenerating dendrites. Epidermal cells act via Draper-mediated recognition to facilitate dendrite degeneration and to engulf and degrade degenerating dendrites. Using multiple dendritic membrane markers to trace phagocytosis, we show that two members of the CD36 family, croquemort (crq) and debris buster (dsb), act at distinct stages of phagosome maturation for dendrite clearance. Our finding reveals the physiological importance of coordination between neurons and their surrounding epidermis, for both dendrite fragmentation and clearance. PMID:24412417

  5. Viral piracy: HIV-1 targets dendritic cells for transmission.

    PubMed

    Lekkerkerker, Annemarie N; van Kooyk, Yvette; Geijtenbeek, Teunis B H

    2006-04-01

    Dendritic cells (DCs), the professional antigen presenting cells, are critical for host immunity by inducing specific immune responses against a broad variety of pathogens. Remarkably the human immunodeficiency virus-1 (HIV-1) subverts DC function leading to spread of the virus. At an early phase of HIV-1 transmission, DCs capture HIV-1 at mucosal surfaces and transmit the virus to T cells in secondary lymphoid tissues. Capture of the virus on DCs takes place via C-type lectins of which the dendritic cell-specific intercellular adhesion molecule-3 (ICAM-3) grabbing nonintegrin (DC-SIGN) is the best studied. DC-SIGN-captured HIV-1 particles accumulate in CD81(+) multivesicular bodies (MVBs) in DCs and are subsequently transmitted to CD4+ T cells resulting in infection of T cells. The viral cell-to-cell transmission takes place at the DC-T cell interface termed the infectious synapse. Recent studies demonstrate that direct infection of DCs contributes to the transmission to T cells at a later phase. Moreover, the infected DCs may function as cellular reservoirs for HIV-1. This review discusses the different processes that govern viral piracy of DCs by HIV-1, emphasizing the intracellular routing of the virus from capture on the cell surface to egress in the infectious synapse. PMID:16611055

  6. Dendritic web-type solar cell mini-modules

    NASA Technical Reports Server (NTRS)

    Campbell, R. B.

    1985-01-01

    Twenty-five minimodules composed of dendritic web solar cells with nominal glass size of 12 by 40 cm were provided for study. The modules were identical with respect to design, materials, and manufacturing and assembly processes to full scale modules. The modules were also electrically functional. These minimodules were fabricated to provide test vehicle for environmental testing and to assess reliability of process and design procedures. The module design and performance are outlined.

  7. Induction and identification of rabbit peripheral blood derived dendritic cells

    NASA Astrophysics Data System (ADS)

    Zhou, Jing; Yang, FuYuan; Chen, WenLi

    2012-03-01

    Purpose: To study a method of the induction of dendritic cells (DCs) from rabbit peripheral blood. Methods: Peripheral blood cells were removed from rabbit, filtered through nylon mesh. Peripheral blood mononuclear cells (PBMC) were isolated from the blood cells by Ficoll-Hypaque centrifugation (density of 1.077g/cm3).To obtain DCs, PBMC were cultured in RPMI1640 medium containing 10% fetal calf serum, 50U/mL penicillin and streptomycin, referred to subsequently as complete medium, at 37°C in 5% CO2 atmosphere for 4 hours. Nonadherent cells were aspirated, adherent cells were continued incubated in complete medium, supplemented with granulocyte/macrophage colony-stimulating factor (GM-CSF, 50ng/ml),and interleukin 4 (IL-4, 50ng/ml) for 9 days. Fluorescein labeled antibodies(anti-CD14, anti-HLA-DR, anti-CD86) were used to sign cells cultured for 3,6,9 days respectively, Then flow cytometry was performed. Results: Ratio of anti-HLA-DR and anti-CD86 labeled cells increased with induction time extension, in contrast with anti-CD14. Conclusion: Dendritic cells can be effectively induced by the method of this experiment, cell maturation status increased with induction time extension.

  8. 3D visualization of HIV transfer at the virological synapse between dendritic cells and T cells

    PubMed Central

    Felts, Richard L.; Narayan, Kedar; Estes, Jacob D.; Shi, Dan; Trubey, Charles M.; Fu, Jing; Hartnell, Lisa M.; Ruthel, Gordon T.; Schneider, Douglas K.; Nagashima, Kunio; Bess, Julian W.; Bavari, Sina; Lowekamp, Bradley C.; Bliss, Donald; Lifson, Jeffrey D.; Subramaniam, Sriram

    2010-01-01

    The efficiency of HIV infection is greatly enhanced when the virus is delivered at conjugates between CD4+ T cells and virus-bearing antigen-presenting cells such as macrophages or dendritic cells via specialized structures known as virological synapses. Using ion abrasion SEM, electron tomography, and superresolution light microscopy, we have analyzed the spatial architecture of cell-cell contacts and distribution of HIV virions at virological synapses formed between mature dendritic cells and T cells. We demonstrate the striking envelopment of T cells by sheet-like membrane extensions derived from mature dendritic cells, resulting in a shielded region for formation of virological synapses. Within the synapse, filopodial extensions emanating from CD4+ T cells make contact with HIV virions sequestered deep within a 3D network of surface-accessible compartments in the dendritic cell. Viruses are detected at the membrane surfaces of both dendritic cells and T cells, but virions are not released passively at the synapse; instead, virus transfer requires the engagement of T-cell CD4 receptors. The relative seclusion of T cells from the extracellular milieu, the burial of the site of HIV transfer, and the receptor-dependent initiation of virion transfer by T cells highlight unique aspects of cell-cell HIV transmission. PMID:20624966

  9. Nectin-1 spots regulate the branching of olfactory mitral cell dendrites.

    PubMed

    Fujiwara, Takeshi; Inoue, Takahito; Maruo, Tomohiko; Rikitake, Yoshiyuki; Ieki, Nao; Mandai, Kenji; Kimura, Kazushi; Kayahara, Tetsuro; Wang, Shujie; Itoh, Yu; Sai, Kousyoku; Mori, Masahiro; Mori, Kensaku; Takai, Yoshimi; Mizoguchi, Akira

    2015-09-01

    Olfactory mitral cells extend lateral secondary dendrites that contact the lateral secondary and apical primary dendrites of other mitral cells in the external plexiform layer (EPL) of the olfactory bulb. The lateral dendrites further contact granule cell dendrites, forming dendrodendritic reciprocal synapses in the EPL. These dendritic structures are critical for odor information processing, but it remains unknown how they are formed. We recently showed that the immunoglobulin-like cell adhesion molecule nectin-1 constitutes a novel adhesion apparatus at the contacts between mitral cell lateral dendrites, between mitral cell lateral and apical dendrites, and between mitral cell lateral dendrites and granule cell dendritic spine necks in the deep sub-lamina of the EPL of the developing mouse olfactory bulb and named them nectin-1 spots. We investigated here the role of the nectin-1 spots in the formation of dendritic structures in the EPL of the mouse olfactory bulb. We showed that in cultured nectin-1-knockout mitral cells, the number of branching points of mitral cell dendrites was reduced compared to that in the control cells. In the deep sub-lamina of the EPL in the nectin-1-knockout olfactory bulb, the number of branching points of mitral cell lateral dendrites and the number of dendrodendritic reciprocal synapses were reduced compared to those in the control olfactory bulb. These results indicate that the nectin-1 spots regulate the branching of mitral cell dendrites in the deep sub-lamina of the EPL and suggest that the nectin-1 spots are required for odor information processing in the olfactory bulb. PMID:26169026

  10. Antigen loading of dendritic cells with whole tumor cell preparations.

    PubMed

    Thumann, Peter; Moc, Isabelle; Humrich, Jens; Berger, Thomas G; Schultz, Erwin S; Schuler, Gerold; Jenne, Lars

    2003-06-01

    Dendritic cells (DC) based vaccinations have been widely used for the induction of anti-tumoral immunity in clinical studies. Antigen loading of DC with whole tumor cell preparations is an attractive method whenever tumor cell material is available. In order to determine parameters for the loading procedure, we performed dose finding and timing experiments. We found that apoptotic and necrotic melanoma cells up to a ratio of one-to-one, equivalent to 1mg/ml protein per 1 x 10(6) DC, can be added to monocyte derived DC without effecting DC recovery extensively. Using the isolated protein content of tumor cells (lysate) as a parameter, up to 5 mg/ml protein per 1 x 10(6) DC can be added. To achieve significant protein uptake at least 1 mg/ml of protein have to be added for more than 24 h as tested with FITC-labelled ovalbumin. Maturation inducing cytokines can be added simultaneously with the tumor cell preparations to immature DC without affecting the uptake. Furthermore, we tested the feasibility of cryopreservation of loaded and matured DC to facilitate the generation of ready to use aliquots. DC were cryopreserved in a mix of human serum albumin, DMSO and 5% glucose. After thawing, surface expression of molecules indicating the mature status (CD83, costimulatory and MHC molecules), was found to be unaltered. Furthermore, cryopreserved DC kept the capability to stimulate allogenic T-cell proliferation in mixed leukocyte reactions at full level. Loaded and matured DC pulsed with influenza matrix peptide (IMP) retained the capacity to induce the generation of IMP-specific cytotoxic T-lymphocytes after cryopreservation as measured by ELISPOT and tetramer staining. The expression of the chemokine receptor CXCR-4 and CCR-7 remained unaltered during cryopreservation and the migratory responsiveness towards MIP-3beta was unaltered as measured in a migration assay. Thus we conclude that the large scale loading and maturation of DC with whole tumor cell preparations can be

  11. EBI2 augments Tfh cell fate by promoting interaction with IL-2-quenching dendritic cells.

    PubMed

    Li, Jianhua; Lu, Erick; Yi, Tangsheng; Cyster, Jason G

    2016-05-01

    T follicular helper (Tfh) cells are a subset of T cells carrying the CD4 antigen; they are important in supporting plasma cell and germinal centre responses. The initial induction of Tfh cell properties occurs within the first few days after activation by antigen recognition on dendritic cells, although how dendritic cells promote this cell-fate decision is not fully understood. Moreover, although Tfh cells are uniquely defined by expression of the follicle-homing receptor CXCR5 (refs 1, 2), the guidance receptor promoting the earlier localization of activated T cells at the interface of the B-cell follicle and T zone has been unclear. Here we show that the G-protein-coupled receptor EBI2 (GPR183) and its ligand 7α,25-dihydroxycholesterol mediate positioning of activated CD4 T cells at the interface of the follicle and T zone. In this location they interact with activated dendritic cells and are exposed to Tfh-cell-promoting inducible co-stimulator (ICOS) ligand. Interleukin-2 (IL-2) is a cytokine that has multiple influences on T-cell fate, including negative regulation of Tfh cell differentiation. We demonstrate that activated dendritic cells in the outer T zone further augment Tfh cell differentiation by producing membrane and soluble forms of CD25, the IL-2 receptor α-chain, and quenching T-cell-derived IL-2. Mice lacking EBI2 in T cells or CD25 in dendritic cells have reduced Tfh cells and mount defective T-cell-dependent plasma cell and germinal centre responses. These findings demonstrate that distinct niches within the lymphoid organ T zone support distinct cell fate decisions, and they establish a function for dendritic-cell-derived CD25 in controlling IL-2 availability and T-cell differentiation. PMID:27147029

  12. Functional Properties of Dendritic Gap Junctions in Cerebellar Golgi Cells.

    PubMed

    Szoboszlay, Miklos; Lőrincz, Andrea; Lanore, Frederic; Vervaeke, Koen; Silver, R Angus; Nusser, Zoltan

    2016-06-01

    The strength and variability of electrical synaptic connections between GABAergic interneurons are key determinants of spike synchrony within neuronal networks. However, little is known about how electrical coupling strength is determined due to the inaccessibility of gap junctions on the dendritic tree. We investigated the properties of gap junctions in cerebellar interneurons by combining paired somato-somatic and somato-dendritic recordings, anatomical reconstructions, immunohistochemistry, electron microscopy, and modeling. By fitting detailed compartmental models of Golgi cells to their somato-dendritic voltage responses, we determined their passive electrical properties and the mean gap junction conductance (0.9 nS). Connexin36 immunofluorescence and freeze-fracture replica immunogold labeling revealed a large variability in gap junction size and that only 18% of the 340 channels are open in each plaque. Our results establish that the number of gap junctions per connection is the main determinant of both the strength and variability in electrical coupling between Golgi cells. PMID:27133465

  13. Unique immunomodulatory effects of azelastine on dendritic cells in vitro.

    PubMed

    Schumacher, S; Kietzmann, M; Stark, H; Bäumer, W

    2014-11-01

    Allergic contact dermatitis and atopic dermatitis are among the most common inflammatory skin diseases in western countries, and antigen-presenting cells like dendritic cells (DC) are key players in their pathophysiology. Histamine, an important mediator of allergic reactions, influences DC maturation and cytokine secretion, which led us to investigate the immunomodulatory potential of the well-known histamine H1 receptor antagonists: azelastine, olopatadine, cetirizine, and pyrilamine. Unlike other H1 antihistamines, azelastine decreased lipopolysaccharide-induced tumor necrosis factor α and interleukin-12 secretion from murine bone marrow-derived DC. This effect was independent of histamine receptors H1, H2, or H4 and may be linked to inhibition of the nuclear factor kappa B pathway. Moreover, only azelastine reduced proliferation of allogenic T cells in a mixed leukocyte reaction. We then tested topical application of the H1 antihistamines on mice sensitized against toluene-2,4-diisocyanate, a model of Th2-mediated allergic contact dermatitis. In contrast to the in vitro results, all investigated substances were efficacious in reducing allergic ear swelling. Azelastine has unique effects on dendritic cells and T cell interaction in vitro. However, this did not translate into superior in vivo efficacy for Th2-mediated allergic dermatitis, possibly due to the effects of the antihistamines on other cell types involved in skin inflammation. Future research will have to clarify whether these properties are relevant to in vivo models of allergic inflammation with a different T cell polarization. PMID:25119779

  14. Directing dendritic cell immunotherapy towards successful cancer treatment

    PubMed Central

    Sabado, Rachel Lubong; Bhardwaj, Nina

    2010-01-01

    The use of dendritic cells (DCs) for tumor immunotherapy represents a powerful approach for harnessing the patient's own immune system to eliminate tumor cells. However, suboptimal conditions for generating potent immunostimulatory DCs, as well as the induction of tolerance and suppression mediated by the tumors and its microenvironment have contributed to limited success. Combining DC vaccines with new approaches that enhance immunogenicity and overcome the regulatory mechanisms underlying peripheral tolerance may be the key to achieving effective and durable anti-tumor immune responses that translate to better clinical outcomes. PMID:20473346

  15. Tolerogenic dendritic cells and their applications in transplantation

    PubMed Central

    Li, Haibin; Shi, Bingyi

    2015-01-01

    In transplantation immunology, the ultimate goal is always to successfully and specifically induce immune tolerance of allografts. Tolerogenic dendritic cells (tol-DCs) with immunoregulatory functions have attracted much attention as they play important roles in inducing and maintaining immune tolerance. Here, we focused on tol-DCs that have the potential to promote immune tolerance after solid-organ transplantation. We focus on their development and interactions with other regulatory cells, and we also explore various tol-DC engineering protocols. Harnessing tol-DCs represents a promising cellular therapy for promoting long-term graft functional survival in transplant recipients that will most likely be achieved in the future. PMID:25109681

  16. Targeting Antigens to Dendritic Cell Receptors for Vaccine Development

    PubMed Central

    Apostolopoulos, Vasso; Thalhammer, Theresia; Tzakos, Andreas G.

    2013-01-01

    Dendritic cells (DCs) are highly specialized antigen presenting cells of the immune system which play a key role in regulating immune responses. Depending on the method of antigen delivery, DCs stimulate immune responses or induce tolerance. As a consequence of the dual function of DCs, DCs are studied in the context of immunotherapy for both cancer and autoimmune diseases. In vaccine development, a major aim is to induce strong, specific T-cell responses. This is achieved by targeting antigen to cell surface molecules on DCs that efficiently channel the antigen into endocytic compartments for loading onto MHC molecules and stimulation of T-cell responses. The most attractive cell surface receptors, expressed on DCs used as targets for antigen delivery for cancer and other diseases, are discussed. PMID:24228179

  17. Dendritic cells in progression and pathology of HIV infection

    PubMed Central

    Manches, Olivier; Frleta, Davor; Bhardwaj, Nina

    2014-01-01

    Although the major targets of HIV infection are CD4+ T cells, dendritic cells (DC) represent a crucial subset in HIV infection as they influence viral transmission, target cell infection and antigen presentation of HIV antigens. DC are potent antigen presenting cells that can modulate anti-viral immune responses. Through secretion of inflammatory cytokines and interferons (IFN), DC also alter T cell proliferation and differentiation, participating in the immune dysregulation characteristic of chronic HIV infection. Their wide distribution in close proximity with the mucosal epithelia makes them one of the first cell types to encounter HIV during sexual transmission [1]. We will discuss here the multiple roles that DC play at different stages of HIV infection, emphasizing their relevance to HIV pathology and progression. PMID:24246474

  18. Dendritic Cell Cancer Vaccines: From the Bench to the Bedside

    PubMed Central

    Katz, Tamar; Avivi, Irit; Benyamini, Noam; Rosenblatt, Jacalyn; Avigan, David

    2014-01-01

    The recognition that the development of cancer is associated with acquired immunodeficiency, mostly against cancer cells themselves, and understanding pathways inducing this immunosuppression, has led to a tremendous development of new immunological approaches, both vaccines and drugs, which overcome this inhibition. Both “passive” (e.g. strategies relying on the administration of specific T cells) and “active” vaccines (e.g. peptide-directed or whole-cell vaccines) have become attractive immunological approaches, inducing cell death by targeting tumor-associated antigens. Whereas peptide-targeted vaccines are usually directed against a single antigen, whole-cell vaccines (e.g. dendritic cell vaccines) are aimed to induce robust responsiveness by targeting several tumor-related antigens simultaneously. The combination of vaccines with new immuno-stimulating agents which target “immunosuppressive checkpoints” (anti-CTLA-4, PD-1, etc.) is likely to improve and maintain immune response induced by vaccination. PMID:25386340

  19. Negative permeability and subwavelength focusing of quasi-periodic dendritic cell metamaterials.

    PubMed

    Zhou, Xin; Fu, Quan H; Zhao, Jing; Yang, Yang; Zhao, Xiao P

    2006-08-01

    We present the design for a hexagonal cell made of quasi-periodic dendritic arranged collections of plasmonic metallic wires that may exhibit a resonant magnetic collective response. When such quasi-periodic dendritic cells are etched on a host medium, they may provide metamaterials with negative effective permeability. We also show that a clear point image is observed, as expected, with our left-handed metamaterials (LHMs) lens composed of metallic dendritic cells and wire strips. These prominent characteristics of quasi-periodic dendritic cells potentially enable us to prepare infrared or visible domain LHMs by using a general chemical method. PMID:19529087

  20. Investigating Evolutionary Conservation of Dendritic Cell Subset Identity and Functions

    PubMed Central

    Vu Manh, Thien-Phong; Bertho, Nicolas; Hosmalin, Anne; Schwartz-Cornil, Isabelle; Dalod, Marc

    2015-01-01

    Dendritic cells (DCs) were initially defined as mononuclear phagocytes with a dendritic morphology and an exquisite efficiency for naïve T-cell activation. DC encompass several subsets initially identified by their expression of specific cell surface molecules and later shown to excel in distinct functions and to develop under the instruction of different transcription factors or cytokines. Very few cell surface molecules are expressed in a specific manner on any immune cell type. Hence, to identify cell types, the sole use of a small number of cell surface markers in classical flow cytometry can be deceiving. Moreover, the markers currently used to define mononuclear phagocyte subsets vary depending on the tissue and animal species studied and even between laboratories. This has led to confusion in the definition of DC subset identity and in their attribution of specific functions. There is a strong need to identify a rigorous and consensus way to define mononuclear phagocyte subsets, with precise guidelines potentially applicable throughout tissues and species. We will discuss the advantages, drawbacks, and complementarities of different methodologies: cell surface phenotyping, ontogeny, functional characterization, and molecular profiling. We will advocate that gene expression profiling is a very rigorous, largely unbiased and accessible method to define the identity of mononuclear phagocyte subsets, which strengthens and refines surface phenotyping. It is uniquely powerful to yield new, experimentally testable, hypotheses on the ontogeny or functions of mononuclear phagocyte subsets, their molecular regulation, and their evolutionary conservation. We propose defining cell populations based on a combination of cell surface phenotyping, expression analysis of hallmark genes, and robust functional assays, in order to reach a consensus and integrate faster the huge but scattered knowledge accumulated by different laboratories on different cell types, organs, and

  1. Human Decidua Contains Potent Immunostimulatory CD83+ Dendritic Cells

    PubMed Central

    Kämmerer, Ulrike; Schoppet, Michael; McLellan, Alexander D.; Kapp, Michaela; Huppertz, Hans-Iko; Kämpgen, Eckhart; Dietl, Johannes

    2000-01-01

    Dendritic cells (DCs) are sentinel cells of the immune system important in initiating antigen-specific T-cell responses to microbial and transplantation antigens. DCs are particularly found in surface tissues such as skin and mucosa, where the organism is threatened by infectious agents. The human decidua, despite its proposed immunosuppressive function, hosts a variety of immunocompetent CD45 cells such as natural killer cells, macrophages, and T cells. Here we describe the detection, isolation, and characterization of CD45+, CD40+, HLA-DR++, and CD83+ cells from human early pregnancy decidua with typical DC morphology. CD83+ as well as CD1a+ cells were found in close vicinity to endometrial glands, with preference to the basal layer of the decidua. In vitro, decidual CD83+ cells could be enriched to ∼30%, with the remainder of cells encompassing DC-bound CD3+ T cells. Stimulation of allogeneic T cells in a mixed leukocyte reaction by the decidual cell fraction enriched for CD83+ cells, was similar to that obtained with blood monocyte-derived DCs, demonstrating the potent immunostimulatory capacity of these cells. Decidual DCs with morphological, phenotypic, and functional characteristics of immunostimulatory DCs might be important mediators in the regulation of immunological balance between maternal and fetal tissue, leading to successful pregnancy. PMID:10880386

  2. Radiation tolerance of boron doped dendritic web silicon solar cells

    NASA Technical Reports Server (NTRS)

    Rohatgi, A.

    1980-01-01

    The potential of dendritic web silicon for giving radiation hard solar cells is compared with the float zone silicon material. Solar cells with n(+)-p-P(+) structure and approximately 15% (AMl) efficiency were subjected to 1 MeV electron irradiation. Radiation tolerance of web cell efficiency was found to be at least as good as that of the float zone silicon cell. A study of the annealing behavior of radiation-induced defects via deep level transient spectroscopy revealed that E sub v + 0.31 eV defect, attributed to boron-oxygen-vacancy complex, is responsible for the reverse annealing of the irradiated cells in the temperature range of 150 to 350 C.

  3. Regulation of Intestinal Immune System by Dendritic Cells

    PubMed Central

    Ko, Hyun-Jeong

    2015-01-01

    Innate immune cells survey antigenic materials beneath our body surfaces and provide a front-line response to internal and external danger signals. Dendritic cells (DCs), a subset of innate immune cells, are critical sentinels that perform multiple roles in immune responses, from acting as principal modulators to priming an adaptive immune response through antigen-specific signaling. In the gut, DCs meet exogenous, non-harmful food antigens as well as vast commensal microbes under steady-state conditions. In other instances, they must combat pathogenic microbes to prevent infections. In this review, we focus on the function of intestinal DCs in maintaining intestinal immune homeostasis. Specifically, we describe how intestinal DCs affect IgA production from B cells and influence the generation of unique subsets of T cell. PMID:25713503

  4. Polyelectrolyte coating of ferumoxytol nanoparticles for labeling of dendritic cells

    NASA Astrophysics Data System (ADS)

    Celikkin, Nehar; Jakubcová, Lucie; Zenke, Martin; Hoss, Mareike; Wong, John Erik; Hieronymus, Thomas

    2015-04-01

    Engineered magnetic nanoparticles (MNPs) are emerging to be used as cell tracers, drug delivery vehicles, and contrast agents for magnetic resonance imaging (MRI) for enhanced theragnostic applications in biomedicine. In vitro labeling of target cell populations with MNPs and their implantation into animal models and patients shows promising outcomes in monitoring successful cell engraftment, differentiation and migration by using MRI. Dendritic cells (DCs) are professional antigen-presenting cells that initiate adaptive immune responses. Thus, DCs have been the focus of cellular immunotherapy and are increasingly applied in clinical trials. Here, we addressed the coating of different polyelectrolytes (PE) around ferumoxytol particles using the layer-by-layer technique. The impact of PE-coated ferumoxytol particles for labeling of DCs and Flt3+ DC progenitors was then investigated. The results from our studies revealed that PE-coated ferumoxytol particles can be readily employed for labeling of DC and DC progenitors and thus are potentially suitable as contrast agents for MRI tracking.

  5. Interaction of Salmonella Typhimurium with Dendritic Cells Derived from Pluripotent Embryonic Stem Cells

    PubMed Central

    Rossi, Raffaella; Hale, Christine; Goulding, David; Andrews, Robert; Abdellah, Zarah; Fairchild, Paul J.; Dougan, Gordon

    2012-01-01

    Using an in vitro differentiation protocol we isolated cells with the properties of dendritic cells (DCs) from immunologically refractive pluripotent murine embryonic stem cells (ESCs). These ES-derived dendritic cells (ESDCs) expressed cytokines and were able to present antigen to a T cell line. Infection of ESDCs with Salmonella Typhimurium stimulated the expression of immune cell markers and thousands of murine genes, many associated with the immune response. Consequently, this system provides a novel in vitro model, amenable to genetic modification, for monitoring host/pathogen interactions. PMID:23284947

  6. Gangliosides inhibit the development from monocytes to dendritic cells

    PubMed Central

    WÖLFL, M; BATTEN, W Y; POSOVSZKY, C; BERNHARD, H; BERTHOLD, F

    2002-01-01

    Dendritic cell (DC) development and function is critical in the initiation phase of any antigen-specific immune response against tumours. Impaired function of DC is one explanation as to how tumours escape immunosurveillance. In the presence of various soluble tumour-related factors DC precursors lose their ability to differentiate into mature DC and to activate T cells. Gangliosides are glycosphingolipids shed by tumours of neuroectodermal origin such as melanoma and neuroblastoma. In this investigation we address the question of whether gangliosides suppress the development and function of monocyte-derived DC in vitro. In the presence of gangliosides, the monocytic DC precursors showed increased adherence, cell spreading and a reduced number of dendrites. The expression of MHC class II molecules, co-stimulatory molecules and the GM-CSF receptor (CD116) on the ganglioside-treated DC was significantly reduced. Furthermore, the function of ganglioside-treated DC was impaired as observed in endocytosis, chemotactic and T cell proliferation assays. In contrast to monocytic DC precursors, mature DC were unaffected even when higher doses of gangliosides were added to the culture. With regard to their carbohydrate structure, five different gangliosides (GM2, GM3, GD2, GD3, GT1b), which are typically shed by melanoma and neuroblastoma, were tested for their ability to suppress DC development and function. Suppression was induced by GM2, but not by the other gangliosides. These data suggest that certain gangliosides impair DC precursors, implying a possible mechanism for tumour escape. PMID:12452834

  7. Resistivity and thickness effects in dendritic web silicon solar cells

    NASA Astrophysics Data System (ADS)

    Meier, D. L.; Hwang, J. M.; Greggi, J.; Campbell, R. B.

    The decrease of minority carrier lifetime as resistivity decreases in dendritic-web silicon solar cells is addressed. This variation is shown to be consistent with the presence of defect levels in the bandgap which arise from extended defects in the web material. The extended defects are oxide precipitates (SiOx) and the dislocation cores they decorate. Sensitivity to this background distribution of defect levels increases with doping because the Fermi level moves closer to the majority carrier band edge. For high-resistivity dendritic-web silicon, which has a low concentration of these extended defects, cell efficiencies as high as 16.6 percent (4 sq cm, 40 ohm-cm boron-doped base, AM1.5 global, 100 mW/sq cm, 25 C JPL LAPSS1 measurement) and a corresponding electron lifetime of 38 microsec have been obtained. Thickness effects occur in bifacial cell designs and in designs which use light trapping. In some cases, the dislocation/precipitate defect can be passivated through the full thickness of web cells by hydrogen ion implantation.

  8. Resistivity and thickness effects in dendritic web silicon solar cells

    NASA Technical Reports Server (NTRS)

    Meier, D. L.; Hwang, J. M.; Greggi, J.; Campbell, R. B.

    1987-01-01

    The decrease of minority carrier lifetime as resistivity decreases in dendritic-web silicon solar cells is addressed. This variation is shown to be consistent with the presence of defect levels in the bandgap which arise from extended defects in the web material. The extended defects are oxide precipitates (SiOx) and the dislocation cores they decorate. Sensitivity to this background distribution of defect levels increases with doping because the Fermi level moves closer to the majority carrier band edge. For high-resistivity dendritic-web silicon, which has a low concentration of these extended defects, cell efficiencies as high as 16.6 percent (4 sq cm, 40 ohm-cm boron-doped base, AM1.5 global, 100 mW/sq cm, 25 C JPL LAPSS1 measurement) and a corresponding electron lifetime of 38 microsec have been obtained. Thickness effects occur in bifacial cell designs and in designs which use light trapping. In some cases, the dislocation/precipitate defect can be passivated through the full thickness of web cells by hydrogen ion implantation.

  9. Nectin-1 spots as a novel adhesion apparatus that tethers mitral cell lateral dendrites in a dendritic meshwork structure of the developing mouse olfactory bulb.

    PubMed

    Inoue, Takahito; Fujiwara, Takeshi; Rikitake, Yoshiyuki; Maruo, Tomohiko; Mandai, Kenji; Kimura, Kazushi; Kayahara, Tetsuro; Wang, Shujie; Itoh, Yu; Sai, Kousyoku; Mori, Masahiro; Mori, Kensaku; Mizoguchi, Akira; Takai, Yoshimi

    2015-08-15

    Mitral cells project lateral dendrites that contact the lateral and primary dendrites of other mitral cells and granule cell dendrites in the external plexiform layer (EPL) of the olfactory bulb. These dendritic structures are critical for odor information processing, but it remains unknown how they are formed. In immunofluorescence microscopy, the immunofluorescence signal for the cell adhesion molecule nectin-1 was concentrated on mitral cell lateral dendrites in the EPL of the developing mouse olfactory bulb. In electron microscopy, the immunogold particles for nectin-1 were symmetrically localized on the plasma membranes at the contacts between mitral cell lateral dendrites, which showed bilateral darkening without dense cytoskeletal undercoats characteristic of puncta adherentia junctions. We named the contacts where the immunogold particles for nectin-1 were symmetrically accumulated "nectin-1 spots." The nectin-1 spots were 0.21 μm in length on average and the distance between the plasma membranes was 20.8 nm on average. In 3D reconstruction of serial sections, clusters of the nectin-1 spots formed a disc-like structure. In the mitral cell lateral dendrites of nectin-1-knockout mice, the immunogold particles for nectin-1 were undetectable and the plasma membrane darkening was electron-microscopically normalized, but the plasma membranes were partly separated from each other. The nectin-1 spots were further identified between mitral cell lateral and primary dendrites and between mitral cell lateral dendrites and granule cell dendritic spine necks. These results indicate that the nectin-1 spots constitute a novel adhesion apparatus that tethers mitral cell dendrites in a dendritic meshwork structure of the developing mouse olfactory bulb. PMID:25967681

  10. Replication of human immunodeficiency virus type 1 in primary dendritic cell cultures.

    PubMed Central

    Langhoff, E; Terwilliger, E F; Bos, H J; Kalland, K H; Poznansky, M C; Bacon, O M; Haseltine, W A

    1991-01-01

    The ability of the human immunodeficiency virus type 1 (HIV-1) to replicate in primary blood dendritic cells was investigated. Dendritic cells compose less than 1% of the circulating leukocytes and are nondividing cells. Highly purified preparations of dendritic cells were obtained using recent advances in cell fractionation. The results of these experiments show that dendritic cells, in contrast to monocytes and T cells, support the active replication of all strains of HIV-1 tested, including T-cell tropic and monocyte/macrophage tropic isolates. The dendritic cell cultures supported much more virus production than did cultures of primary unseparated T cells, CD4+ T cells, and adherent as well as nonadherent monocytes. Replication of HIV-1 in dendritic cells produces no noticeable cytopathic effect nor does it decrease total cell number. The ability of the nonreplicating dendritic cells to support high levels of replication of HIV-1 suggests that this antigen-presenting cell population, which is also capable of supporting clonal T-cell growth, may play a central role in HIV pathogenesis, serving as a source of continued infection of CD4+ T cells and as a reservoir of virus infection. Images PMID:1910172

  11. Dendritic cell-based cancer immunotherapy for colorectal cancer

    PubMed Central

    Kajihara, Mikio; Takakura, Kazuki; Kanai, Tomoya; Ito, Zensho; Saito, Keisuke; Takami, Shinichiro; Shimodaira, Shigetaka; Okamoto, Masato; Ohkusa, Toshifumi; Koido, Shigeo

    2016-01-01

    Colorectal cancer (CRC) is one of the most common cancers and a leading cause of cancer-related mortality worldwide. Although systemic therapy is the standard care for patients with recurrent or metastatic CRC, the prognosis is extremely poor. The optimal sequence of therapy remains unknown. Therefore, alternative strategies, such as immunotherapy, are needed for patients with advanced CRC. This review summarizes evidence from dendritic cell-based cancer immunotherapy strategies that are currently in clinical trials. In addition, we discuss the possibility of antitumor immune responses through immunoinhibitory PD-1/PD-L1 pathway blockade in CRC patients. PMID:27158196

  12. Targeting dendritic cells: a promising strategy to improve vaccine effectiveness

    PubMed Central

    Macri, Christophe; Dumont, Claire; Johnston, Angus PR; Mintern, Justine D

    2016-01-01

    Dendritic cell (DC) targeting is a novel strategy to enhance vaccination efficacy. This approach is based on the in situ delivery of antigen via antibodies that are specific for endocytic receptors expressed at the surface of DCs. Here we review the complexity of the DC subsets and the antigen presentation pathways that need to be considered in the settings of DC targeting. We also summarize current knowledge about antigen delivery to DCs via DEC-205, Clec9A and Clec12A, receptor targets that strongly enhance cellular and humoral immune responses. Finally, we discuss the intracellular trafficking criteria of the targeted receptors that may impact their effectiveness as DC targets. PMID:27217957

  13. Follicular Dendritic Cell Sarcoma Mediastinum - a case report.

    PubMed

    Bushan, Kirti

    2014-12-01

    Follicular dendritic cell tumor (FDCT) are extremely rare difficult to diagnose category tumors.There has been a considerable controversy in medical community regarding precise classification and optimal management of this tumor with some treating it as a form of non Hodgkins lymphoma and some as soft tissue sarcomas.The number of published cases are still low and documentation too heterogenous to give statistically ified therapeutic recommendation of these tumors.This case report aims to highlight various aspects of diagnosing and treating this rare entity. PMID:25767341

  14. Topical vaccination with functionalized particles targeting dendritic cells.

    PubMed

    Baleeiro, Renato B; Wiesmüller, Karl-Heinz; Reiter, Yoran; Baude, Barbara; Dähne, Lars; Patzelt, Alexa; Lademann, Jürgen; Barbuto, José A; Walden, Peter

    2013-08-01

    Needle-free vaccination, for reasons of safety, economy, and convenience, is a central goal in vaccine development, but it also needs to meet the immunological requirements for efficient induction of prophylactic and therapeutic immune responses. Combining the principles of noninvasive delivery to dendritic cells (DCs) through skin and the immunological principles of cell-mediated immunity, we developed microparticle-based topical vaccines. We show here that the microparticles are efficient carriers for coordinated delivery of the essential vaccine constituents to DCs for cross-presentation of the antigens and stimulation of T-cell responses. When applied to the skin, the microparticles penetrate into hair follicles and target the resident DCs, the immunologically most potent cells and site for induction of efficient immune responses. The microparticle vaccine principle can be applied to different antigen formats such as peptides and proteins, or nucleic acids coding for the antigens. PMID:23426134

  15. Modulation of dendritic cell maturation and function by B lymphocytes.

    PubMed

    Bayry, Jagadeesh; Lacroix-Desmazes, Sébastien; Kazatchkine, Michel D; Hermine, Olivier; Tough, David F; Kaveri, Srini V

    2005-07-01

    Investigating the signals that regulate the function of dendritic cells (DC), the sentinels of the immune system, is critical to understanding the role of DC in the regulation of immune responses. Accumulating lines of evidence indicate that in addition to innate stimuli and T cell-derived signals, B lymphocytes exert a profound regulatory effect in vitro and in vivo on the Ag-presenting function of DC. The identification of B cells as a cellular source of cytokines, chemokines, and autoantibodies that are critically involved in the process of maturation, migration, and function of DC provides a rationale for immunotherapeutic intervention of autoimmune and inflammatory conditions by targeting B cells. Conversely, efficient cross-presentation of Ags by DC pulsed with immune complexes provides an alternative approach in the immunotherapy of cancer and infectious diseases. PMID:15972625

  16. Stimulation of dendritic cells enhances immune response after photodynamic therapy

    NASA Astrophysics Data System (ADS)

    Mroz, Pawel; Castano, Ana P.; Hamblin, Michael R.

    2009-02-01

    Photodynamic therapy (PDT) involves the administration of photosensitizers followed by illumination of the primary tumor with red light producing reactive oxygen species that cause vascular shutdown and tumor cell necrosis and apoptosis. Anti-tumor immunity is stimulated after PDT due to the acute inflammatory response, priming of the immune system to recognize tumor-associated antigens (TAA). The induction of specific CD8+ Tlymphocyte cells that recognize major histocompatibility complex class I (MHC-I) restricted epitopes of TAAs is a highly desirable goal in cancer therapy. The PDT killed tumor cells may be phagocytosed by dendritic cells (DC) that then migrate to draining lymph nodes and prime naÃve T-cells that recognize TAA epitopes. This process is however, often sub-optimal, in part due to tumor-induced DC dysfunction. Instead of DC that can become mature and activated and have a potent antigen-presenting and immune stimulating phenotype, immature dendritic cells (iDC) are often found in tumors and are part of an immunosuppressive milieu including regulatory T-cells and immunosuppressive cytokines such as TGF-beta and IL10. We here report on the use of a potent DC activating agent, an oligonucleotide (ODN) that contains a non-methylated CpG motif and acts as an agonist of toll like receptor (TLR) 9. TLR activation is a danger signal to notify the immune system of the presence of invading pathogens. CpG-ODN (but not scrambled non-CpG ODN) increased bone-marrow DC activation after exposure to PDT-killed tumor cells, and significantly increased tumor response to PDT and mouse survival after peri-tumoral administration. CpG may be a valuable immunoadjuvant to PDT especially for tumors that produce DC dysfunction.

  17. A multifunctional core-shell nanoparticle for dendritic cell-based cancer immunotherapy

    NASA Astrophysics Data System (ADS)

    Cho, Nam-Hyuk; Cheong, Taek-Chin; Min, Ji Hyun; Wu, Jun Hua; Lee, Sang Jin; Kim, Daehong; Yang, Jae-Seong; Kim, Sanguk; Kim, Young Keun; Seong, Seung-Yong

    2011-10-01

    Dendritic cell-based cancer immunotherapy requires tumour antigens to be delivered efficiently into dendritic cells and their migration to be monitored in vivo. Nanoparticles have been explored as carriers for antigen delivery, but applications have been limited by the toxicity of the solvents used to make nanoparticles, and by the need to use transfection agents to deliver nanoparticles into cells. Here we show that an iron oxide-zinc oxide core-shell nanoparticle can deliver carcinoembryonic antigen into dendritic cells while simultaneously acting as an imaging agent. The nanoparticle-antigen complex is efficiently taken up by dendritic cells within one hour and can be detected in vitro by confocal microscopy and in vivo by magnetic resonance imaging. Mice immunized with dendritic cells containing the nanoparticle-antigen complex showed enhanced tumour antigen specific T-cell responses, delayed tumour growth and better survival than controls.

  18. Ragweed subpollen particles of respirable size activate human dendritic cells.

    PubMed

    Pazmandi, Kitti; Kumar, Brahma V; Szabo, Krisztina; Boldogh, Istvan; Szoor, Arpad; Vereb, Gyorgy; Veres, Agota; Lanyi, Arpad; Rajnavolgyi, Eva; Bacsi, Attila

    2012-01-01

    Ragweed (Ambrosia artemisiifolia) pollen grains, which are generally considered too large to reach the lower respiratory tract, release subpollen particles (SPPs) of respirable size upon hydration. These SPPs contain allergenic proteins and functional NAD(P)H oxidases. In this study, we examined whether exposure to SPPs initiates the activation of human monocyte-derived dendritic cells (moDCs). We found that treatment with freshly isolated ragweed SPPs increased the intracellular levels of reactive oxygen species (ROS) in moDCs. Phagocytosis of SPPs by moDCs, as demonstrated by confocal laser-scanning microscopy, led to an up-regulation of the cell surface expression of CD40, CD80, CD86, and HLA-DQ and an increase in the production of IL-6, TNF-α, IL-8, and IL-10. Furthermore, SPP-treated moDCs had an increased capacity to stimulate the proliferation of naïve T cells. Co-culture of SPP-treated moDCs with allogeneic CD3(+) pan-T cells resulted in increased secretion of IFN-γ and IL-17 by T cells of both allergic and non-allergic subjects, but induced the production of IL-4 exclusively from the T cells of allergic individuals. Addition of exogenous NADPH further increased, while heat-inactivation or pre-treatment with diphenyleneiodonium (DPI), an inhibitor of NADPH oxidases, strongly diminished, the ability of SPPs to induce phenotypic and functional changes in moDCs, indicating that these processes were mediated, at least partly, by the intrinsic NAD(P)H oxidase activity of SPPs. Collectively, our data suggest that inhaled ragweed SPPs are fully capable of activating dendritic cells (DCs) in the airways and SPPs' NAD(P)H oxidase activity is involved in initiation of adaptive immune responses against innocuous pollen proteins. PMID:23251688

  19. Immunohistochemical detection of dendritic cell markers in cattle.

    PubMed

    Romero-Palomo, F; Risalde, M A; Molina, V; Sánchez-Cordón, P J; Pedrera, M; Gómez-Villamandos, J C

    2013-11-01

    Dendritic cells (DCs) are "professional" antigen-presenting cells with a critical role in the regulation of innate and adaptive immune responses and thus have been considered of great interest in the study of a variety of infectious diseases. The objective of this investigation was to characterize the in vivo distribution of DCs in bovine tissues by using potential DC markers to establish a basis for the study of DCs in diseased tissues. Markers evaluated included MHCII, CD208, CD1b, CD205, CNA.42, and S100 protein, the latter 2 being expressed by follicular dendritic cells whose origin and role are different from the rest of hematopoietic DCs. Paraffin wax-embedded tissues from 6 healthy Friesian calves were subjected to the avidin-biotin-peroxidase method, and the most appropriate fixatives, dilutions, and antigen retrieval pretreatments were studied for each of the primary antibodies. The most significant results included the localization of CD208-positive cells not only in the T zone of lymphoid organs but also within lymphoid follicles; CD1b-positive cells were mainly found in thymus and interfollicular areas of some lymph nodes; cells stained with anti-CD205 antibody were scarce, and their location was mainly in nonlymphoid tissues; and CNA.42- and S100 protein-positive cells localized in primary lymphoid follicles and light zones of germinal centers, although showing differences in the staining pattern. Furthermore, MHCII was established as one of the most sensitive markers for any DC of hematopoietic origin. These results increase our understanding of DC immunolabeling and will help in future DC studies of both healthy and diseased tissues. PMID:23528943

  20. Follicular Dendritic Cells Retain Infectious HIV in Cycling Endosomes

    PubMed Central

    Heesters, Balthasar A.; Lindqvist, Madelene; Vagefi, Parsia A.; Scully, Eileen P.; Schildberg, Frank A.; Altfeld, Marcus; Walker, Bruce D.; Kaufmann, Daniel E.; Carroll, Michael C.

    2015-01-01

    Despite the success of antiretroviral therapy (ART), it does not cure Human Immunodeficiency Virus (HIV) and discontinuation results in viral rebound. Follicular dendritic cells (FDC) are in direct contact with CD4+ T cells and they retain intact antigen for prolonged periods. We found that human FDC isolated from patients on ART retain infectious HIV within a non-degradative cycling compartment and transmit infectious virus to uninfected CD4 T cells in vitro. Importantly, treatment of the HIV+ FDC with a soluble complement receptor 2 purges the FDC of HIV virions and prevents viral transmission in vitro. Our results provide an explanation for how FDC can retain infectious HIV for extended periods and suggest a therapeutic strategy to achieve cure in HIV-infected humans. PMID:26623655

  1. Dendritic cells and macrophages in the genitourinary tract

    PubMed Central

    Iijima, N; Thompson, JM; Iwasaki, A

    2009-01-01

    Dendritic cells (DCs) and macrophages are antigen-presenting cells (APCs) that are important in innate immune defense as well as in the generation and regulation of adaptive immunity against a wide array of pathogens. The genitourinary (GU) tract, which serves an important reproductive function, is constantly exposed to numerous agents of sexually transmitted infections (STIs). To combat these STIs, several subsets of DCs and macrophages are strategically localized within the GU tract. In the female genital mucosa, recruitment and function of these APCs are uniquely governed by sex hormones. This review summarizes the latest advances in our understanding of DCs and macrophages in the GU tract with respect to their subsets, lineage, and function. In addition, we discuss the divergent roles of these cells in immune defense against STIs as well as in maternal tolerance to the fetus. PMID:19079212

  2. Polysialylation controls dendritic cell trafficking by regulating chemokine recognition.

    PubMed

    Kiermaier, Eva; Moussion, Christine; Veldkamp, Christopher T; Gerardy-Schahn, Rita; de Vries, Ingrid; Williams, Larry G; Chaffee, Gary R; Phillips, Andrew J; Freiberger, Friedrich; Imre, Richard; Taleski, Deni; Payne, Richard J; Braun, Asolina; Förster, Reinhold; Mechtler, Karl; Mühlenhoff, Martina; Volkman, Brian F; Sixt, Michael

    2016-01-01

    The addition of polysialic acid to N- and/or O-linked glycans, referred to as polysialylation, is a rare posttranslational modification that is mainly known to control the developmental plasticity of the nervous system. Here we show that CCR7, the central chemokine receptor controlling immune cell trafficking to secondary lymphatic organs, carries polysialic acid. This modification is essential for the recognition of the CCR7 ligand CCL21. As a consequence, dendritic cell trafficking is abrogated in polysialyltransferase-deficient mice, manifesting as disturbed lymph node homeostasis and unresponsiveness to inflammatory stimuli. Structure-function analysis of chemokine-receptor interactions reveals that CCL21 adopts an autoinhibited conformation, which is released upon interaction with polysialic acid. Thus, we describe a glycosylation-mediated immune cell trafficking disorder and its mechanistic basis. PMID:26657283

  3. Resident and “inflammatory” dendritic cells in human skin

    PubMed Central

    Zaba, Lisa C.; Krueger, James G; Lowes, Michelle A.

    2009-01-01

    Dendritic cells (DCs) are a heterogeneous group of antigen-presenting leukocytes that play an important role in activation of both the innate and acquired arms of the immune system. While 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 non-inflamed human skin during steady-state, there are three main cutaneous DC populations: epidermal Langerhans cells (LCs), dermal myeloid DCs, and dermal plasmacytoid DCs (pDCs). In psoriasis, a model for cutaneous inflammation, there is an additional population of myeloid dermal DCs – “inflammatory DCs” – which appear to be critical for disease pathogenesis. PMID:18685620

  4. Dendritic Cells in the Gut: Interaction with Intestinal Helminths

    PubMed Central

    Mendlovic, Fela; Flisser, Ana

    2010-01-01

    The mucosal environment in mammals is highly tolerogenic; however, after exposure to pathogens or danger signals, it is able to shift towards an inflammatory response. Dendritic cells (DCs) orchestrate immune responses and are highly responsible, through the secretion of cytokines and expression of surface markers, for the outcome of such immune response. In particular, the DC subsets found in the intestine have specialized functions and interact with different immune as well as nonimmune cells. Intestinal helminths primarily induce Th2 responses where DCs have an important yet not completely understood role. In addition, this cross-talk results in the induction of regulatory T cells (T regs) as a result of the homeostatic mucosal environment. This review highlights the importance of studying the particular relation “helminth-DC-milieu” in view of the significance that each of these factors plays. Elucidating the mechanisms that trigger Th2 responses may provide the understanding of how we might modulate inflammatory processes. PMID:20224759

  5. Dendritic cell development-History, advances, and open questions.

    PubMed

    Puhr, Sarah; Lee, Jaeyop; Zvezdova, Ekaterina; Zhou, Yu J; Liu, Kang

    2015-12-01

    Dendritic cells (DCs) are uniquely potent in orchestrating T cell immune response, thus they are indispensable immune sentinels. They originate from progenitors in the bone marrow through hematopoiesis, a highly regulated developmental process involving multiple cellular and molecular events. This review highlights studies of DC development-from the discovery of DCs as glass-adherent antigen presenting cells to the debate and resolution of their origin and lineage map. In particular, we summarize the roles of lineage-specific cytokines, the placement of distinct hematopoietic progenitors within the DC lineage and transcriptional programs governing DC development, which together have allowed us to diagram the current view of DC hematopoiesis. Important open questions and debates on the DC development and relevant models are also discussed. PMID:27040276

  6. CT findings associated with blastic plasmacytoid dendritic cell neoplasm: a case report

    PubMed Central

    Choi, Jung W; Jeong, Katherine; Sokol, Lubomir

    2016-01-01

    Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy that is frequently misdiagnosed. We present a case of a 53-year-old man diagnosed with blastic plasmacytoid dendritic cell neoplasm with extensive computed tomography (CT) findings and provide an imaging focused review of this uncommon malignancy. PMID:27504192

  7. β-III spectrin is critical for development of purkinje cell dendritic tree and spine morphogenesis.

    PubMed

    Gao, Yuanzheng; Perkins, Emma M; Clarkson, Yvonne L; Tobia, Steven; Lyndon, Alastair R; Jackson, Mandy; Rothstein, Jeffrey D

    2011-11-16

    Mutations in the gene encoding β-III spectrin give rise to spinocerebellar ataxia type 5, a neurodegenerative disease characterized by progressive thinning of the molecular layer, loss of Purkinje cells and increasing motor deficits. A mouse lacking full-length β-III spectrin (β-III⁻/⁻) displays a similar phenotype. In vitro and in vivo analyses of Purkinje cells lacking β-III spectrin, reveal a critical role for β-III spectrin in Purkinje cell morphological development. Disruption of the normally well ordered dendritic arborization occurs in Purkinje cells from β-III⁻/⁻ mice, specifically showing a loss of monoplanar organization, smaller average dendritic diameter and reduced densities of Purkinje cell spines and synapses. Early morphological defects appear to affect distribution of dendritic, but not axonal, proteins. This study confirms that thinning of the molecular layer associated with disease pathogenesis is a consequence of Purkinje cell dendritic degeneration, as Purkinje cells from 8-month-old β-III⁻/⁻ mice have drastically reduced dendritic volumes, surface areas and total dendritic lengths compared with 5- to 6-week-old β-III⁻/⁻ mice. These findings highlight a critical role of β-III spectrin in dendritic biology and are consistent with an early developmental defect in β-III⁻/⁻ mice, with abnormal Purkinje cell dendritic morphology potentially underlying disease pathogenesis. PMID:22090485

  8. Inorganic arsenic impairs differentiation and functions of human dendritic cells

    SciTech Connect

    Macoch, Mélinda; Morzadec, Claudie; Fardel, Olivier; Vernhet, Laurent

    2013-01-15

    Experimental studies have demonstrated that the antileukemic trivalent inorganic arsenic prevents the development of severe pro-inflammatory diseases mediated by excessive Th1 and Th17 cell responses. Differentiation of Th1 and Th17 subsets is mainly regulated by interleukins (ILs) secreted from dendritic cells (DCs) and the ability of inorganic arsenic to impair interferon-γ and IL-17 secretion by interfering with the physiology of DCs is unknown. In the present study, we demonstrate that high concentrations of sodium arsenite (As(III), 1–2 μM) clinically achievable in plasma of arsenic-treated patients, block differentiation of human peripheral blood monocytes into immature DCs (iDCs) by inducing their necrosis. Differentiation of monocytes in the presence of non-cytotoxic concentrations of As(III) (0.1 to 0.5 μM) only slightly impacts endocytotic activity of iDCs or expression of co-stimulatory molecules in cells activated with lipopolysaccharide. However, this differentiation in the presence of As(III) strongly represses secretion of IL-12p70 and IL-23, two major regulators of Th1 and Th17 activities, from iDCs stimulated with different toll-like receptor (TLR) agonists in metalloid-free medium. Such As(III)-exposed DCs also exhibit reduced mRNA levels of IL12A and/or IL12B genes when activated with TLR agonists. Finally, differentiation of monocytes with non-cytotoxic concentrations of As(III) subsequently reduces the ability of activated DCs to stimulate the release of interferon-γ and IL-17 from Th cells. In conclusion, our results demonstrate that clinically relevant concentrations of inorganic arsenic markedly impair in vitro differentiation and functions of DCs, which may contribute to the putative beneficial effects of the metalloid towards inflammatory autoimmune diseases. Highlights: ► Inorganic arsenic impairs differentiation and functions of human dendritic cells (DCs) ► Arsenite (> 1 μM) blocks differentiation of dendritic cells by

  9. Modulation of Dendritic Cell Activation and Subsequent Th1 Cell Polarization by Lidocaine.

    PubMed

    Jeon, Young-Tae; Na, Hyeongjin; Ryu, Heeju; Chung, Yeonseok

    2015-01-01

    Dendritic cells play an essential role in bridging innate and adaptive immunity by recognizing cellular stress including pathogen- and damage-associated molecular patterns and by shaping the types of antigen-specific T cell immunity. Although lidocaine is widely used in clinical settings that trigger cellular stress, it remains unclear whether such treatment impacts the activation of innate immune cells and subsequent differentiation of T cells. Here we showed that lidocaine inhibited the production of IL-6, TNFα and IL-12 from dendritic cells in response to toll-like receptor ligands including lipopolysaccharide, poly(I:C) and R837 in a dose-dependent manner. Notably, the differentiation of Th1 cells was significantly suppressed by the addition of lidocaine while the same treatment had little effect on the differentiation of Th17, Th2 and regulatory T cells in vitro. Moreover, lidocaine suppressed the ovalbumin-specific Th1 cell responses in vivo induced by the adoptive transfer of ovalbumin-pulsed dendritic cells. These results demonstrate that lidocaine inhibits the activation of dendritic cells in response to toll-like receptor signals and subsequently suppresses the differentiation of Th1 cell responses. PMID:26445366

  10. Dendritic cells and oral transmission of prion diseases.

    PubMed

    Huang, Fang-Ping; MacPherson, G Gordon

    2004-04-19

    Transmissible spongiform encephalopathies (scrapie, BSE, Kuru) develop as central nervous system (CNS) diseases after long incubation periods, and many of which may arise following the consumption of infected material. The infectious agent is thought to be a misfolded form (scrapie associated PrP (PrP(Sc))) of a normal host protein (cellular isoform of PrP (PrP(C))), which is relatively resistant to proteolytic degradation and which serves as a template, directing host prion protein (PrP) to accumulate in the misfolded form. Animal experiments have shown that CNS disease is preceded by a period in which the agent accumulates in secondary lymphoid organs (Peyer's patches (PP), lymph nodes, spleen), particularly follicular dendritic cells (FDCs) in the B cell areas of these organs. How the agent is transmitted from the intestinal lumen to the FDCs is largely unknown. Dendritic cells (DCs, cells quite distinct from FDCs) are cells that are specialised to acquire antigens from peripheral tissues and to transport them to secondary lymphoid organs for presentation to T and B lymphocytes. We have shown that DCs can acquire PrP(Sc) from the intestinal lumen and deliver it to mesenteric lymph nodes. In this review we discuss the different stages involved in the migration of PrP(Sc) from the intestine to FDCs and consider the different stages and barriers involved in this process. We conclude that transport of the causative agent, using PrP(Sc) as a biomarker, from the intestine to FDCs is a very inefficient process, which may help to account for the apparent low frequency of individuals who have consumed infected material that go on to develop clinical disease. PMID:15063597

  11. Migratory dendritic cells transfer antigen to a lymph node-resident dendritic cell population for efficient CTL priming.

    PubMed

    Allan, Rhys S; Waithman, Jason; Bedoui, Sammy; Jones, Claerwen M; Villadangos, Jose A; Zhan, Yifan; Lew, Andrew M; Shortman, Ken; Heath, William R; Carbone, Francis R

    2006-07-01

    Skin dendritic cells (DCs) are thought to act as key initiators of local T cell immunity. Here we show that after skin infection with herpes simplex virus (HSV), cytotoxic T lymphocyte (CTL) activation required MHC class I-restricted presentation by nonmigratory CD8(+) DCs rather than skin-derived DCs. Despite a lack of direct presentation by migratory DCs, blocking their egress from infected skin substantially inhibited class I-restricted presentation and HSV-specific CTL responses. These results support the argument for initial transport of antigen by migrating DCs, followed by its transfer to the lymphoid-resident DCs for presentation and CTL priming. Given that relatively robust CTL responses were seen with small numbers of skin-emigrant DCs, we propose that this inter-DC antigen transfer functions to amplify presentation across a larger network of lymphoid-resident DCs for efficient T cell activation. PMID:16860764

  12. GM-CSF Controls Nonlymphoid Tissue Dendritic Cell Homeostasis but Is Dispensable for the Differentiation of Inflammatory Dendritic Cells

    PubMed Central

    Greter, Melanie; Helft, Julie; Chow, Andrew; Hashimoto, Daigo; Mortha, Arthur; Agudo-Cantero, Judith; Bogunovic, Milena; Gautier, Emmanuel L.; Miller, Jennifer; Leboeuf, Marylene; Lu, Geming; Aloman, Costica; Brown, Brian D.; Pollard, Jeffrey W.; Xiong, Huabao; Randolph, Gwendalyn J.; Chipuk, Jerry E.; Frenette, Paul S.; Merad, Miriam

    2012-01-01

    SUMMARY GM-CSF (Csf-2) is a critical cytokine for the in vitro generation of dendritic cells (DCs) and is thought to control the development of inflammatory DCs and resident CD103+ DCs in some tissues. Here we showed that in contrast to the current understanding, Csf-2 receptor acts in the steady state to promote the survival and homeostasis of nonlymphoid tissue-resident CD103+ and CD11b+ DCs. Absence of Csf-2 receptor on lung DCs abrogated the induction of CD8+ T cell immunity after immunization with particulate antigens. In contrast, Csf-2 receptor was dispensable for the differentiation and innate function of inflammatory DCs during acute injuries. Instead, inflammatory DCs required Csf-1 receptor for their development. Thus, Csf-2 is important in vaccine-induced CD8+ T cell immunity through the regulation of nonlymphoid tissue DC homeostasis rather than control of inflammatory DCs in vivo. PMID:22749353

  13. Dendritic and Langerhans cells respond to Aβ peptides differently: implication for AD immunotherapy

    PubMed Central

    Cheng, Jiang; Lin, Xiaoyang; Morgan, David; Gordon, Marcia; Chen, Xi; Wang, Zhen-Hai; Li, Hai-Ning; He, Lan-Jie; Zhou, Shu-Feng; Cao, Chuanhai

    2015-01-01

    Both wild-type and mutated beta-amyloid (Aβ) peptides can elicit an immune response when delivered subcutaneously. However, only mutated forms of Aβ can sensitize dendritic cells when administered intravenously or intraperitoneally. To understand the role of mutation and delivery routes in creating immune responses, and the function of dendritic cells as therapeutic agents, we used fluorescent-conjugated WT Aβ1-40 (WT40) and artificially mutated Aβ1-40 (22W40) peptides to treat dendritic and Langerhans cells from young and/or old mice at different time points. The cell types were analyzed by flow cytometry and confocal microscopy to identify differences in function and antigen presentation, and Luminex and Western blots for cell activation and associated mechanisms. Our results demonstrated that the artificial mutant, 22W40, enhanced dendritic cell's phagocytosis and antigen presentation better than the WT40. Interestingly, Langerhans cells were more effective at early presentation. The artificial mutant 22W40 increased CD8α+ dendritic cells, CD8+ T-cells, and IFN-γ production when co-cultured with self-lymphocytes and dendritic cells from aged mice (30-month-old). Here, the 22W40 mutant peptide has been found to be potent enough to activate DCs, and that dendritic cell-based therapy may be a more effective treatment for age-related diseases, such as Alzheimer's disease (AD). PMID:26473448

  14. Dendritic and Langerhans cells respond to Aβ peptides differently: implication for AD immunotherapy.

    PubMed

    Cheng, Jiang; Lin, Xiaoyang; Morgan, David; Gordon, Marcia; Chen, Xi; Wang, Zhen-Hai; Li, Hai-Ning; He, Lan-Jie; Zhou, Shu-Feng; Cao, Chuanhai

    2015-11-01

    Both wild-type and mutated beta-amyloid (Aβ) peptides can elicit an immune response when delivered subcutaneously. However, only mutated forms of Aβ can sensitize dendritic cells when administered intravenously or intraperitoneally. To understand the role of mutation and delivery routes in creating immune responses, and the function of dendritic cells as therapeutic agents, we used fluorescent-conjugated WT Aβ1-40 (WT40) and artificially mutated Aβ1-40 (22W40) peptides to treat dendritic and Langerhans cells from young and/or old mice at different time points. The cell types were analyzed by flow cytometry and confocal microscopy to identify differences in function and antigen presentation, and Luminex and Western blots for cell activation and associated mechanisms. Our results demonstrated that the artificial mutant, 22W40, enhanced dendritic cell's phagocytosis and antigen presentation better than the WT40. Interestingly, Langerhans cells were more effective at early presentation. The artificial mutant 22W40 increased CD8α+ dendritic cells, CD8+ T-cells, and IFN-γ production when co-cultured with self-lymphocytes and dendritic cells from aged mice (30-month-old). Here, the 22W40 mutant peptide has been found to be potent enough to activate DCs, and that dendritic cell-based therapy may be a more effective treatment for age-related diseases, such as Alzheimer's disease (AD). PMID:26473448

  15. Immunological Characterization of Whole Tumour Lysate-Loaded Dendritic Cells for Cancer Immunotherapy

    PubMed Central

    Ottobrini, Luisa; Biasin, Mara; Borelli, Manuela; Lucignani, Giovanni; Trabattoni, Daria; Clerici, Mario

    2016-01-01

    Introduction Dendritic cells play a key role as initiators of T-cell responses, and even if tumour antigen-loaded dendritic cells can induce anti-tumour responses, their efficacy has been questioned, suggesting a need to enhance immunization strategies. Matherials & Methods We focused on the characterization of bone marrow-derived dendritic cells pulsed with whole tumour lysate (TAA-DC), as a source of known and unknown antigens, in a mouse model of breast cancer (MMTV-Ras). Dendritic cells were evaluated for antigen uptake and for the expression of MHC class I/II and costimulatory molecules and markers associated with maturation. Results Results showed that antigen-loaded dendritic cells are characterized by a phenotypically semi-mature/mature profile and by the upregulation of genes involved in antigen presentation and T-cell priming. Activated dendritic cells stimulated T-cell proliferation and induced the production of high concentrations of IL-12p70 and IFN-γ but only low levels of IL-10, indicating their ability to elicit a TH1-immune response. Furthermore, administration of Antigen loaded-Dendritic Cells in MMTV-Ras mice evoked a strong anti-tumour response in vivo as demonstrated by a general activation of immunocompetent cells and the release of TH1 cytokines. Conclusion Data herein could be useful in the design of antitumoral DC-based therapies, showing a specific activation of immune system against breast cancer. PMID:26795765

  16. Dendritic cell maturation and cross-presentation: timing matters!

    PubMed

    Alloatti, Andrés; Kotsias, Fiorella; Magalhaes, Joao Gamelas; Amigorena, Sebastian

    2016-07-01

    As a population, dendritic cells (DCs) appear to be the best cross-presenters of internalized antigens on major histocompatibility complex class I molecules in the mouse. To do this, DCs have developed a number of unique and dedicated means to control their endocytic and phagocytic pathways: among them, the capacity to limit acidification of their phagosomes, to prevent proteolytic degradation, to delay fusion of phagosomes to lysosomes, to recruit ER proteins to phagosomes, and to export phagocytosed antigens to the cytosol. The regulation of phagocytic functions, and thereby of antigen processing and presentation by innate signaling, represents a critical level of integration of adaptive and innate immune responses. Understanding how innate signals control antigen cross-presentation is critical to define effective vaccination strategies for CD8(+) T-cell responses. PMID:27319345

  17. Engineered Lentivector Targeting of Dendritic Cells for In Vivo Immunization

    PubMed Central

    Yang, Lili; Yang, Haiguang; Rideout, Kendra; Cho, Taehoon; Joo, Kye il; Ziegler, Leslie; Elliot, Abigail; Walls, Anthony; Yu, Dongzi; Baltimore, David; Wang, Pin

    2008-01-01

    We report a method of inducing antigen production in dendritic cells (DCs) by in vivo targeting with lentiviral vectors that specifically bind to the DC surface protein, DC-SIGN. To target the DCs, the lentivector was enveloped with a viral glycoprotein from Sindbis virus, engineered to be DC-SIGN-specific. In vitro, this lentivector specifically transduced DCs and induced DC maturation. A remarkable frequency (up to 12%) of ovalbumin (OVA)-specific CD8+ T cells and a significant antibody response were observed 2 weeks following injection of a targeted lentiviral vector encoding an OVA transgene into naïve mice. These mice were solidly protected against the growth of the OVA-expressing E.G7 tumor and this methodology could even induce regression of an established tumor. Thus, lentiviral vectors targeting DCs provide a simple method of producing effective immunity and may provide an alternative route for immunization with protein antigens. PMID:18297056

  18. The role of dendritic cells in male reproductive tract.

    PubMed

    Wang, Peng; Duan, Yong-Gang

    2016-09-01

    Dendritic cells (DCs) are the most potent professional antigen-presenting cells. The central role of various DC subsets as bridges between innate and adaptive immunity has become more and more evident. However, the role of DC subsets in male reproductive tract remains largely unexplored, in particular distinct DC subsets (including myeloid and plasmacytoid DCs), their maturation stage, and tissue distribution, as well as state of health or disease. Furthermore, infection and inflammation of male genital tract are thought to be a primary etiological factor of male infertility. This review sheds some light on this complex and rapidly growing field. It summarized the recent findings and deals with the characterization and role of DCs in male reproductive tract, that is, testis, epididymis, prostate, seminal vesicle, semen, and foreskin, which might help to understand the immunopathological mechanisms of male infertility and design effective vaccines for male reproductive health. PMID:27353336

  19. Cochlin produced by follicular dendritic cells promotes antibacterial innate immunity.

    PubMed

    Py, Bénédicte F; Gonzalez, Santiago F; Long, Kai; Kim, Mi-Sung; Kim, Young-A; Zhu, Hong; Yao, Jianhua; Degauque, Nicolas; Villet, Régis; Ymele-Leki, Patrick; Gadjeva, Mihaela; Pier, Gerald B; Carroll, Michael C; Yuan, Junying

    2013-05-23

    Cochlin, an extracellular matrix protein, shares homologies with the Factor C, a serine protease found in horseshoe crabs, which is critical for antibacterial responses. Mutations in the COCH gene are responsible for human DFNA9 syndrome, a disorder characterized by neurodegeneration of the inner ear that leads to hearing loss and vestibular impairments. The physiological function of cochlin, however, is unknown. Here, we report that cochlin is specifically expressed by follicular dendritic cells and selectively localized in the fine extracellular network of conduits in the spleen and lymph nodes. During inflammation, cochlin was cleaved by aggrecanases and secreted into blood circulation. In models of lung infection with Pseudomonas aeruginosa and Staphylococcus aureus, Coch(-/-) mice show reduced survival linked to defects in local cytokine production, recruitment of immune effector cells, and bacterial clearance. By producing cochlin, FDCs thus contribute to the innate immune response in defense against bacteria. PMID:23684986

  20. Optimizing Dendritic Cell-Based Approaches for Cancer Immunotherapy

    PubMed Central

    Datta, Jashodeep; Terhune, Julia H.; Lowenfeld, Lea; Cintolo, Jessica A.; Xu, Shuwen; Roses, Robert E.; Czerniecki, Brian J.

    2014-01-01

    Dendritic cells (DC) are professional antigen-presenting cells uniquely suited for cancer immunotherapy. They induce primary immune responses, potentiate the effector functions of previously primed T-lymphocytes, and orchestrate communication between innate and adaptive immunity. The remarkable diversity of cytokine activation regimens, DC maturation states, and antigen-loading strategies employed in current DC-based vaccine design reflect an evolving, but incomplete, understanding of optimal DC immunobiology. In the clinical realm, existing DC-based cancer immunotherapy efforts have yielded encouraging but inconsistent results. Despite recent U.S. Federal and Drug Administration (FDA) approval of DC-based sipuleucel-T for metastatic castration-resistant prostate cancer, clinically effective DC immunotherapy as monotherapy for a majority of tumors remains a distant goal. Recent work has identified strategies that may allow for more potent “next-generation” DC vaccines. Additionally, multimodality approaches incorporating DC-based immunotherapy may improve clinical outcomes. PMID:25506283

  1. Blue light irradiation suppresses dendritic cells activation in vitro.

    PubMed

    Fischer, Michael R; Abel, Manuela; Lopez Kostka, Susanna; Rudolph, Berenice; Becker, Detlef; von Stebut, Esther

    2013-08-01

    Blue light is a UV-free irradiation suitable for treating chronic skin inflammation, for example, atopic dermatitis, psoriasis, and hand- and foot eczema. However, a better understanding of the mode of action is still missing. For this reason, we investigated whether dendritic cells (DC) are directly affected by blue light irradiation in vitro. Here, we report that irradiation neither induced apoptosis nor maturation of monocyte-derived and myeloid DC. However, subsequent DC maturation upon LPS/IFNγ stimulation was impaired in a dose-dependent manner as assessed by maturation markers and cytokine release. Moreover, the potential of this DC to induce cytokine secretion from allogeneic CD4 T cells was reduced. In conclusion, unlike UV irradiation, blue light irradiation at high and low doses only resulted in impaired DC maturation upon activation and a reduced subsequent stimulatory capacity in allogeneic MLRs with strongest effects at higher doses. PMID:23879817

  2. Dendritic Cells and Their Multiple Roles during Malaria Infection

    PubMed Central

    Amorim, Kelly N. S.; Chagas, Daniele C. G.; Sulczewski, Fernando B.

    2016-01-01

    Dendritic cells (DCs) play a central role in the initiation of adaptive immune responses, efficiently presenting antigens to T cells. This ability relies on the presence of numerous surface and intracellular receptors capable of sensing microbial components as well as inflammation and on a very efficient machinery for antigen presentation. In this way, DCs sense the presence of a myriad of pathogens, including Plasmodium spp., the causative agent of malaria. Despite many efforts to control this infection, malaria is still responsible for high rates of morbidity and mortality. Different groups have shown that DCs act during Plasmodium infection, and data suggest that the phenotypically distinct DCs subsets are key factors in the regulation of immunity during infection. In this review, we will discuss the importance of DCs for the induction of immunity against the different stages of Plasmodium, the outcomes of DCs activation, and also what is currently known about Plasmodium components that trigger such activation. PMID:27110574

  3. Curcumin prevents human dendritic cell response to immune stimulants

    SciTech Connect

    Shirley, Shawna A.; Montpetit, Alison J.; Lockey, R.F.; Mohapatra, Shyam S.

    2008-09-26

    Curcumin, a compound found in the Indian spice turmeric, has anti-inflammatory and immunomodulatory properties, though the mechanism remains unclear. Dendritic cells (DCs) are important to generating an immune response and the effect of curcumin on human DCs has not been explored. The role curcumin in the DC response to bacterial and viral infection was investigated in vitro using LPS and Poly I:C as models of infection. CD14{sup +} monocytes, isolated from human peripheral blood, were cultured in GM-CSF- and IL-4-supplemented medium to generate immature DCs. Cultures were incubated with curcumin, stimulated with LPS or Poly I:C and functional assays were performed. Curcumin prevents DCs from responding to immunostimulants and inducing CD4{sup +} T cell proliferation by blocking maturation marker, cytokine and chemokine expression and reducing both migration and endocytosis. These data suggest a therapeutic role for curcumin as an immune suppressant.

  4. Metabolic reprogramming in macrophages and dendritic cells in innate immunity

    PubMed Central

    Kelly, Beth; O'Neill, Luke AJ

    2015-01-01

    Activation of macrophages and dendritic cells (DCs) by pro-inflammatory stimuli causes them to undergo a metabolic switch towards glycolysis and away from oxidative phosphorylation (OXPHOS), similar to the Warburg effect in tumors. However, it is only recently that the mechanisms responsible for this metabolic reprogramming have been elucidated in more detail. The transcription factor hypoxia-inducible factor-1α (HIF-1α) plays an important role under conditions of both hypoxia and normoxia. The withdrawal of citrate from the tricarboxylic acid (TCA) cycle has been shown to be critical for lipid biosynthesis in both macrophages and DCs. Interference with this process actually abolishes the ability of DCs to activate T cells. Another TCA cycle intermediate, succinate, activates HIF-1α and promotes inflammatory gene expression. These new insights are providing us with a deeper understanding of the role of metabolic reprogramming in innate immunity. PMID:26045163

  5. Modulation of Dendritic Cells by Nanotechnology-Based Immunotherapeutic Strategies.

    PubMed

    Mogrão, Joana; da Costa, Catarina A; Gaspar, Rogério; Florindo, Helena F

    2016-03-01

    In preceding decades, different mechanisms have been proposed to "instruct" dendritic cells (DCs) to induce immune responses against tumor antigens (TAs), thus breaking immune tolerance. Immunotherapy has been, for the last two decades, an attractive and promising therapeutic approach to fight cancer. This review will approach the nature of the immune response during cancer development and its correlation with DC function, as well as cancer vaccine principles and limitations. An overview of several delivery strategies used for in vivo modulation of DCs and direct activation of T cells will be provided, highlighting their advantages, limitations, and optimization strategies. This manuscript also presents a critical and systematic review of recent clinical trials that are investigating the therapeutic effect of these approaches, discussing prognostic outcomes of combined-treatment modalities. PMID:27280242

  6. Dendritic Cells and Their Multiple Roles during Malaria Infection.

    PubMed

    Amorim, Kelly N S; Chagas, Daniele C G; Sulczewski, Fernando B; Boscardin, Silvia B

    2016-01-01

    Dendritic cells (DCs) play a central role in the initiation of adaptive immune responses, efficiently presenting antigens to T cells. This ability relies on the presence of numerous surface and intracellular receptors capable of sensing microbial components as well as inflammation and on a very efficient machinery for antigen presentation. In this way, DCs sense the presence of a myriad of pathogens, including Plasmodium spp., the causative agent of malaria. Despite many efforts to control this infection, malaria is still responsible for high rates of morbidity and mortality. Different groups have shown that DCs act during Plasmodium infection, and data suggest that the phenotypically distinct DCs subsets are key factors in the regulation of immunity during infection. In this review, we will discuss the importance of DCs for the induction of immunity against the different stages of Plasmodium, the outcomes of DCs activation, and also what is currently known about Plasmodium components that trigger such activation. PMID:27110574

  7. Dendritic cells and cytokines in immune rejection of cancer.

    PubMed

    Ferrantini, Maria; Capone, Imerio; Belardelli, Filippo

    2008-02-01

    Dendritic cells (DCs) play a crucial role in linking innate and adaptive immunity and, thus, in the generation of a protective immune response against both infectious diseases and tumors. The ability of DCs to prime and expand an immune response is regulated by signals acting through soluble mediators, mainly cytokines and chemokines. Understanding how cytokines influence DC functions and orchestrate the interactions of DCs with other immune cells is strictly instrumental to the progress in cancer immunotherapy. Herein, we will illustrate how certain cytokines and immune stimulating molecules can induce and sustain the antitumor immune response by acting on DCs. We will also discuss these cytokine-DC interactions in the light of clinical results in cancer patients. PMID:18054517

  8. Mechanisms of Dendritic Cell Lysosomal Killing of Cryptococcus

    PubMed Central

    Hole, Camaron R.; Bui, Hoang; Wormley, Floyd L.; Wozniak, Karen L.

    2012-01-01

    Cryptococcus neoformans is an opportunistic pulmonary fungal pathogen that disseminates to the CNS causing fatal meningitis in immunocompromised patients. Dendritic cells (DCs) phagocytose C. neoformans following inhalation. Following uptake, cryptococci translocate to the DC lysosomal compartment and are killed by oxidative and non-oxidative mechanisms. DC lysosomal extracts kill cryptococci in vitro; however, the means of antifungal activity remain unknown. Our studies determined non-oxidative antifungal activity by DC lysosomal extract. We examined DC lysosomal killing of cryptococcal strains, anti-fungal activity of purified lysosomal enzymes, and mechanisms of killing against C. neoformans. Results confirmed DC lysosome fungicidal activity against all cryptococcal serotypes. Purified lysosomal enzymes, specifically cathepsin B, inhibited cryptococcal growth. Interestingly, cathepsin B combined with its enzymatic inhibitors led to enhanced cryptococcal killing. Electron microscopy revealed structural changes and ruptured cryptococcal cell walls following treatment. Finally, additional studies demonstrated that osmotic lysis was responsible for cryptococcal death. PMID:23074646

  9. Mechanisms of dendritic cell lysosomal killing of Cryptococcus.

    PubMed

    Hole, Camaron R; Bui, Hoang; Wormley, Floyd L; Wozniak, Karen L

    2012-01-01

    Cryptococcus neoformans is an opportunistic pulmonary fungal pathogen that disseminates to the CNS causing fatal meningitis in immunocompromised patients. Dendritic cells (DCs) phagocytose C. neoformans following inhalation. Following uptake, cryptococci translocate to the DC lysosomal compartment and are killed by oxidative and non-oxidative mechanisms. DC lysosomal extracts kill cryptococci in vitro; however, the means of antifungal activity remain unknown. Our studies determined non-oxidative antifungal activity by DC lysosomal extract. We examined DC lysosomal killing of cryptococcal strains, anti-fungal activity of purified lysosomal enzymes, and mechanisms of killing against C. neoformans. Results confirmed DC lysosome fungicidal activity against all cryptococcal serotypes. Purified lysosomal enzymes, specifically cathepsin B, inhibited cryptococcal growth. Interestingly, cathepsin B combined with its enzymatic inhibitors led to enhanced cryptococcal killing. Electron microscopy revealed structural changes and ruptured cryptococcal cell walls following treatment. Finally, additional studies demonstrated that osmotic lysis was responsible for cryptococcal death. PMID:23074646

  10. Curcumin prevents human dendritic cell response to immune stimulants

    PubMed Central

    Shirley, Shawna A.; Montpetit, Alison J.; Lockey, R.F.; Mohapatra, Shyam S.

    2012-01-01

    Curcumin, a compound found in the Indian spice turmeric, has anti-inflammatory and immunomodulatory properties, though the mechanism remains unclear. Dendritic cells (DCs) are important to generating an immune response and the effect of curcumin on human DCs has not been explored. The role curcumin in the DC response to bacterial and viral infection was investigated in vitro using LPS and Poly I:C as models of infection. CD14+ monocytes, isolated from human peripheral blood, were cultured in GM-CSF- and IL-4-supplemented medium to generate immature DCs. Cultures were incubated with curcumin, stimulated with LPS or Poly I:C and functional assays were performed. Curcumin prevents DCs from responding to immunostimulants and inducing naïve CD4+ T cell proliferation by blocking maturation marker, cytokine and chemokine expression and reducing both migration and endocytosis. These data suggest a therapeutic role for curcumin as an immune suppressant. PMID:18639521

  11. Mechanisms of Dendritic Cell Lysosomal Killing of Cryptococcus

    NASA Astrophysics Data System (ADS)

    Hole, Camaron R.; Bui, Hoang; Wormley, Floyd L.; Wozniak, Karen L.

    2012-10-01

    Cryptococcus neoformans is an opportunistic pulmonary fungal pathogen that disseminates to the CNS causing fatal meningitis in immunocompromised patients. Dendritic cells (DCs) phagocytose C. neoformans following inhalation. Following uptake, cryptococci translocate to the DC lysosomal compartment and are killed by oxidative and non-oxidative mechanisms. DC lysosomal extracts kill cryptococci in vitro; however, the means of antifungal activity remain unknown. Our studies determined non-oxidative antifungal activity by DC lysosomal extract. We examined DC lysosomal killing of cryptococcal strains, anti-fungal activity of purified lysosomal enzymes, and mechanisms of killing against C. neoformans. Results confirmed DC lysosome fungicidal activity against all cryptococcal serotypes. Purified lysosomal enzymes, specifically cathepsin B, inhibited cryptococcal growth. Interestingly, cathepsin B combined with its enzymatic inhibitors led to enhanced cryptococcal killing. Electron microscopy revealed structural changes and ruptured cryptococcal cell walls following treatment. Finally, additional studies demonstrated that osmotic lysis was responsible for cryptococcal death.

  12. The role of dendritic cells in CNS autoimmunity

    PubMed Central

    Zozulya, Alla L.; Clarkson, Benjamin D.; Ortler, Sonja; Fabry, Zsuzsanna

    2010-01-01

    Multiple sclerosis (MS) is a chronic immune-mediated, central nervous system (CNS) demyelinating disease. Clinical and histopathological features suggest an inflammatory etiology involving resident CNS innate cells as well as invading adaptive immune cells. Encephalitogenic myelin-reactive T cells have been implicated in the initiation of an inflammatory cascade, eventually resulting in demyelination and axonal damage (the histological hallmarks of MS). Dendritic cells (DC) have recently emerged as key modulators of this immunopathological cascade, as supported by studies in humans and experimental disease models. In one such model, experimental autoimmune encephalomyelitis (EAE), CNS microvessel-associated DC have been shown to be essential for local antigen recognition by myelin-reactive T cells. Moreover, the functional state and compartmental distribution of DC derived from CNS and associated lymphatics seem to be limiting factors in both the induction and effector phases of EAE. Moreover, DC modulate and balance the recruitment of encephalitogenic and regulatory T cells into CNS tissue. This capacity is critically influenced by DC surface expression of co-stimulatory or co-inhibitory molecules. The fact that DC accumulate in the CNS before T cells and can direct T-cell responses suggests that they are key determinants of CNS autoimmune outcomes. Here we provide a comprehensive review of recent advances in our understanding of CNS-derived DC and their relevance to neuroinflammation. PMID:20217033

  13. The Role of Dendritic Cells in Central Tolerance.

    PubMed

    Oh, Jaehak; Shin, Jeoung-Sook

    2015-06-01

    Dendritic cells (DCs) play a significant role in establishing self-tolerance through their ability to present self-antigens to developing T cells in the thymus. DCs are predominantly localized in the medullary region of thymus and present a broad range of self-antigens, which include tissue-restricted antigens expressed and transferred from medullary thymic epithelial cells, circulating antigens directly captured by thymic DCs through coticomedullary junction blood vessels, and peripheral tissue antigens captured and transported by peripheral tissue DCs homing to the thymus. When antigen-presenting DCs make a high affinity interaction with antigen-specific thymocytes, this interaction drives the interacting thymocytes to death, a process often referred to as negative selection, which fundamentally blocks the self-reactive thymocytes from differentiating into mature T cells. Alternatively, the interacting thymocytes differentiate into the regulatory T (Treg) cells, a distinct T cell subset with potent immune suppressive activities. The specific mechanisms by which thymic DCs differentiate Treg cells have been proposed by several laboratories. Here, we review the literatures that elucidate the contribution of thymic DCs to negative selection and Treg cell differentiation, and discusses its potential mechanisms and future directions. PMID:26140042

  14. Dendritic-Tumor Fusion Cell-Based Cancer Vaccines

    PubMed Central

    Koido, Shigeo

    2016-01-01

    Dendritic cells (DCs) are potent antigen-presenting cells (APCs) that play a critical role in the induction of antitumor immunity. Therefore, various strategies have been developed to deliver tumor-associated antigens (TAAs) to DCs as cancer vaccines. The fusion of DCs and whole tumor cells to generate DC-tumor fusion cells (DC-tumor FCs) is an alternative strategy to treat cancer patients. The cell fusion method allows DCs to be exposed to the broad array of TAAs originally expressed by whole tumor cells. DCs then process TAAs endogenously and present them through major histocompatibility complex (MHC) class I and II pathways in the context of costimulatory molecules, resulting in simultaneous activation of both CD4+ and CD8+ T cells. DC-tumor FCs require optimized enhanced immunogenicity of both DCs and whole tumor cells. In this context, an effective fusion strategy also needs to produce immunogenic DC-tumor FCs. We discuss the potential ability of DC-tumor FCs and the recent progress in improving clinical outcomes by DC-tumor FC-based cancer vaccines. PMID:27240347

  15. Time-Lapse Retinal Ganglion Cell Dendritic Field Degeneration Imaged in Organotypic Retinal Explant Culture

    PubMed Central

    Johnson, Thomas V.; Oglesby, Ericka N.; Steinhart, Matthew R.; Cone-Kimball, Elizabeth; Jefferys, Joan; Quigley, Harry A.

    2016-01-01

    Purpose To develop an ex vivo organotypic retinal explant culture system suitable for multiple time-point imaging of retinal ganglion cell (RGC) dendritic arbors over a period of 1 week, and capable of detecting dendrite neuroprotection conferred by experimental treatments. Methods Thy1-YFP mouse retinas were explanted and maintained in organotypic culture. Retinal ganglion cell dendritic arbors were imaged repeatedly using confocal laser scanning microscopy. Maximal projection z-stacks were traced by two masked investigators and dendritic fields were analyzed for characteristics including branch number, size, and complexity. One group of explants was treated with brain derived neurotrophic factor (BDNF) and ciliary neurotrophic factor (CNTF) added to the culture media. Changes in individual dendritic fields over time were detected using pair-wise comparison testing. Results Retinal ganglion cells in mouse retinal explant culture began to degenerate after 3 days with 52.4% surviving at 7 days. Dendritic field parameters showed minimal change over 8 hours in culture. Intra- and interobserver measurements of dendrite characteristics were strongly correlated (Spearman rank correlations consistently > 0.80). Statistically significant (P < 0.001) dendritic tree degeneration was detected following 7 days in culture including: 40% to 50% decreases in number of branch segments, number of junctions, number of terminal branches, and total branch length. Scholl analyses similarly demonstrated a significant decrease in dendritic field complexity. Treatment of explants with BDNF+CNTF significantly attenuated dendritic field degeneration. Conclusions Retinal explant culture of Thy1-YFP tissue provides a useful model for time-lapse imaging of RGC dendritic field degeneration over a course of several days, and is capable of detecting neuroprotective amelioration of dendritic pruning within individual RGCs. PMID:26811145

  16. Direct Transfection of Dendritic Cells in the Epidermis After Plasmid Delivery Enhanced by Surface Electroporation

    PubMed Central

    Amante, Dinah H.; Smith, Trevor R.F.; Kiosses, Bill B.; Sardesai, Niranjan Y.; Humeau, Laurent M.P.F.

    2014-01-01

    Abstract The skin is rich in antigen-presenting cells and as such is an excellent target tissue for vaccination strategies. Electroporation is a physical delivery method that potentiates the uptake of DNA vaccines into target cells. Intradermal electroporation offers a minimally invasive solution to DNA delivery in the clinic. Here we describe the direct transfection of dendritic cells in the epidermis, using a surface dermal electroporation device, and specifically show a dendritic cell transfected with plasmid expressing green fluorescent protein. The dendritic cell has used its motile capabilities after transfection to move from the epidermis into the dermis, making its way to the lymphatic system. PMID:25470335

  17. Direct transfection of dendritic cells in the epidermis after plasmid delivery enhanced by surface electroporation.

    PubMed

    Amante, Dinah H; Smith, Trevor R F; Kiosses, Bill B; Sardesai, Niranjan Y; Humeau, Laurent M P F; Broderick, Kate E

    2014-12-01

    The skin is rich in antigen-presenting cells and as such is an excellent target tissue for vaccination strategies. Electroporation is a physical delivery method that potentiates the uptake of DNA vaccines into target cells. Intradermal electroporation offers a minimally invasive solution to DNA delivery in the clinic. Here we describe the direct transfection of dendritic cells in the epidermis, using a surface dermal electroporation device, and specifically show a dendritic cell transfected with plasmid expressing green fluorescent protein. The dendritic cell has used its motile capabilities after transfection to move from the epidermis into the dermis, making its way to the lymphatic system. PMID:25470335

  18. Interactions between airway epithelial cells and dendritic cells during viral infections using an in vitro co-culture model

    EPA Science Inventory

    Rationale: Historically, single cell culture models have been limited in pathological and physiological relevance. A co-culture model of dendritic cells (DCs) and differentiated human airway epithelial cells was developed to examine potential interactions between these two cell t...

  19. Role of regulatory dendritic cells in allergy and asthma.

    PubMed

    Akbari, Omid; Umetsu, Dale T

    2005-01-01

    Dendritic cells (DCs) are the most efficient inducers of all immune responses, and are capable of either inducing productive immunity or maintaining the state of tolerance to self antigens and allergens. In this review, we summarize the emerging literature on DCs, with emphasis on the regulatory function of DCs in allergy and asthma. In particular, we summarize recent data regarding the relationship between DC subsets and TH1, TH2, and regulatory T (TReg) cells. The diverse functions of DCs have been attributed to distinct lineages of DCs, which arise from common immature precursor cells that differentiate in response to specific maturation-inducing or local microenvironment conditions. These subsets of DCs induce different lineages of T cells, such as TH1, TH2, and TReg cells, including Th1Reg and Th2Reg cells, which regulate allergic diseases and asthma. Subsets of DCs regulate the induction of a variety of T-cell subtypes, which suppress the development of allergy and asthma, thus providing anti-inflammatory responses and protective immunity. PMID:15659264

  20. Muscarinic regulation of Kenyon cell dendritic arborizations in adult worker honey bees.

    PubMed

    Dobrin, Scott E; Herlihy, J Daniel; Robinson, Gene E; Fahrbach, Susan E

    2011-09-01

    The experience of foraging under natural conditions increases the volume of mushroom body neuropil in worker honey bees. A comparable increase in neuropil volume results from treatment of worker honey bees with pilocarpine, an agonist for muscarinic-type cholinergic receptors. A component of the neuropil growth induced by foraging experience is growth of dendrites in the collar region of the calyces. We show here, via analysis of Golgi-impregnated collar Kenyon cells with wedge arborizations, that significant increases in standard measures of dendritic complexity were also found in worker honey bees treated with pilocarpine. This result suggests that signaling via muscarinic-type receptors promotes the increase in Kenyon cell dendritic complexity associated with foraging. Treatment of worker honey bees with scopolamine, a muscarinic inhibitor, inhibited some aspects of dendritic growth. Spine density on the Kenyon cell dendrites varied with sampling location, with the distal portion of the dendritic field having greater total spine density than either the proximal or medial section. This observation may be functionally significant because of the stratified organization of projections from visual centers to the dendritic arborizations of the collar Kenyon cells. Pilocarpine treatment had no effect on the distribution of spines on dendrites of the collar Kenyon cells. PMID:21262388

  1. Plasmacytoid dendritic cells: development, functions, and role in atherosclerotic inflammation

    PubMed Central

    Chistiakov, Dimitry A.; Orekhov, Alexander N.; Sobenin, Igor A.; Bobryshev, Yuri V.

    2014-01-01

    Plasmacytoid dendritic cells (pDCs) are a specialized subset of DCs that links innate and adaptive immunity. They sense viral and bacterial pathogens and release high levels of Type I interferons (IFN-I) in response to infection. pDCs were shown to contribute to inflammatory responses in the steady state and in pathology. In atherosclerosis, pDCs are involved in priming vascular inflammation and atherogenesis through production of IFN-I and chemokines that attract inflammatory cells to inflamed sites. pDCs also contribute to the proinflammatory activation of effector T cells, cytotoxic T cells, and conventional DCs. However, tolerogenic populations of pDCs are found that suppress atherosclerosis-associated inflammation through down-regulation of function and proliferation of proinflammatory T cell subsets and induction of regulatory T cells with potent immunomodulatory properties. Notably, atheroprotective tolerogenic DCs could be induced by certain self-antigens or bacterial antigens that suggests for great therapeutic potential of these DCs for development of DC-based anti-atherogenic vaccines. PMID:25120492

  2. Follicular Dendritic Cells Emerge from Ubiquitous Perivascular Precursors

    PubMed Central

    Krautler, Nike Julia; Kana, Veronika; Kranich, Jan; Tian, Yinghua; Perera, Dushan; Lemm, Doreen; Schwarz, Petra; Armulik, Annika; Browning, Jeffrey L.; Tallquist, Michelle; Buch, Thorsten; Oliveira-Martins, José B.; Zhu, Caihong; Hermann, Mario; Wagner, Ulrich; Brink, Robert; Heikenwalder, Mathias; Aguzzi, Adriano

    2013-01-01

    Summary The differentiation of follicular dendritic cells (FDC) is essential to the remarkable microanatomic plasticity of lymphoid follicles. Here we show that FDC arise from ubiquitous perivascular precursors (preFDC) expressing platelet-derived growth factor receptor β (PDGFRβ). PDGFRβ-Cre-driven reporter gene recombination resulted in FDC labeling, whereas conditional ablation of PDGFRβ+-derived cells abolished FDC, indicating that FDC originate from PDGFRβ+ cells. Lymphotoxin-α-overexpressing prion protein (PrP)+ kidneys developed PrP+ FDC after transplantation into PrP mice, confirming that preFDC exist outside lymphoid organs. Adipose tissue-derived PDGFRβ+ stromal-vascular cells responded to FDC maturation factors and, when transplanted into lymphotoxin β receptor (LTβR) kidney capsules, differentiated into Mfge8+CD21/35+ FcγRIIβ+PrP+ FDC capable of trapping immune complexes and recruiting B cells. Spleens of lymphocyte-deficient mice contained perivascular PDGFRβ+ FDC precursors whose expansion required both lymphoid tissue inducer (LTi) cells and lymphotoxin. The ubiquity of preFDC and their strategic location at blood vessels may explain the de novo generation of organized lymphoid tissue at sites of lymphocytic inflammation. PMID:22770220

  3. Defining human dendritic cell progenitors by multiparametric flow cytometry.

    PubMed

    Breton, Gaëlle; Lee, Jaeyop; Liu, Kang; Nussenzweig, Michel C

    2015-09-01

    Human dendritic cells (DCs) develop from progressively restricted bone marrow (BM) progenitors: these progenitor cells include granulocyte, monocyte and DC progenitor (GMDP) cells; monocyte and DC progenitor (MDP) cells; and common DC progenitor (CDP) and DC precursor (pre-DC) cells. These four DC progenitors can be defined on the basis of the expression of surface markers such as CD34 and hematopoietin receptors. In this protocol, we describe five multiparametric flow cytometry panels that can be used as a tool (i) to simultaneously detect or phenotype the four DC progenitors, (ii) to isolate DC progenitors to enable in vitro differentiation or (iii) to assess the in vitro differentiation and proliferation of DC progenitors. The entire procedure from isolation of cells to flow cytometry can be completed in 3-7 h. This protocol provides optimized antibody panels, as well as gating strategies, for immunostaining of BM and cord blood specimens to study human DC hematopoiesis in health, disease and vaccine settings. PMID:26292072

  4. Defining human dendritic cell progenitors by multiparametric flow cytometry

    PubMed Central

    Breton, Gaëlle; Lee, Jaeyop; Liu, Kang; Nussenzweig, Michel C

    2015-01-01

    Human dendritic cells (DCs) develop from progressively restricted bone marrow (BM) progenitors: these progenitor cells include granulocyte, monocyte and DC progenitor (GMDP) cells; monocyte and DC progenitor (MDP) cells; and common DC progenitor (CDP) and DC precursor (pre-DC) cells. These four DC progenitors can be defined on the basis of the expression of surface markers such as CD34 and hematopoietin receptors. In this protocol, we describe five multiparametric flow cytometry panels that can be used as a tool (i) to simultaneously detect or phenotype the four DC progenitors, (ii) to isolate DC progenitors to enable in vitro differentiation or (iii) to assess the in vitro differentiation and proliferation of DC progenitors. The entire procedure from isolation of cells to flow cytometry can be completed in 3–7 h. This protocol provides optimized antibody panels, as well as gating strategies, for immunostaining of BM and cord blood specimens to study human DC hematopoiesis in health, disease and vaccine settings. PMID:26292072

  5. Dendritic cell targeted vaccines: Recent progresses and challenges.

    PubMed

    Chen, Pengfei; Liu, Xinsheng; Sun, Yuefeng; Zhou, Peng; Wang, Yonglu; Zhang, Yongguang

    2016-03-01

    Dendritic cells (DCs) are known to be a set of morphology, structure and function of heterogeneous professional antigen presenting cells (APCs), as well as the strongest functional antigen presenting cells, which can absorb, process and present antigens. As the key regulators of innate and adaptive immune responses, DCs are at the center of the immune system and capable of interacting with both B cells and T cells, thereby manipulating the humoral and cellular immune responses. DCs provide an essential link between the innate and adaptive immunity, and the strong immune activation function of DCs and their properties of natural adjuvants, make them a valuable target for antigen delivery. Targeting antigens to DC-specific endocytic receptors in combination with the relevant antibodies or ligands along with immunostimulatory adjuvants has been recently recognized as a promising strategy for designing an effective vaccine that elicits a strong and durable T cell response against intracellular pathogens and cancer. This opinion article provides a brief summary of the rationales, superiorities and challenges of existing DC-targeting approaches. PMID:26513200

  6. Follicular dendritic cells emerge from ubiquitous perivascular precursors.

    PubMed

    Krautler, Nike Julia; Kana, Veronika; Kranich, Jan; Tian, Yinghua; Perera, Dushan; Lemm, Doreen; Schwarz, Petra; Armulik, Annika; Browning, Jeffrey L; Tallquist, Michelle; Buch, Thorsten; Oliveira-Martins, José B; Zhu, Caihong; Hermann, Mario; Wagner, Ulrich; Brink, Robert; Heikenwalder, Mathias; Aguzzi, Adriano

    2012-07-01

    The differentiation of follicular dendritic cells (FDC) is essential to the remarkable microanatomic plasticity of lymphoid follicles. Here we show that FDC arise from ubiquitous perivascular precursors (preFDC) expressing platelet-derived growth factor receptor β (PDGFRβ). PDGFRβ-Cre-driven reporter gene recombination resulted in FDC labeling, whereas conditional ablation of PDGFRβ(+)-derived cells abolished FDC, indicating that FDC originate from PDGFRβ(+) cells. Lymphotoxin-α-overexpressing prion protein (PrP)(+) kidneys developed PrP(+) FDC after transplantation into PrP(-) mice, confirming that preFDC exist outside lymphoid organs. Adipose tissue-derived PDGFRβ(+) stromal-vascular cells responded to FDC maturation factors and, when transplanted into lymphotoxin β receptor (LTβR)(-) kidney capsules, differentiated into Mfge8(+)CD21/35(+)FcγRIIβ(+)PrP(+) FDC capable of trapping immune complexes and recruiting B cells. Spleens of lymphocyte-deficient mice contained perivascular PDGFRβ(+) FDC precursors whose expansion required both lymphoid tissue inducer (LTi) cells and lymphotoxin. The ubiquity of preFDC and their strategic location at blood vessels may explain the de novo generation of organized lymphoid tissue at sites of lymphocytic inflammation. PMID:22770220

  7. Aging and the Dendritic Cell System: Implications for Cancer

    PubMed Central

    Shurin, Michael R.; Shurin, Galina V.; Chatta, Gurkamal S.

    2007-01-01

    The immune system shows a decline in responsiveness to antigens both with aging, as well as in the presence of tumors. The malfunction of the immune system with age can be attributed to developmental and functional alterations in several cell populations. Previous studies have shown defects in humoral responses and abnormalities in T cell function in aged individuals, but have not distinguished between abnormalities in antigen presentation and intrinsic T cell or B cell defects in aged individuals. Dendritic cells (DC) play a pivotal role in regulating immune responses by presenting antigens to naïve T lymphocytes, modulating Th1/Th2/Treg balance, producing numerous regulatory cytokines and chemokines, and modifying survival of immune effectors. DC are receiving increased attention due to their involvement in the immunobiology of tolerance and autoimmunity, as well as their potential role as biological adjuvants in tumor vaccines. Recent advances in the molecular and cell biology of different DC populations allow for addressing the issue of DC and aging both in rodents and humans. Since DC play a crucial role in initiating and regulating immune responses, it is reasonable to hypothesize that they are directly involved in altered antitumor immunity in aging. However, the results of studies focusing on DC in the elderly are conflicting. The present review summarizes the available human and experimental animal data on quantitative and qualitative alterations of DC in aging and discusses the potential role of the DC system in the increased incidence of cancer in the elderly. PMID:17446082

  8. Targeting Skin Dendritic Cells to Improve Intradermal Vaccination

    PubMed Central

    Romani, N.; Flacher, V.; Tripp, C. H.; Sparber, F.; Ebner, S.; Stoitzner, P.

    2014-01-01

    Vaccinations in medicine are typically administered into the muscle beneath the skin or into the subcutaneous fat. As a consequence, the vaccine is immunologically processed by antigen-presenting cells of the skin or the muscle. Recent evidence suggests that the clinically seldom used intradermal route is effective and possibly even superior to the conventional subcutaneous or intramuscular route. Several types of professional antigen-presenting cells inhabit the healthy skin. Epidermal Langerhans cells (CD207/langerin+), dermal langerinneg, and dermal langerin+ dendritic cells (DC) have been described, the latter subset so far only in mouse skin. In human skin langerinneg dermal DC can be further classified based on their reciprocal expression of CD1a and CD14. The relative contributions of these subsets to the generation of immunity or tolerance are still unclear. Yet, specializations of these different populations have become apparent. Langerhans cells in human skin appear to be specialized for induction of cytotoxic T lymphocytes; human CD14+ dermal DC can promote antibody production by B cells. It is currently attempted to rationally devise and improve vaccines by harnessing such specific properties of skin DC. This could be achieved by specifically targeting functionally diverse skin DC subsets. We discuss here advances in our knowledge on the immunological properties of skin DC and strategies to significantly improve the outcome of vaccinations by applying this knowledge. PMID:21253784

  9. Adaptive (T and B cells) immunity and control by dendritic cells in atherosclerosis.

    PubMed

    Ait-Oufella, Hafid; Sage, Andrew P; Mallat, Ziad; Tedgui, Alain

    2014-05-01

    Chronic inflammation in response to lipoprotein accumulation in the arterial wall is central in the development of atherosclerosis. Both innate and adaptive immunity are involved in this process. Adaptive immune responses develop against an array of potential antigens presented to effector T lymphocytes by antigen-presenting cells, especially dendritic cells. Functional analysis of the role of different T-cell subsets identified the Th1 responses as proatherogenic, whereas regulatory T-cell responses exert antiatherogenic activities. The effect of Th2 and Th17 responses is still debated. Atherosclerosis is also associated with B-cell activation. Recent evidence established that conventional B-2 cells promote atherosclerosis. In contrast, innate B-1 B cells offer protection through secretion of natural IgM antibodies. This review discusses the recent development in our understanding of the role of T- and B-cell subsets in atherosclerosis and addresses the role of dendritic cell subpopulations in the control of adaptive immunity. PMID:24812352

  10. Spherical Lactic Acid Bacteria Activate Plasmacytoid Dendritic Cells Immunomodulatory Function via TLR9-Dependent Crosstalk with Myeloid Dendritic Cells

    PubMed Central

    Jounai, Kenta; Ikado, Kumiko; Sugimura, Tetsu; Ano, Yasuhisa; Braun, Jonathan; Fujiwara, Daisuke

    2012-01-01

    Plasmacytoid dendritic cells (pDC) are a specialized sensor of viral and bacterial nucleic acids and a major producer of IFN-α that promotes host defense by priming both innate and acquired immune responses. Although synthetic Toll-like receptor (TLR) ligands, pathogenic bacteria and viruses activate pDC, there is limited investigation of non-pathogenic microbiota that are in wide industrial dietary use, such as lactic acid bacteria (LAB). In this study, we screened for LAB strains, which induce pDC activation and IFN-α production using murine bone marrow (BM)-derived Flt-3L induced dendritic cell culture. Microbial strains with such activity on pDC were absent in a diversity of bacillary strains, but were observed in certain spherical species (Lactococcus, Leuconostoc, Streptococcus and Pediococcus), which was correlated with their capacity for uptake by pDC. Detailed study of Lactococcus lactis subsp. lactis JCM5805 and JCM20101 revealed that the major type I and type III interferons were induced (IFN-α, -β, and λ). IFN-α induction was TLR9 and MyD88-dependent; a slight impairment was also observed in TLR4-/- cells. While these responses occurred with purified pDC, IFN-α production was synergistic upon co-culture with myeloid dendritic cells (mDC), an interaction that required direct mDC-pDC contact. L. lactis strains also stimulated expression of immunoregulatory receptors on pDC (ICOS-L and PD-L1), and accordingly augmented pDC induction of CD4+CD25+FoxP3+ Treg compared to the Lactobacillus strain. Oral administration of L. lactis JCM5805 induced significant activation of pDC resident in the intestinal draining mesenteric lymph nodes, but not in a remote lymphoid site (spleen). Taken together, certain non-pathogenic spherical LAB in wide dietary use has potent and diverse immunomodulatory effects on pDC potentially relevant to anti-viral immunity and chronic inflammatory disease. PMID:22505996

  11. Molecular Mechanisms of Induction of Tolerant and Tolerogenic Intestinal Dendritic Cells in Mice

    PubMed Central

    Steimle, Alex; Frick, Julia-Stefanie

    2016-01-01

    How does the host manage to tolerate its own intestinal microbiota? A simple question leading to complicated answers. In order to maintain balanced immune responses in the intestine, the host immune system must tolerate commensal bacteria in the gut while it has to simultaneously keep the ability to fight pathogens and to clear infections. If this tender equilibrium is disturbed, severe chronic inflammatory reactions can result. Tolerogenic intestinal dendritic cells fulfil a crucial role in balancing immune responses and therefore creating homeostatic conditions and preventing from uncontrolled inflammation. Although several dendritic cell subsets have already been characterized to play a pivotal role in this process, less is known about definite molecular mechanisms of how intestinal dendritic cells are converted into tolerogenic ones. Here we review how gut commensal bacteria interact with intestinal dendritic cells and why this bacteria-host cell interaction is crucial for induction of dendritic cell tolerance in the intestine. Hereby, different commensal bacteria can have distinct effects on the phenotype of intestinal dendritic cells and these effects are mainly mediated by impacting toll-like receptor signalling in dendritic cells. PMID:26981546

  12. Electrical activity in cerebellar cultures determines Purkinje cell dendritic growth patterns.

    PubMed

    Schilling, K; Dickinson, M H; Connor, J A; Morgan, J I

    1991-12-01

    In primary dissociated cultures of mouse cerebellum a number of Purkinje cell-specific marker proteins and characteristic ionic currents appear at the appropriate developmental time. During the first week after plating, Purkinje cell dendrites elongate, but as electrical activity emerges the dendrites stop growing and branch. If endogenous electrical activity is inhibited by chronic tetrodotoxin or high magnesium treatment, dendrites continue to elongate, as if they were still immature. At the time that branching begins, intracellular calcium levels become sensitive to tetrodotoxin, suggesting that this cation may be involved in dendrite growth. Even apparently mature Purkinje cells alter their dendritic growth in response to changes in activity, suggesting long-term plasticity. PMID:1684902

  13. Dendritic cells in humans--from fetus to adult.

    PubMed

    McGovern, Naomi; Chan, Jerry K Y; Ginhoux, Florent

    2015-02-01

    The human immune system evolves continuously during development from the embryo into the adult, reflecting the ever-changing environment and demands of our body. This ability of our immune system to sense external cues and adapt as we develop is just as important in the early tolerogenic environment of the fetus, as it is in the constantly pathogen-challenged adult. Dendritic cells (DCs), the professional antigen-sensing and antigen-presenting components of the immune system, play a crucial role in this process where they act as sentinels, both initiating and regulating immune responses. Here, we provide an overview of the human immune system in the developing fetus and the adult, with a focus on DC ontogeny and function during these discrete but intimately linked life stages. PMID:25323843

  14. Dendritic Cells Are the Major Antigen Presenting Cells in Inflammatory Lesions of Murine Mycoplasma Respiratory Disease

    PubMed Central

    Sun, Xiangle; Jones, Harlan P.; Dobbs, Nicole; Bodhankar, Sheetal; Simecka, Jerry W.

    2013-01-01

    Mycoplasmas cause chronic respiratory diseases in animals and humans, and to date, development of vaccines have been problematic. Using a murine model of mycoplasma pneumonia, lymphocyte responses, specifically T cells, were shown to confer protection as well as promote immunopathology in mycoplasma disease. Because T cells play such a critical role, it is important to define the role of antigen presenting cells (APC) as these cells may influence either exacerbation of mycoplasma disease pathogenesis or enhancement of protective immunity. The roles of APC, such as dendritic cells and/or macrophages, and their ability to modulate adaptive immunity in mycoplasma disease are currently unknown. Therefore, the purpose of this study was to identify individual pulmonary APC populations that may contribute to the activation of T cell responses during mycoplasma disease pathogenesis. The present study indeed demonstrates increasing numbers of CD11c− F4/80+ cells, which contain macrophages, and more mature/activated CD11c+ F4/80− cells, containing DC, in the lungs after infection. CD11c− F4/80+ macrophage-enriched cells and CD11c+ F4/80− dendritic cell-enriched populations showed different patterns of cytokine mRNA expression, supporting the idea that these cells have different impacts on immunity in response to infection. In fact, DC containing CD11c+ F4/80− cell populations from the lungs of infected mice were most capable of stimulating mycoplasma-specific CD4+ Th cell responses in vitro. In vivo, these CD11c+F4/80− cells were co-localized with CD4+ Th cells in inflammatory infiltrates in the lungs of mycoplasma-infected mice. Thus, CD11c+F4/80− dendritic cells appear to be the major APC population responsible for pulmonary T cell stimulation in mycoplasma-infected mice, and these dendritic cells likely contribute to responses impacting disease pathogenesis. PMID:23390557

  15. Dendritic cell vaccination in glioblastoma after fluorescence-guided resection

    PubMed Central

    Valle, Ricardo Diez; de Cerio, Ascension Lopez-Diaz; Inoges, Susana; Tejada, Sonia; Pastor, Fernando; Villanueva, Helena; Gallego, Jaime; Espinos, Jaime; Aristu, Javier; Idoate, Miguel Angel; Andreu, Enrique; Bendandi, Maurizio

    2012-01-01

    AIM: To assess whether the addition of a customized, active immunotherapy to standard of care including fluorescence-guided surgery, may provide hints of an improved survival for patients with poor-prognosis, incurable glioblastoma multiform. METHODS: Preliminary to our ongoing, phase-II clinical trial, we conducted a small pilot study enrolling five consecutive patients with resectable glioblastoma. In terms of Recursive Partitioning Analysis, four patients were class V and one was class IV. In all five cases, fluorescence-guided surgery was employed, followed by rapid steroid discontinuation. Patients were then treated with a combination of standard radio-chemotherapy with temozolomide and tumor lysate-pulsed, mature dendritic cell-based vaccinations. RESULTS: Though all five patients ultimately progressed, with any further treatment left to the sole decision of the treating oncologist, active immunotherapy was very well tolerated and induced specific immune responses in all three patients for whom enough material was available for such an assessment. Median progression-free survival was 16.1 mo. Even more important, median and mean overall survival were 27 mo and 26 mo, respectively. Three patients have died with an overall survival of 9 mo, 27 mo and 27.4 mo, while the other two are still alive at 32 mo and 36 mo, the former receiving treatment with bevacizumab, while the latter has now been off therapy for 12 mo. Four of five patients were alive at two years. CONCLUSION: Active immunotherapy with tumor lysate-pulsed, autologous dendritic cells is feasible, safe, well tolerated and biologically efficacious. A phase-II study is ongoing to possibly improve further on our very encouraging clinical results. PMID:23293753

  16. Probiotic modulation of dendritic cell function is influenced by ageing.

    PubMed

    You, Jialu; Dong, Honglin; Mann, Elizabeth R; Knight, Stella C; Yaqoob, Parveen

    2014-02-01

    Dendritic cells (DCs) are critical for the generation of T-cell responses. DC function may be modulated by probiotics, which confer health benefits in immunocompromised individuals, such as the elderly. This study investigated the effects of four probiotics, Bifidobacterium longum bv. infantis CCUG 52486, B. longum SP 07/3, Lactobacillus rhamnosus GG (L.GG) and L. casei Shirota (LcS), on DC function in an allogeneic mixed leucocyte reaction (MLR) model, using DCs and T-cells from young and older donors in different combinations. All four probiotics enhanced expression of CD40, CD80 and CCR7 on both young and older DCs, but enhanced cytokine production (TGF-β, TNF-α) by old DCs only. LcS induced IL-12 and IFNγ production by DC to a greater degree than other strains, while B. longum bv. infantis CCUG 52486 favoured IL-10 production. Stimulation of young T cells in an allogeneic MLR with DC was enhanced by probiotic pretreatment of old DCs, which demonstrated greater activation (CD25) than untreated controls. However, pretreatment of young or old DCs with LPS or probiotics failed to enhance the proliferation of T-cells derived from older donors. In conclusion, this study demonstrates that ageing increases the responsiveness of DCs to probiotics, but this is not sufficient to overcome the impact of immunosenescence in the MLR. PMID:24094416

  17. Role of Dendritic Cells in the Pathogenesis of Whipple's Disease

    PubMed Central

    Schinnerling, Katina; Geelhaar-Karsch, Anika; Allers, Kristina; Friebel, Julian; Conrad, Kristina; Loddenkemper, Christoph; Kühl, Anja A.; Erben, Ulrike; Ignatius, Ralf; Schneider, Thomas

    2014-01-01

    Accumulation of Tropheryma whipplei-stuffed macrophages in the duodenum, impaired T. whipplei-specific Th1 responses, and weak secretion of interleukin-12 (IL-12) are hallmarks of classical Whipple's disease (CWD). This study addresses dendritic cell (DC) functionality during CWD. We documented composition, distribution, and functionality of DC ex vivo or after in vitro maturation by fluorescence-activated cell sorting (FACS) and by immunohistochemistry in situ. A decrease in peripheral DC of untreated CWD patients compared to healthy donors was due to reduced CD11chigh myeloid DC (M-DC). Decreased maturation markers CD83, CD86, and CCR7, as well as low IL-12 production in response to stimulation, disclosed an immature M-DC phenotype. In vitro-generated monocyte-derived DC from CWD patients showed normal maturation and T cell-stimulatory capacity under proinflammatory conditions but produced less IL-12 and failed to activate T. whipplei-specific Th1 cells. In duodenal and lymphoid tissues, T. whipplei was found within immature DC-SIGN+ DC. DC and proliferating lymphocytes were reduced in lymph nodes of CWD patients compared to levels in controls. Our results indicate that dysfunctional IL-12 production by DC provides suboptimal conditions for priming of T. whipplei-specific T cells during CWD and that immature DC carrying T. whipplei contribute to the dissemination of the bacterium. PMID:25385798

  18. Dendritic Cell-Based Immunotherapy Treatment for Glioblastoma Multiforme

    PubMed Central

    Yang, Liu; Guo, Geng; Niu, Xiao-yuan; Liu, Jing

    2015-01-01

    Glioblastoma multiforme (GBM) is the most malignant glioma and patients diagnosed with this disease had poor outcomes even treated with the combination of conventional treatment (surgery, chemotherapy, and radiation). Dendritic cells (DCs) are the most powerful antigen presenting cells and DC-based vaccination has the potential to target and eliminate GBM cells and enhance the responses of these cells to the existing therapies with minimal damage to the healthy tissues around them. It can enhance recognition of GBM cells by the patients' immune system and activate vast, potent, and long-lasting immune reactions to eliminate them. Therefore, this therapy can prolong the survival of GBM patients and has wide and bright future in the treatment of GBM. Also, the efficacy of this therapy can be strengthened in several ways at some degree: the manipulation of immune regulatory components or costimulatory molecules on DCs; the appropriate choices of antigens for loading to enhance the effectiveness of the therapy; regulation of positive regulators or negative regulators in GBM microenvironment. PMID:26167495

  19. Thrombin regulates the function of human blood dendritic cells

    SciTech Connect

    Yanagita, Manabu; Kobayashi, Ryohei; Kashiwagi, Yoichiro; Shimabukuro, Yoshio; Murakami, Shinya E-mail: ipshinya@dent.osaka-u.ac.jp

    2007-12-14

    Thrombin is the key enzyme in the coagulation cascade and activates endothelial cells, neutrophils and monocytes via protease-activated receptors (PARs). At the inflammatory site, immune cells have an opportunity to encounter thrombin. However little is known about the effect of thrombin for dendritic cells (DC), which are efficient antigen-presenting cells and play important roles in initiating and regulating immune responses. The present study revealed that thrombin has the ability to stimulate blood DC. Plasmacytoid DC (PDC) and myeloid DC (MDC) isolated from PBMC expressed PAR-1 and released MCP-1, IL-10, and IL-12 after thrombin stimulation. Unlike blood DC, monocyte-derived DC (MoDC), differentiated in vitro did not express PAR-1 and were unresponsive to thrombin. Effects of thrombin on blood DC were significantly diminished by the addition of anti-PAR-1 Ab or hirudin, serine protease inhibitor. Moreover, thrombin induced HLA-DR and CD86 expression on DC and the thrombin-treated DC induced allogenic T cell proliferation. These findings indicate that thrombin plays a role in the regulation of blood DC functions.

  20. Tissue dendritic cells as portals for HIV entry.

    PubMed

    Harman, Andrew N; Kim, Min; Nasr, Najla; Sandgren, Kerrie J; Cameron, Paul U

    2013-09-01

    Dendritic cells (DCs) are found at the portals of pathogen entry such as the mucosal surfaces of the respiratory, gastrointestinal and genital tracts where they represent the first line of contact between the immune system and the foreign invaders. They are found throughout the body in multiple subsets where they express unique combinations of C-type lectin receptors to best aid them in detection of pathogens associated with their anatomical location. DCs are important in the establishment in HIV infection for two reasons. Firstly, they are one of the first cells to encounter the virus, and the specific interaction that occurs between these cells and HIV is critical to HIV establishing a foothold infection. Secondly and most importantly, HIV is able to efficiently transfer the virus to its primary target cell, the CD4(+) T lymphocyte, in which it replicates explosively. Infection of CD4(+) T lymphocytes via DCs is far more efficient than direct infection. This review surveys the various DCs subsets found within the human sexual mucosa and their interactions with HIV. Mechanisms of HIV uptake are discussed as well as how the virus then traffics through the DC and is transferred to T cells. Until recently, most research has focussed on vaginal transmission despite the increased transmission rate associated with anal intercourse. Here, we also discuss recent advances in our understanding of HIV transmission in the colon. PMID:23908074

  1. Costimulatory Molecules on Immunogenic Versus Tolerogenic Human Dendritic Cells

    PubMed Central

    Hubo, Mario; Trinschek, Bettina; Kryczanowsky, Fanny; Tuettenberg, Andrea; Steinbrink, Kerstin; Jonuleit, Helmut

    2013-01-01

    Dendritic cells (DC) are sentinels of immunity, essential for homeostasis of T cell-dependent immune responses. Both functions of DC, initiation of antigen-specific T cell immunity and maintenance of tissue-specific tolerance originate from distinct stages of differentiation, immunogenic versus tolerogenic. Dependent on local micro milieu and inflammatory stimuli, tissue resident immature DC with functional plasticity differentiate into tolerogenic or immunogenic DC with stable phenotypes. They efficiently link innate and adaptive immunity and are ideally positioned to modify T cell-mediated immune responses. Since the T cell stimulatory properties of DC are significantly influenced by their expression of signal II ligands, it is critical to understand the impact of distinct costimulatory pathways on DC function. This review gives an overview of functional different human DC subsets with unique profiles of costimulatory molecules and outlines how different costimulatory pathways together with the immunosuppressive cytokine IL-10 bias immunogenic versus tolerogenic DC functions. Furthermore, we exemplarily describe protocols for the generation of two well-defined monocyte-derived DC subsets for their clinical use, immunogenic versus tolerogenic. PMID:23565116

  2. Antihelminthic niclosamide modulates dendritic cells activation and function.

    PubMed

    Wu, Chieh-Shan; Li, Yi-Rong; Chen, Jeremy J W; Chen, Ying-Che; Chu, Chiang-Liang; Pan, I-Hong; Wu, Yu-Shan; Lin, Chi-Chen

    2014-01-01

    Dendritic cells (DCs) link the sensing of the environment by the innate immune system to the initiation of adaptive immune responses. Accordingly, DCs are considered to be a major target in the development of immunomodulating compounds. In this study, the effect of niclosamide, a Food and Drug Administration-approved antihelminthic drug, on the activation of lipopolysaccharide (LPS)-stimulated murine bone marrow-derived DCs was examined. Our experimental results show that niclosamide reduced the pro-inflammatory cytokine and chemokine expression of LPS-activated DCs. In addition, niclosamide also affected the expression of MHC and costimulatory molecules and influenced the ability of the cells to take up antigens. Therefore, in mixed cell cultures composed of syngeneic OVA-specific T cells and DCs, niclosamide-treated DCs showed a decreased ability to stimulate T cell proliferation and IFN-γ production. Furthermore, intravenous injection of niclosamide also attenuated contact hypersensitivity (CHS) in mice during sensitization with 2,4-dinitro-1-fluorobenzene. Blocking the LPS-induced activation of MAPK-ERK, JNK and NF-κB may contribute to the inhibitory effect of niclosamide on DC activation. Collectively, our findings suggest that niclosamide can manipulate the function of DCs. These results provide new insight into the immunopharmacological role of niclosamide and suggest that it may be useful for the treatment of chronic inflammatory disorders or DC-mediated autoimmune diseases. PMID:24561310

  3. Taxifolin glycoside inhibits dendritic cell responses stimulated by lipopolysaccharide and lipoteichoic acid.

    PubMed

    Kim, Yun Jeong; Choi, Sun Eun; Lee, Min Won; Lee, Chung Soo

    2008-11-01

    Antigen-presenting dendritic cells may play an important role in the pathogenesis of atopic dermatitis. Taxifolin is demonstrated to have anti-inflammatory effects. The present study was designed to assess the effect of taxifolin glycoside against stimulated responses of dendritic cells isolated from mouse bone marrow and spleen. Dendritic cells exposed to lipopolysaccharide, lipoteichoic acid or interleukin (IL)-1beta exhibited increased production of IL-12 p70 and tumour necrosis factor alpha, increased formation of reactive oxygen species (ROS) and nitric oxide (NO), and elevation of intracellular Ca2+ levels. Treatment with taxifolin glycoside inhibited responses stimulated by the microbial products or IL-1beta in dendritic cells in a dose-dependent manner. Taxifolin glycoside had a significant inhibitory effect on the production of cytokines, formation of ROS and NO, and change in intracellular Ca2+ levels in dendritic cells of bone marrow and spleen. The results show that taxifolin glycoside seems to inhibit the dendritic cell responses stimulated by microbial products and IL-1beta, suggesting that taxifolin glycoside may exert an inhibitory effect against dendritic-cell-mediated immune responses. PMID:18957167

  4. Retinoic acid-primed human dendritic cells inhibit Th9 cells and induce Th1/Th17 cell differentiation.

    PubMed

    Rampal, Ritika; Awasthi, Amit; Ahuja, Vineet

    2016-07-01

    All-trans-retinoic acid plays a central role in mucosal immunity, where it promotes its synthesis by up-regulating CD103 expression on dendritic cells, induces gut tropic (α4β7(+) and CCR9(+)) T cells, and inhibits Th1/Th17 differentiation. Recently, murine studies have highlighted the proinflammatory role of retinoic acid in maintaining inflammation under a variety of pathologic conditions. However, as a result of limited human data, we investigated the effect of retinoic acid on human dendritic cells and CD4(+) T cell responses in the presence of polarizing (Th1/Th9/Th17) and inflammatory (LPS-induced dendritic cells) conditions. We report a novel role of retinoic acid in an inflammatory setup, where retinoic acid-primed dendritic cells (retinoic acid-monocyte-derived dendritic cells) up-regulated CCR9(+)T cells, which were observed to express high levels of IFN-γ in the presence of Th1/Th17 conditions. Retinoic acid-monocyte-derived dendritic cells, under Th17 conditions, also favored the induction of IL-17(+) T cells. Furthermore, in the presence of TGF-β1 and IL-4, retinoic acid-monocyte-derived dendritic cells inhibited IL-9 and induced IFN-γ expression on T cells. Experiments with naïve CD4(+) T cells, activated in the presence of Th1/Th17 conditions and absence of DCs, indicated that retinoic acid inhibited IFN-γ and IL-17 expression on T cells. These data revealed that in the face of inflammatory conditions, retinoic acid, in contrast from its anti-inflammatory role, could maintain or aggravate the intestinal inflammation. PMID:26980802

  5. Interaction of Rotavirus with Human Myeloid Dendritic Cells

    PubMed Central

    Narváez, Carlos F.; Angel, Juana; Franco, Manuel A.

    2005-01-01

    We have previously shown that very few rotavirus (RV)-specific T cells that secrete gamma interferon circulate in recently infected and seropositive adults and children. Here, we have studied the interaction of RV with myeloid immature (IDC) and mature dendritic cells (MDC) in vitro. RV did not induce cell death of IDC or MDC and induced maturation of between 12 and 48% of IDC. Nonetheless, RV did not inhibit the maturation of IDC or change the expression of maturation markers on MDC. After treatment with RV, few IDC expressed the nonstructural viral protein NSP4. In contrast, a discrete productive viral infection was shown in MDC of a subset of volunteers, and between 3 and 46% of these cells expressed NSP4. RV-treated IDC secreted interleukin 6 (IL-6) (but not IL-1β, IL-8, IL-10, IL-12, tumor necrosis factor alpha, or transforming growth factor beta), and MDC released IL-6 and small amounts of IL-10 and IL-12p70. The patterns of cytokines secreted by T cells stimulated by staphylococcal enterotoxin B presented by MDC infected with RV or uninfected were comparable. The frequencies and patterns of cytokines secreted by memory RV-specific T cells evidenced after stimulation of peripheral blood mononuclear cells (PBMC) with RV were similar to those evidenced after stimulation of PBMC with RV-infected MDC. Finally, IDC treated with RV strongly stimulated naive allogeneic CD4+ T cells to secrete Th1 cytokines. Thus, although RV does not seem to be a strong maturing stimulus for DC, it promotes their capacity to prime Th1 cells. PMID:16282452

  6. Passive carriage of rabies virus by dendritic cells.

    PubMed

    Senba, Kazuyo; Matsumoto, Takashi; Yamada, Kentaro; Shiota, Seiji; Iha, Hidekatsu; Date, Yukari; Ohtsubo, Motoaki; Nishizono, Akira

    2013-01-01

    The rabies virus (RABV) is highly neurotropic and it uses evasive strategies to successfully evade the host immune system. Because rabies is often fatal, understanding the basic processes of the virus-host interactions, particularly in the initial events of infection, is critical for the design of new therapeutic approaches to target RABV. Here, we examined the possible role of dendritic cells (DCs) in the transmission of RABV to neural cells at peripheral site of exposure. Viral replication only occurred at a low level in the DC cell line, JAWS II, after its infection with either pathogenic RABV (CVS strain) or low-pathogenic RABV (ERA strain), and no progeny viruses were produced in the culture supernatants. However, both viral genomic RNAs were retained in the long term after infection and maintained their infectivity. The biggest difference between CVS and ERA was in their ability to induce type I interferons. Although the ERA-infected JAWS II cells exhibited cytopathic effect and were apparently killed by normal spleen cells in vitro, the CVS-infected JAWS II cells showed milder cytopathic effect and less lysis when cocultured with spleen cells. Strongly increased expression of major histocompatibility complex classes I, costimulatory molecules (CD80 and CD86), type I interferons and Toll- like receptor 3, and was observed only in the ERA-inoculated JAWS II cells and not in those inoculated with CVS. During the silencing of the cellular immune response in the DCs, the pathogenic CVS strain cryptically maintained an infectious viral genome and was capable of transmitting infectious RABV to permissive neural cells. These findings demonstrate that DCs may play a role in the passive carriage of RABV during natural rabies infections. PMID:24024103

  7. Type 1 diabetes genetic susceptibility and dendritic cell function: potential targets for treatment.

    PubMed

    Hotta-Iwamura, Chie; Tarbell, Kristin V

    2016-07-01

    Type 1 diabetes is an autoimmune disease that results from the defective induction or maintenance of T cell tolerance against islet β cell self-antigens. Under steady-state conditions, dendritic cells with tolerogenic properties are critical for peripheral immune tolerance. Tolerogenic dendritic cells can induce T cell anergy and deletion and, in some contexts, induce or expand regulatory T cells. Dendritic cells contribute to both immunomodulatory effects and triggering of pathogenesis in type 1 diabetes. This immune equilibrium is affected by both genetic and environmental factors that contribute to the development of type 1 diabetes. Genome-wide association studies and disease association studies have identified >50 polymorphic loci that lend susceptibility or resistance to insulin-dependent diabetes mellitus. In parallel, diabetes susceptibility regions known as insulin-dependent diabetes loci have been identified in the nonobese diabetic mouse, a model for human type 1 diabetes, providing a better understanding of potential immunomodulatory factors in type 1 diabetes risk. Most genetic candidates have annotated immune cell functions, but the focus has been on changes to T and B cells. However, it is likely that some of the genomic susceptibility in type 1 diabetes directly interrupts the tolerogenic potential of dendritic cells in the pathogenic context of ongoing autoimmunity. Here, we will review how gene polymorphisms associated with autoimmune diabetes may influence dendritic cell development and maturation processes that could lead to alterations in the tolerogenic function of dendritic cells. These insights into potential tolerogenic and pathogenic roles for dendritic cells have practical implications for the clinical manipulation of dendritic cells toward tolerance to prevent and treat type 1 diabetes. PMID:26792821

  8. Dendritic patch-clamp recordings from cerebellar granule cells demonstrate electrotonic compactness

    PubMed Central

    Delvendahl, Igor; Straub, Isabelle; Hallermann, Stefan

    2015-01-01

    Cerebellar granule cells (GCs), the smallest neurons in the brain, have on average four short dendrites that receive high-frequency mossy fiber inputs conveying sensory information. The short length of the dendrites suggests that GCs are electrotonically compact allowing unfiltered integration of dendritic inputs. The small average diameter of the dendrites (~0.7 µm), however, argues for dendritic filtering. Previous studies based on somatic recordings and modeling indicated that GCs are electrotonically extremely compact. Here, we performed patch-clamp recordings from GC dendrites in acute brain slices of mice to directly analyze the electrotonic properties of GCs. Strikingly, the input resistance did not differ significantly between dendrites and somata of GCs. Furthermore, spontaneous excitatory postsynaptic potentials (EPSP) were similar in amplitude at dendritic and somatic recording sites. From the dendritic and somatic input resistances we determined parameters characterizing the electrotonic compactness of GCs. These data directly demonstrate that cerebellar GCs are electrotonically compact and thus ideally suited for efficient high-frequency information transfer. PMID:25852483

  9. Macrophages and dendritic cells in the post-testicular environment.

    PubMed

    Da Silva, Nicolas; Barton, Claire R

    2016-01-01

    Macrophages (MΦ) and dendritic cells (DCs) are heterogeneous families of functionally and developmentally related immune cells that play crucial roles in tissue homeostasis and the regulation of immune responses. During the past 5 years, immunologists have generated a considerable amount of data that challenge dogmas about the ontogeny and functions of these highly versatile cells. The male excurrent duct system plays a critical role in the establishment of fertility by allowing sperm maturation, transport and storage. In addition, it is challenged by pathogens and must establish a protective and tolerogenic environment for a continuous flow of autoantigenic spermatozoa. The post-testicular environment and, in particular, the epididymis contain an intricate network of DCs and MΦ; however, the immunophysiology of this intriguing and highly specialized mucosal system is poorly understood. This review summarizes the current trends in mouse MΦ and DC biology and speculates about their roles in the steady-state epididymis. Unraveling immune cell functions in the male reproductive tract is an essential prerequisite for the design of innovative strategies aimed at controlling male fertility and treating infertility. PMID:26337514

  10. Targeting Dendritic Cell Function during Systemic Autoimmunity to Restore Tolerance

    PubMed Central

    Mackern-Oberti, Juan P.; Vega, Fabián; Llanos, Carolina; Bueno, Susan M.; Kalergis, Alexis M.

    2014-01-01

    Systemic autoimmune diseases can damage nearly every tissue or cell type of the body. Although a great deal of progress has been made in understanding the pathogenesis of autoimmune diseases, current therapies have not been improved, remain unspecific and are associated with significant side effects. Because dendritic cells (DCs) play a major role in promoting immune tolerance against self-antigens (self-Ags), current efforts are focusing at generating new therapies based on the transfer of tolerogenic DCs (tolDCs) during autoimmunity. However, the feasibility of this approach during systemic autoimmunity has yet to be evaluated. TolDCs may ameliorate autoimmunity mainly by restoring T cell tolerance and, thus, indirectly modulating autoantibody development. In vitro induction of tolDCs loaded with immunodominant self-Ags and subsequent cell transfer to patients would be a specific new therapy that will avoid systemic immunosuppression. Herein, we review recent approaches evaluating the potential of tolDCs for the treatment of systemic autoimmune disorders. PMID:25229821

  11. Targeting dendritic cell function during systemic autoimmunity to restore tolerance.

    PubMed

    Mackern-Oberti, Juan P; Vega, Fabián; Llanos, Carolina; Bueno, Susan M; Kalergis, Alexis M

    2014-01-01

    Systemic autoimmune diseases can damage nearly every tissue or cell type of the body. Although a great deal of progress has been made in understanding the pathogenesis of autoimmune diseases, current therapies have not been improved, remain unspecific and are associated with significant side effects. Because dendritic cells (DCs) play a major role in promoting immune tolerance against self-antigens (self-Ags), current efforts are focusing at generating new therapies based on the transfer of tolerogenic DCs (tolDCs) during autoimmunity. However, the feasibility of this approach during systemic autoimmunity has yet to be evaluated. TolDCs may ameliorate autoimmunity mainly by restoring T cell tolerance and, thus, indirectly modulating autoantibody development. In vitro induction of tolDCs loaded with immunodominant self-Ags and subsequent cell transfer to patients would be a specific new therapy that will avoid systemic immunosuppression. Herein, we review recent approaches evaluating the potential of tolDCs for the treatment of systemic autoimmune disorders. PMID:25229821

  12. Tumor-derived factors modulating dendritic cell function.

    PubMed

    Zong, Jinbao; Keskinov, Anton A; Shurin, Galina V; Shurin, Michael R

    2016-07-01

    Dendritic cells (DC) play unique and diverse roles in the tumor occurrence, development, progression and response to therapy. First of all, DC can actively uptake tumor-associated antigens, process them and present antigenic peptides to T cells inducing and maintaining tumor-specific T cell responses. DC interaction with different immune effector cells may also support innate antitumor immunity, as well as humoral responses also known to inhibit tumor development in certain cases. On the other hand, DC are recruited to the tumor site by specific tumor-derived and stroma-derived factors, which may also impair DC maturation, differentiation and function, thus resulting in the deficient formation of antitumor immune response or development of DC-mediated tolerance and immune suppression. Identification of DC-stimulating and DC-suppressing/polarizing factors in the tumor environment and the mechanism of DC modulation are important for designing effective DC-based vaccines and for recovery of immunodeficient resident DC responsible for maintenance of clinically relevant antitumor immunity in patients with cancer. DC-targeting tumor-derived factors and their effects on resident and administered DC in the tumor milieu are described and discussed in this review. PMID:26984847

  13. Dendritic cell-based in vitro assays for vaccine immunogenicity

    PubMed Central

    Vandebriel, Rob J.; Hoefnagel, Marcel H.N.

    2012-01-01

    Dendritic cells (DC) are pivotal in the induction of adaptive immune responses because they can activate naive T-cells. Moreover, they steer these adaptive immune responses by integrating various stimuli, such as from different pathogen associated molecular patterns and the cytokine milieu. Immature DC are very well capable of ingesting protein antigens, whereas mature DC are efficient presenters of peptides to naive T cells. Human DC can be readily cultured from peripheral blood mononuclear cells, which are isolated from human blood. There is a strong need to monitor in a high-throughput fashion the immunogenicity of candidate vaccines during the process of vaccine development. Furthermore, regulators require efficacy and safety testing for batch release. For some vaccines, these tests require animal testing, causing pain and discomfort, which cannot be contested because it would interfere with the test results. With the aims of promoting vaccine development and reducing the number of animals for batch release testing, we propose to use more broadly human DC for vaccine immunogenicity testing. In this commentary, this proposition is illustrated by several examples in which the maturation of human DC was successfully used to test for vaccine and adjuvant immunogenicity. PMID:22951585

  14. Dendritic Cell Activation by Glucan Isolated from Umbilicaria Esculenta

    PubMed Central

    Kim, Hyung Sook; Kim, Jee Youn; Lee, Hong Kyung; Kim, Moo Sung; Lee, Sang Rin; Kang, Jong Soon; Kim, Hwan Mook; Lee, Kyung-Ae; Hong, Jin Tae; Kim, Youngsoo

    2010-01-01

    Background Lichen-derived glucans have been known to stimulate the functions of immune cells. However, immunostimulatory activity of glucan obtained from edible lichen, Umbilicaria esculenta, has not been reported. Thus we evaluated the phenotype and functional maturation of dendritic cells (DCs) following treatment of extracted glucan (PUE). Methods The phenotypic and functional maturation of PUE-treated DCs was assessed by flow cytometric analysis and cytokine production, respectively. PUE-treated DCs was also used for mixed leukocyte reaction to evaluate T cell-priming capacity. Finally we detected the activation of MAPK and NF-κB by immunoblot. Results Phenotypic maturation of DCs was shown by the elevated expressions of CD40, CD80, CD86, and MHC class I/II molecules. Functional activation of DCs was proved by increased cytokine production of IL-12, IL-1β, TNF-α, and IFN-α/β, decreased endocytosis, and enhanced proliferation of allogenic T cells. Polymyxin B, specific inhibitor of lipopolysaccharide (LPS), did not affect PUE activity, which suggested that PUE was free of LPS contamination. As a mechanism of action, PUE increased phosphorylation of ERK, JNK, and p38 MAPKs, and enhanced nuclear translocation of NF-κB p50/p65 in DCs. Conclusion These results indicate that PUE induced DC maturation via MAPK and NF-κB signaling pathways. PMID:21286379

  15. CXCR4 engagement promotes dendritic cell survival and maturation

    SciTech Connect

    Kabashima, Kenji Sugita, Kazunari; Shiraishi, Noriko; Tamamura, Hirokazu; Fujii, Nobutaka; Tokura, Yoshiki

    2007-10-05

    It has been reported that human monocyte derived-dendritic cells (DCs) express CXCR4, responsible for chemotaxis to CXCL12. However, it remains unknown whether CXCR4 is involved in other functions of DCs. Initially, we found that CXCR4 was expressed on bone marrow-derived DCs (BMDCs). The addition of specific CXCR4 antagonist, 4-F-Benzoyl-TN14003, to the culture of mouse BMDCs decreased their number, especially the mature subset of them. The similar effect was found on the number of Langerhans cells (LCs) but not keratinocytes among epidermal cell suspensions. Since LCs are incapable of proliferating in vitro, these results indicate that CXCR4 engagement is important for not only maturation but also survival of DCs. Consistently, the dinitrobenzene sulfonic acid-induced, antigen-specific in vitro proliferation of previously sensitized lymph node cells was enhanced by CXCL12, and suppressed by CXCR4 antagonist. These findings suggest that CXCL12-CXCR4 engagement enhances DC maturation and survival to initiate acquired immune response.

  16. Influence of follicular dendritic cells on HIV dynamics.

    PubMed Central

    Hlavacek, W S; Stilianakis, N I; Perelson, A S

    2000-01-01

    In patients infected with human immunodeficiency virus type 1 (HIV-1), a large amount of virus is associated with follicular dendritic cells (FDCs) in lymphoid tissue. To assess the influence of FDCs on viral dynamics during antiretroviral therapy we have developed a mathematical model for treatment of HIV-1 infection that includes FDCs. Here, we use this model to analyse measurements of HIV-1 dynamics in the blood and lymphoid tissue of a representative patient, who was treated with a combination of HIV-1 reverse transcriptase and protease inhibitors. We show that loss of virus from FDCs during therapy can make a much larger contribution to plasma virus than production of virus by infected cells. This result challenges the notion that long-lived infected cells are a significant source of HIV-1 during drug therapy. Due to release of FDC-associated virus, we find that it is necessary to revise upward previous estimates of c, the rate at which free virus is cleared, and delta, the rate at which productively infected cells die. Furthermore, we find that potentially infectious virus, present before treatment, is released from FDCs during therapy and that the persistence of this virus can be affected by whether therapy includes reverse transcriptase inhibitors. PMID:11186306

  17. Role of Dendritic Cells in the Induction of Lymphocyte Tolerance

    PubMed Central

    Osorio, Fabiola; Fuentes, Camila; López, Mercedes N.; Salazar-Onfray, Flavio; González, Fermín E.

    2015-01-01

    The ability of dendritic cells (DCs) to trigger tolerance or immunity is dictated by the context in which an antigen is encountered. A large body of evidence indicates that antigen presentation by steady-state DCs induces peripheral tolerance through mechanisms such as the secretion of soluble factors, the clonal deletion of autoreactive T cells, and feedback control of regulatory T cells. Moreover, recent understandings on the function of DC lineages and the advent of murine models of DC depletion have highlighted the contribution of DCs to lymphocyte tolerance. Importantly, these findings are now being applied to human research in the contexts of autoimmune diseases, allergies, and transplant rejection. Indeed, DC-based immunotherapy research has made important progress in the area of human health, particularly in regards to cancer. A better understanding of several DC-related aspects including the features of DC lineages, milieu composition, specific expression of surface molecules, the control of signaling responses, and the identification of competent stimuli able to trigger and sustain a tolerogenic outcome will contribute to the success of DC-based immunotherapy in the area of lymphocyte tolerance. This review will discuss the latest advances in the biology of DC subtypes related to the induction of regulatory T cells, in addition to presenting current ex vivo protocols for tolerogenic DC production. Particular attention will be given to the molecules and signals relevant for achieving an adequate tolerogenic response for the treatment of human pathologies. PMID:26539197

  18. Regulatory Multitasking of Tolerogenic Dendritic Cells – Lessons Taken from Vitamin D3-Treated Tolerogenic Dendritic Cells

    PubMed Central

    Nikolic, Tatjana; Roep, Bart O.

    2013-01-01

    Tolerogenic dendritic cells (DCs) work through silencing of differentiated antigen-specific T cells, activation and expansion of naturally occurring T regulatory cells (Tregs), transfer of regulatory properties to T cells, and the differentiation of naïve T cells into Tregs. Due to an operational definition based on T cell activation assays, the identity of tolerogenic DCs has been a matter of debate and it need not represent a specialized DC subset. Human tolerogenic DCs generated in vitro using inhibitory cytokines, growth factors, natural immunomodulators, or genetic manipulation have been effective and several of these tolerogenic DCs are currently being tested for clinical use. Ex vivo generated tolerogenic DCs reduce activation of naïve T cells using various means, promote a variety of regulatory T cells and most importantly, frequently show stable inhibitory phenotypes upon repetitive maturation with inflammatory factors. Yet, tolerogenic DCs differ with respect to the phenotype or the number of regulatory mechanisms they employ to modulate the immune system. In our experience, tolerogenic DCs generated using the biologically active form of vitamin D (VD3-DCs), alone, or combined with dexamethasone are proficient in their immunoregulatory functions. These tolerogenic DCs show a stable maturation-resistant semi-mature phenotype with low expression of activating co-stimulatory molecules, no production of the IL-12 family of cytokines and high expression of inhibitory molecules and IL-10. VD3-DCs induce increased apoptosis of effector T cells and induce antigen-specific regulatory T cells, which work through linked suppression ensuring infectious tolerance. Lessons learned on VD3-DCs help understanding the contribution of different pattern-recognition receptors (PRRs) and secondary signals to the tolerogenic function and how a cross-talk between DCs and T cells translates into immune regulation. PMID:23717310

  19. Group 2 innate lymphoid cells license dendritic cells to potentiate memory T helper 2 cell responses

    PubMed Central

    Halim, Timotheus YF; Hwang, You Yi; Scanlon, Seth T; Zaghouani, Habib; Garbi, Natalio; Fallon, Padraic G; McKenzie, Andrew NJ

    2015-01-01

    Rapid memory CD4+ T helper 2 (TH2) cell activation during allergic inflammation requires their recruitment into the affected tissue. Here we demonstrate that group 2 innate lymphoid cells (ILC2) play a critical role in memory TH2 cell responses, with targeted ILC2 depletion profoundly impairing TH2 cell localization to the lungs and skin of sensitized mice after allergen re-challenge. ILC2-derived interleukin-13 (IL-13) is critical for eliciting IRF4+CD11b+CD103− dendritic cells (DCs) to produce the TH2 cell-attracting chemokine CCL17. Consequently, the sentinel function of DCs is contingent on ILC2s for the generation of an efficient memory TH2 cell response. These results elucidate a key new innate mechanism in the regulation of the immune memory response to allergens. PMID:26523868

  20. Membrane specializations and endosome maturation in dendritic cells and B cells.

    PubMed

    Boes, Marianne; Cuvillier, Armelle; Ploegh, Hidde

    2004-04-01

    Interest in the cell biology of antigen presentation is centered on dendritic cells (DCs) as initiators of the immune response. The ability to examine primary antigen-presenting cells, as opposed to cell lines, has opened a new window for study of antigen processing and peptide acquisition by Class II major histocompatibility complex (MHC) products, especially where intracellular trafficking of peptide-Class-II complexes is concerned. Here, we review the dynamics of Class II MHC-positive intracellular structures in dendritic cells as well as B cells. We focus on the generation of multivesicular bodies, where Class II MHC products acquire antigenic peptide, on the endosomal transport of peptide-loaded Class II MHC to the cell surface and on the importance of Class II MHC localization in membrane microdomains. PMID:15066635

  1. CD45 negatively regulates tumour necrosis factor and interleukin-6 production in dendritic cells.

    PubMed

    Piercy, Jenny; Petrova, Svetla; Tchilian, Elma Z; Beverley, Peter C L

    2006-06-01

    CD45 is known to regulate signalling through many different surface receptors in diverse haemopoietic cell types. Here we report for the first time that CD45-/- bone marrow dendritic cells (BMDC) are more activated than CD45+/+ cells and that tumour necrosis factor (TNF) and interleukin-6 (IL-6) production by BMDC and splenic dendritic cells (sDC), is increased following stimulation via Toll-like receptor (TLR)3 and TLR9. Nuclear factor-kappaB activation, an important downstream consequence of TLR3 and TLR9 signalling, is also increased in CD45-/- BMDC. BMDC of CD45-/- mice also produce more TNF and IL-6 following stimulation with the cytokines TNF and interferon-alpha. These results show that TLR signalling is increased in CD45-/- dendritic cells and imply that CD45 is a negative regulator of TLR and cytokine receptor signalling in dendritic cells. PMID:16771860

  2. Clusters of synaptic inputs on dendrites of layer 5 pyramidal cells in mouse visual cortex

    PubMed Central

    Gökçe, Onur; Bonhoeffer, Tobias; Scheuss, Volker

    2016-01-01

    The spatial organization of synaptic inputs on the dendritic tree of cortical neurons plays a major role for dendritic integration and neural computations, yet, remarkably little is known about it. We mapped the spatial organization of glutamatergic synapses between layer 5 pyramidal cells by combining optogenetics and 2-photon calcium imaging in mouse neocortical slices. To mathematically characterize the organization of inputs we developed an approach based on combinatorial analysis of the likelihoods of specific synapse arrangements. We found that the synapses of intralaminar inputs form clusters on the basal dendrites of layer 5 pyramidal cells. These clusters contain 4 to 14 synapses within ≤30 µm of dendrite. According to the spatiotemporal characteristics of synaptic summation, these numbers suggest that there will be non-linear dendritic integration of synaptic inputs during synchronous activation. DOI: http://dx.doi.org/10.7554/eLife.09222.001 PMID:27431612

  3. Structured Dendritic Inhibition Supports Branch-Selective Integration in CA1 Pyramidal Cells.

    PubMed

    Bloss, Erik B; Cembrowski, Mark S; Karsh, Bill; Colonell, Jennifer; Fetter, Richard D; Spruston, Nelson

    2016-03-01

    Neuronal circuit function is governed by precise patterns of connectivity between specialized groups of neurons. The diversity of GABAergic interneurons is a hallmark of cortical circuits, yet little is known about their targeting to individual postsynaptic dendrites. We examined synaptic connectivity between molecularly defined inhibitory interneurons and CA1 pyramidal cell dendrites using correlative light-electron microscopy and large-volume array tomography. We show that interneurons can be highly selective in their connectivity to specific dendritic branch types and, furthermore, exhibit precisely targeted connectivity to the origin or end of individual branches. Computational simulations indicate that the observed subcellular targeting enables control over the nonlinear integration of synaptic input or the initiation and backpropagation of action potentials in a branch-selective manner. Our results demonstrate that connectivity between interneurons and pyramidal cell dendrites is more precise and spatially segregated than previously appreciated, which may be a critical determinant of how inhibition shapes dendritic computation. VIDEO ABSTRACT. PMID:26898780

  4. Modulation of Dendritic Cell Responses by Parasites: A Common Strategy to Survive

    PubMed Central

    Terrazas, César A.; Terrazas, Luis I.; Gómez-García, Lorena

    2010-01-01

    Parasitic infections are one of the most important causes of morbidity and mortality in our planet and the immune responses triggered by these organisms are critical to determine their outcome. Dendritic cells are key elements for the development of immunity against parasites; they control the responses required to eliminate these pathogens while maintaining host homeostasis. However, there is evidence showing that parasites can influence and regulate dendritic cell function in order to promote a more permissive environment for their survival. In this review we will focus on the strategies protozoan and helminth parasites have developed to interfere with dendritic cell activities as well as in the possible mechanisms involved. PMID:20204070

  5. Dendritic Cells under Hypoxia: How Oxygen Shortage Affects the Linkage between Innate and Adaptive Immunity

    PubMed Central

    Winning, Sandra; Fandrey, Joachim

    2016-01-01

    Dendritic cells (DCs) are considered as one of the main regulators of immune responses. They collect antigens, process them, and present typical antigenic structures to lymphocytes, thereby inducing an adaptive immune response. All these processes take place under conditions of oxygen shortage (hypoxia) which is often not considered in experimental settings. This review highlights how deeply hypoxia modulates human as well as mouse immature and mature dendritic cell functions. It tries to link in vitro results to actual in vivo studies and outlines how hypoxia-mediated shaping of dendritic cells affects the activation of (innate) immunity. PMID:26966693

  6. Blastic Plasmacytoid Dendritic Cell Neoplasm: From Origin of the Cell to Targeted Therapies.

    PubMed

    Laribi, Kamel; Denizon, Nathalie; Besançon, Anne; Farhi, Jonathan; Lemaire, Pierre; Sandrini, Jeremy; Truong, Catherine; Ghnaya, Habib; Baugier de Materre, Alix

    2016-08-01

    Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematological malignancy with an aggressive clinical course. It is grouped with acute myeloid leukemia-related precursor neoplasms in the 2008 World Health Organization classification. Most patients with BPDCN have skin lesions at diagnosis and subsequent or simultaneous involvement of the bone marrow, peripheral blood, and lymph nodes. Patients usually respond to initial chemotherapy but often relapse. Stem cell transplantation may improve survival. This neoplasm is derived from precursors of plasmacytoid dendritic cells and is characterized by the coexpression of the immunophenotypic markers CD4, CD56, CD123, blood dendritic cell antigen-2, blood dendritic cell antigen-4, CD2AP, and lineage(-). Atypical immunophenotype expression may be present, making diagnosis difficult. BPDCN is often associated with a complex karyotype, frequent deletions of tumor suppressor genes, and mutations affecting either the DNA methylation or chromatin remodeling pathways. A better understanding of the etiology and pathophysiology of this neoplasm could open the way to new therapies targeting specific signaling pathways or involving epigenetics. PMID:27026248

  7. Dendritic Cell-Lymphocyte Cross Talk Downregulates Host Restriction Factor SAMHD1 and Stimulates HIV-1 Replication in Dendritic Cells

    PubMed Central

    Biedma, Marina Elizabeth; Lederle, Alexandre; Peressin, Maryse; Lambotin, Mélanie; Proust, Alizé; Decoville, Thomas; Schmidt, Sylvie; Laumond, Géraldine

    2014-01-01

    ABSTRACT Human immunodeficiency virus type 1 (HIV-1) replication in dendritic cells (DCs) is restricted by SAMHD1. This factor is counteracted by the viral protein Vpx; Vpx is found in HIV-2 and simian immunodeficiency virus (SIV) from sooty mangabeys (SIVsm) or from macaques (SIVmac) but is absent from HIV-1. We previously observed that HIV-1 replication in immature DCs is stimulated by cocultivation with primary T and B lymphocytes, suggesting that HIV-1 restriction in DCs may be overcome under coculture conditions. Here, we aimed to decipher the mechanism of SAMHD1-mediated restriction in DC-lymphocyte coculture. We found that coculture with lymphocytes downregulated SAMHD1 expression and was associated with increased HIV-1 replication in DCs. Moreover, in infected DC-T lymphocyte cocultures, DCs acquired maturation status and secreted type 1 interferon (alpha interferon [IFN-α]). The blockade of DC-lymphocyte cross talk by anti-ICAM-1 antibody markedly inhibited the stimulation of HIV-1 replication and prevented the downregulation of SAMHD1 expression in cocultured DCs. These results demonstrate that, in contrast to purified DCs, cross talk with lymphocytes downregulates SAMHD1 expression in DCs, triggering HIV-1 replication and an antiviral immune response. Therefore, HIV-1 replication and immune sensing by DCs should be investigated in more physiologically relevant models of DC/lymphocyte coculture. IMPORTANCE SAMHD1 restricts HIV-1 replication in dendritic cells (DCs). Here, we demonstrate that, in a coculture model of DCs and lymphocytes mimicking early mucosal HIV-1 infection, stimulation of HIV-1 replication in DCs is associated with downregulation of SAMHD1 expression and activation of innate immune sensing by DCs. We propose that DC-lymphocyte cross talk occurring in vivo modulates host restriction factor SAMHD1, promoting HIV-1 replication in cellular reservoirs and stimulating immune sensing. PMID:24574390

  8. Effects of inactivated porcine epidemic diarrhea virus on porcine monocyte-derived dendritic cells and intestinal dendritic cells.

    PubMed

    Gao, Qi; Zhao, Shanshan; Qin, Tao; Yin, Yinyan; Yu, Qinghua; Yang, Qian

    2016-06-01

    Porcine epidemic diarrhea (PED) is a serious infection in neonatal piglets. As the causative agent of PED, porcine epidemic diarrhea virus (PEDV) results in acute diarrhea and dehydration with high mortality rates in swine. Dendritic cells (DCs) are highly effective antigen-presenting cells to uptake and present viral antigens to T cells, which then initiate a distinct immune response. In this study, our results show that the expression of Mo-DCs surface markers such as SWC3a(+)CD1a(+), SWC3a(+)CD80/86(+) and SWC3a(+)SLA-II-DR(+) is increased after incubation with UV-PEDV for 24h. Mo-DCs incubated with UV-PEDV produce higher levels of IL-12 and INF-γ compared to mock-infected Mo-DCs. Interactions between Mo-DCs and UV-PEDV significantly stimulate T-cell proliferation in vitro. Consistent with these results, there is an enhancement in the ability of porcine intestinal DCs to activate T-cell proliferation in vivo. We conclude that UV-PEDV may be a useful and safe vaccine to trigger adaptive immunity. PMID:27234553

  9. Monocyte-Derived Dendritic Cells Exhibit Increased Levels of Lysosomal Proteolysis as Compared to Other Human Dendritic Cell Populations

    PubMed Central

    McCurley, Nathanael; Mellman, Ira

    2010-01-01

    Background Fine control of lysosomal degradation for limited processing of internalized antigens is a hallmark of professional antigen presenting cells. Previous work in mice has shown that dendritic cells (DCs) contain lysosomes with remarkably low protease content. Combined with the ability to modulate lysosomal pH during phagocytosis and maturation, murine DCs enhance their production of class II MHC-peptide complexes for presentation to T cells. Methodology/Principal Findings In this study we extend these findings to human DCs and distinguish between different subsets of DCs based on their ability to preserve internalized antigen. Whereas DCs derived in vitro from CD34+ hematopoietic progenitor cells or isolated from peripheral blood of healthy donors are protease poor, DCs derived in vitro from monocytes (MDDCs) are more similar to macrophages (MΦs) in protease content. Unlike other DCs, MDDCs also fail to reduce their intralysosomal pH in response to maturation stimuli. Indeed, functional characterization of lysosomal proteolysis indicates that MDDCs are comparable to MΦs in the rapid degradation of antigen while other human DC subtypes are attenuated in this capacity. Conclusions/Significance Human DCs are comparable to murine DCs in exhibiting a markedly reduced level of lysosomal proteolysis. However, as an important exception to this, human MDDCs stand apart from all other DCs by a heightened capacity for proteolysis that resembles that of MΦs. Thus, caution should be exercised when using human MDDCs as a model for DC function and cell biology. PMID:20689855

  10. Regional Regulation of Purkinje Cell Dendritic Spines by Integrins and Eph/Ephrins

    PubMed Central

    Heintz, Tristan G.; Eva, Richard; Fawcett, James W.

    2016-01-01

    Climbing fibres and parallel fibres compete for dendritic space on Purkinje cells in the cerebellum. Normally, climbing fibres populate the proximal dendrites, where they suppress the multiple small spines typical of parallel fibres, leading to their replacement by the few large spines that contact climbing fibres. Previous work has shown that ephrins acting via EphA4 are a signal for this change in spine type and density. We have used an in vitro culture model in which to investigate the ephrin effect on Purkinje cell dendritic spines and the role of integrins in these changes. We found that integrins α3, α5 and β4 are present in many of the dendritic spines of cultured Purkinje cells. pFAK, the main downstream signalling molecule from integrins, has a similar distribution, although the intenstity of pFAK staining and the percentage of pFAK+ spines was consistently higher in the proximal dendrites. Activating integrins with Mg2+ led to an increase in the intensity of pFAK staining and an increase in the proportion of pFAK+ spines in both the proximal and distal dendrites, but no change in spine length, density or morphology. Blocking integrin binding with an RGD-containing peptide led to a reduction in spine length, with more stubby spines on both proximal and distal dendrites. Treatment of the cultures with ephrinA3-Fc chimera suppressed dendritic spines specifically on the proximal dendrites and there was also a decrease of pFAK in spines on this domain. This effect was blocked by simultaneous activation of integrins with Mn2+. We conclude that Eph/ephrin signaling regulates proximal dendritic spines in Purkinje cells by inactivating integrin downstream signalling. PMID:27518800

  11. Regional Regulation of Purkinje Cell Dendritic Spines by Integrins and Eph/Ephrins.

    PubMed

    Heintz, Tristan G; Eva, Richard; Fawcett, James W

    2016-01-01

    Climbing fibres and parallel fibres compete for dendritic space on Purkinje cells in the cerebellum. Normally, climbing fibres populate the proximal dendrites, where they suppress the multiple small spines typical of parallel fibres, leading to their replacement by the few large spines that contact climbing fibres. Previous work has shown that ephrins acting via EphA4 are a signal for this change in spine type and density. We have used an in vitro culture model in which to investigate the ephrin effect on Purkinje cell dendritic spines and the role of integrins in these changes. We found that integrins α3, α5 and β4 are present in many of the dendritic spines of cultured Purkinje cells. pFAK, the main downstream signalling molecule from integrins, has a similar distribution, although the intenstity of pFAK staining and the percentage of pFAK+ spines was consistently higher in the proximal dendrites. Activating integrins with Mg2+ led to an increase in the intensity of pFAK staining and an increase in the proportion of pFAK+ spines in both the proximal and distal dendrites, but no change in spine length, density or morphology. Blocking integrin binding with an RGD-containing peptide led to a reduction in spine length, with more stubby spines on both proximal and distal dendrites. Treatment of the cultures with ephrinA3-Fc chimera suppressed dendritic spines specifically on the proximal dendrites and there was also a decrease of pFAK in spines on this domain. This effect was blocked by simultaneous activation of integrins with Mn2+. We conclude that Eph/ephrin signaling regulates proximal dendritic spines in Purkinje cells by inactivating integrin downstream signalling. PMID:27518800

  12. WASp-dependent actin cytoskeleton stability at the dendritic cell immunological synapse is required for extensive, functional T cell contacts.

    PubMed

    Malinova, Dessislava; Fritzsche, Marco; Nowosad, Carla R; Armer, Hannah; Munro, Peter M G; Blundell, Michael P; Charras, Guillaume; Tolar, Pavel; Bouma, Gerben; Thrasher, Adrian J

    2016-05-01

    The immunological synapse is a highly structured and molecularly dynamic interface between communicating immune cells. Although the immunological synapse promotes T cell activation by dendritic cells, the specific organization of the immunological synapse on the dendritic cell side in response to T cell engagement is largely unknown. In this study, confocal and electron microscopy techniques were used to investigate the role of dendritic cell actin regulation in immunological synapse formation, stabilization, and function. In the dendritic cell-restricted absence of the Wiskott-Aldrich syndrome protein, an important regulator of the actin cytoskeleton in hematopoietic cells, the immunological synapse contact with T cells occupied a significantly reduced surface area. At a molecular level, the actin network localized to the immunological synapse exhibited reduced stability, in particular, of the actin-related protein-2/3-dependent, short-filament network. This was associated with decreased polarization of dendritic cell-associated ICAM-1 and MHC class II, which was partially dependent on Wiskott-Aldrich syndrome protein phosphorylation. With the use of supported planar lipid bilayers incorporating anti-ICAM-1 and anti-MHC class II antibodies, the dendritic cell actin cytoskeleton organized into recognizable synaptic structures but interestingly, formed Wiskott-Aldrich syndrome protein-dependent podosomes within this area. These findings demonstrate that intrinsic dendritic cell cytoskeletal remodeling is a key regulatory component of normal immunological synapse formation, likely through consolidation of adhesive interaction and modulation of immunological synapse stability. PMID:26590149

  13. Synthetic and biogenic magnetite nanoparticles for tracking of stem cells and dendritic cells

    NASA Astrophysics Data System (ADS)

    Schwarz, Sebastian; Fernandes, Fabiana; Sanroman, Laura; Hodenius, Michael; Lang, Claus; Himmelreich, Uwe; Schmitz-Rode, Thomas; Schueler, Dirk; Hoehn, Mathias; Zenke, Martin; Hieronymus, Thomas

    2009-05-01

    Accurate delivery of cells to target organs is critical for success of cell-based therapies with stem cells or immune cells such as antigen-presenting dendritic cells (DC). Labeling with contrast agents before implantation provides a powerful means for monitoring cellular migration using magnetic resonance imaging (MRI). In this study, we investigated the uptake of fully synthesized or bacterial magnetic nanoparticles (MNPs) into hematopoietic Flt3 + stem cells and DC from mouse bone marrow. We show that (i) uptake of both synthetic and biogenic nanoparticles into cells endow magnetic activity and (ii) low numbers of MNP-loaded cells are readily detected by MRI.

  14. Generation of immunogenic and tolerogenic clinical-grade dendritic cells.

    PubMed

    Kalantari, Tahereh; Kamali-Sarvestani, Eskandar; Ciric, Bogoljub; Karimi, Mohamad H; Kalantari, Mohsen; Faridar, Alireza; Xu, Hui; Rostami, Abdolmohamad

    2011-12-01

    Immunotherapy with dendritic cells (DCs), which have been manipulated ex vivo to become immunogenic or tolerogenic, has been tested in clinical trials for disease therapy. DCs are sentinels of the immune system, which after exposure to antigenic or inflammatory signals and crosstalk with effector CD4(+) T cells express high levels of costimulatory molecules and cytokines. Upregulation of either costimulatory molecules or cytokines promotes immunologic DCs, whereas their downregulation generates tolerogenic DCs (TDCs), which induce T regulatory cells (Tregs) and a state of tolerance. Immunogenic DCs are used for the therapy of infectious diseases such as HIV-1 and cancer, whereas tolerogenic DCs are used in treating various autoimmune diseases and in transplantation. DC vaccination is still at an early stage, and improvements are mainly needed in quality control of monitoring assays to generate clinical-grade DC products and to assess the effect of DC vaccination in future clinical trials. Here, we review the recent work in DC generation and monitoring approaches for DC-based trials with immunogenic or tolerogenic DCs. PMID:22105838

  15. Targeting dendritic cells for improved HIV-1 vaccines.

    PubMed

    Smed-Sörensen, Anna; Loré, Karin

    2013-01-01

    As dendritic cells (DCs) have the unique capacity to activate antigen-naive T cells they likely play a critical role in eliciting immune responses to vaccines. DCs are therefore being explored as attractive targets for vaccines, but understanding the interaction of DCs and clinically relevant vaccine antigens and adjuvants is a prerequisite. The HIV-1/AIDS epidemic continues to be a significant health problem, and despite intense research efforts over the past 30 years a protective vaccine has not yet been developed. A common challenge in vaccine design is to find a vaccine formulation that best shapes the immune response to protect against and/or control the given pathogen. Here, we discuss the importance of understanding the diversity, anatomical location and function of different human DC subsets in order to identify the optimal target cells for an HIV-1 vaccine. We review human DC interactions with some of the HIV-1 vaccine antigen delivery vehicles and adjuvants currently utilized in preclinical and clinical studies. Specifically, the effects of distinctly different vaccine adjuvants in terms of activation of DCs and improving DC function and vaccine efficacy are discussed. The susceptibility and responses of DCs to recombinant adenovirus vectors are reviewed, as well as the strategy of directly targeting DCs by using DC marker-specific monoclonal antibodies coupled to an antigen. PMID:22975879

  16. Dendritic Cell Responses to Surface Properties of Clinical Titanium Surfaces

    PubMed Central

    Kou, Peng Meng; Schwartz, Zvi; Boyan, Barbara D.

    2010-01-01

    Dendritic cells (DCs) play pivotal roles in responding to foreign entities during an innate immune response and initiating effective adaptive immunity as well as maintaining immune tolerance. The sensitivity of DCs to foreign stimuli also makes them useful cells to assess the inflammatory response to biomaterials. Elucidating the material property-DC phenotype relationships using a well-defined biomaterial system is expected to provide criteria for immuno-modulatory biomaterial design. Clinical titanium (Ti) substrates, including pretreatment (PT), sand-blasted and acid-etched (SLA), and modified SLA (modSLA), with different roughness and surface energy were used to treat DCs and resulted in differential DC responses. PT and SLA induced a mature DC (mDC) phenotype, while modSLA promoted a non-inflammatory environment by supporting an immature DC (iDC) phenotype based on surface marker expression, cytokine production profiles and cell morphology. Principal component analysis (PCA) confirmed these experimental results, and it also indicated that the non-stimulating property of modSLA covaried with certain surface properties, such as high surface hydrophilicity, % oxygen and % Ti of the substrates. In addition to the previous research that demonstrated the superior osteogenic property of modSLA compared to PT and SLA, the result reported herein indicates that modSLA may further benefit implant osteo-integration by reducing local inflammation and its associated osteoclastogenesis. PMID:20977948

  17. Epigenetic program and transcription factor circuitry of dendritic cell development.

    PubMed

    Lin, Qiong; Chauvistré, Heike; Costa, Ivan G; Gusmao, Eduardo G; Mitzka, Saskia; Hänzelmann, Sonja; Baying, Bianka; Klisch, Theresa; Moriggl, Richard; Hennuy, Benoit; Smeets, Hubert; Hoffmann, Kurt; Benes, Vladimir; Seré, Kristin; Zenke, Martin

    2015-11-16

    Dendritic cells (DC) are professional antigen presenting cells that develop from hematopoietic stem cells through successive steps of lineage commitment and differentiation. Multipotent progenitors (MPP) are committed to DC restricted common DC progenitors (CDP), which differentiate into specific DC subsets, classical DC (cDC) and plasmacytoid DC (pDC). To determine epigenetic states and regulatory circuitries during DC differentiation, we measured consecutive changes of genome-wide gene expression, histone modification and transcription factor occupancy during the sequel MPP-CDP-cDC/pDC. Specific histone marks in CDP reveal a DC-primed epigenetic signature, which is maintained and reinforced during DC differentiation. Epigenetic marks and transcription factor PU.1 occupancy increasingly coincide upon DC differentiation. By integrating PU.1 occupancy and gene expression we devised a transcription factor regulatory circuitry for DC commitment and subset specification. The circuitry provides the transcription factor hierarchy that drives the sequel MPP-CDP-cDC/pDC, including Irf4, Irf8, Tcf4, Spib and Stat factors. The circuitry also includes feedback loops inferred for individual or multiple factors, which stabilize distinct stages of DC development and DC subsets. In summary, here we describe the basic regulatory circuitry of transcription factors that drives DC development. PMID:26476451

  18. Adiponectin Receptor Signaling on Dendritic Cells Blunts Antitumor Immunity

    PubMed Central

    Tan, Peng H.; Tyrrell, Helen E.J.; Gao, Liquan; Xu, Danmei; Quan, Jianchao; Gill, Dipender; Rai, Lena; Ding, Yunchuan; Plant, Gareth; Chen, Yuan; Xue, John Z.; Handa, Ashok I.; Greenall, Michael J.; Walsh, Kenneth; Xue, Shao-An

    2015-01-01

    Immune escape is a fundamental trait of cancer. Dendritic cells (DC) that interact with T cells represent a crucial site for the development of tolerance to tumor antigens, but there remains incomplete knowledge about how DC-tolerizing signals evolve during tumorigenesis. In this study, we show that DCs isolated from patients with metastatic or locally advanced breast cancer express high levels of the adiponectin receptors AdipoR1 and AdipoR2, which are sufficient to blunt antitumor immunity. Mechanistic investigations of ligand–receptor interactions on DCs revealed novel signaling pathways for each receptor. AdipoR1 stimulated IL10 production by activating the AMPK and MAPKp38 pathways, whereas AdipoR2 modified inflammatory processes by activating the COX-2 and PPARγ pathways. Stimulation of these pathways was sufficient to block activation of NF-κB in DC, thereby attenuating their ability to stimulate antigen-specific T-cell responses. Together, our findings reveal novel insights into how DC-tolerizing signals evolve in cancer to promote immune escape. Furthermore, by defining a critical role for adiponectin signaling in this process, our work suggests new and broadly applicable strategies for immunometabolic therapy in patients with cancer. PMID:25261236

  19. Epigenetic program and transcription factor circuitry of dendritic cell development

    PubMed Central

    Lin, Qiong; Chauvistré, Heike; Costa, Ivan G.; Gusmao, Eduardo G.; Mitzka, Saskia; Hänzelmann, Sonja; Baying, Bianka; Klisch, Theresa; Moriggl, Richard; Hennuy, Benoit; Smeets, Hubert; Hoffmann, Kurt; Benes, Vladimir; Seré, Kristin; Zenke, Martin

    2015-01-01

    Dendritic cells (DC) are professional antigen presenting cells that develop from hematopoietic stem cells through successive steps of lineage commitment and differentiation. Multipotent progenitors (MPP) are committed to DC restricted common DC progenitors (CDP), which differentiate into specific DC subsets, classical DC (cDC) and plasmacytoid DC (pDC). To determine epigenetic states and regulatory circuitries during DC differentiation, we measured consecutive changes of genome-wide gene expression, histone modification and transcription factor occupancy during the sequel MPP-CDP-cDC/pDC. Specific histone marks in CDP reveal a DC-primed epigenetic signature, which is maintained and reinforced during DC differentiation. Epigenetic marks and transcription factor PU.1 occupancy increasingly coincide upon DC differentiation. By integrating PU.1 occupancy and gene expression we devised a transcription factor regulatory circuitry for DC commitment and subset specification. The circuitry provides the transcription factor hierarchy that drives the sequel MPP-CDP-cDC/pDC, including Irf4, Irf8, Tcf4, Spib and Stat factors. The circuitry also includes feedback loops inferred for individual or multiple factors, which stabilize distinct stages of DC development and DC subsets. In summary, here we describe the basic regulatory circuitry of transcription factors that drives DC development. PMID:26476451

  20. Human cytomegalovirus tropism for mucosal myeloid dendritic cells

    PubMed Central

    Hertel, Laura

    2014-01-01

    SUMMARY Human CMV infections are a serious source of morbidity and mortality for immunocompromised patients and for the developing fetus. Because of this, the development of new strategies to prevent CMV acquisition and transmission is a top priority. Myeloid dendritic cells (DC) residing in the oral and nasal mucosae are among the first immune cells to encounter CMV during entry, and greatly contribute to virus dissemination, reactivation from latency, and horizontal spread. Albeit affected by the immunoevasive tactics of CMV, mucosal DC remain potent inducers of cellular and humoral immune responses against this virus. Their natural functions could thus be exploited to generate long-lasting protective immunity against CMV by vaccination via the oro-nasal mucosae. Although related, epithelial Langerhans-type DC (LC) and dermal monocyte-derived DC (MDDC) interact with CMV in dramatically different ways. While immature MDDC are fully permissive to infection, for instance, immature LC are completely resistant. Understanding these differences is essential to design innovative vaccines and new antiviral compounds to protect these cells from CMV infection in vivo. PMID:24888709

  1. Natural antibodies sustain differentiation and maturation of human dendritic cells

    PubMed Central

    Bayry, Jagadeesh; Lacroix-Desmazes, Sébastien; Donkova-Petrini, Vladimira; Carbonneil, Cédric; Misra, Namita; Lepelletier, Yves; Delignat, Sandrine; Varambally, Sooryanarayana; Oksenhendler, Eric; Lévy, Yves; Debré, Marianne; Kazatchkine, Michel D.; Hermine, Olivier; Kaveri, Srini V.

    2004-01-01

    The differentiation and maturation of dendritic cells (DCs) is governed by various signals in the microenvironment. Monocytes and DCs circulate in peripheral blood, which contains high levels of natural antibodies (NAbs). NAbs are germ-line-encoded and occur in the absence of deliberate immunization or microbial aggression. To assess the importance of NAbs in the milieu on DC development, we examined the status of DCs in patients with X-linked agammaglobulinemia, a disease characterized by paucity of B cells and circulating antibodies. We demonstrate that the in vitro differentiation of DCs is severely impaired in these patients, at least in part because of low levels of circulating NAbs. We identified NAbs reactive with the CD40 molecule as an important component that participates in the development of DCs. CD40-reactive NAbs restored normal phenotypes of DCs in patients. The maturation process induced by CD40-reactive NAbs was accompanied by an increased IL-10 and decreased IL-12 production. The transcription factor analysis revealed distinct signaling pathways operated by CD40-reactive NAbs compared to those by CD40 ligand. These results suggest that B cells promote bystander DC development through NAbs and the interaction between NAbs and DCs may play a role in steady-state migration of DCs. PMID:15381781

  2. ASB2α regulates migration of immature dendritic cells.

    PubMed

    Lamsoul, Isabelle; Métais, Arnaud; Gouot, Emmanuelle; Heuzé, Mélina L; Lennon-Duménil, Ana-Maria; Moog-Lutz, Christel; Lutz, Pierre G

    2013-07-25

    The actin-binding protein filamins (FLNs) are major organizers of the actin cytoskeleton. They control the elasticity and stiffness of the actin network and provide connections with the extracellular microenvironment by anchoring transmembrane receptors to the actin filaments. Although numerous studies have revealed the importance of FLN levels, relatively little is known about the regulation of its stability in physiological relevant settings. Here, we show that the ASB2α cullin 5-ring E3 ubiquitin ligase is highly expressed in immature dendritic cells (DCs) and is down-regulated after DC maturation. We further demonstrate that FLNs are substrates of ASB2α in immature DCs and therefore are not stably expressed in these cells, whereas they exhibit high levels of expression in mature DCs. Using ASB2 conditional knockout mice, we show that ASB2α is a critical regulator of cell spreading and podosome rosette formation in immature DCs. Furthermore, we show that ASB2(-/-) immature DCs exhibit reduced matrix-degrading function leading to defective migration. Altogether, our results point to ASB2α and FLNs as newcomers in DC biology. PMID:23632887

  3. Prospective Clinical Testing of Regulatory Dendritic Cells in Organ Transplantation

    PubMed Central

    Thomson, Angus W.; Zahorchak, Alan F.; Ezzelarab, Mohamed B.; Butterfield, Lisa H.; Lakkis, Fadi G.; Metes, Diana M.

    2016-01-01

    Dendritic cells (DC) are rare, professional antigen-presenting cells with ability to induce or regulate alloimmune responses. Regulatory DC (DCreg) with potential to down-modulate acute and chronic inflammatory conditions that occur in organ transplantation can be generated in vitro under a variety of conditions. Here, we provide a rationale for evaluation of DCreg therapy in clinical organ transplantation with the goal of promoting sustained, donor-specific hyporesponsiveness, while lowering the incidence and severity of rejection and reducing patients’ dependence on anti-rejection drugs. Generation of donor- or recipient-derived DCreg that suppress T cell responses and prolong transplant survival in rodents or non-human primates has been well-described. Recently, good manufacturing practice (GMP)-grade DCreg have been produced at our Institution for prospective use in human organ transplantation. We briefly review experience of regulatory immune therapy in organ transplantation and describe our experience generating and characterizing human monocyte-derived DCreg. We propose a phase I/II safety study in which the influence of donor-derived DCreg combined with conventional immunosuppression on subclinical and clinical rejection and host alloimmune responses will be examined in detail. PMID:26858719

  4. Immunomodulation of phloretin by impairing dendritic cell activation and function.

    PubMed

    Lin, Chi-Chen; Chu, Ching-Liang; Ng, Chin-Sheng; Lin, Ching-Yen; Chen, Der-Yuan; Pan, I-Hong; Huang, Kao-Jean

    2014-05-01

    Dietary compounds in fruits and vegetables have been shown to exert many biological activities. In addition to antioxidant effects, a number of flavonoids are able to modulate inflammatory responses. Here, we demonstrated that phloretin (PT), a natural dihydrochalcone found in many fruits, suppressed the activation and function of mouse dendritic cells (DCs). Phloretin disturbed the multiple intracellular signaling pathways in DCs induced by the Toll-like receptor 4 (TLR4) agonist lipopolysaccharide (LPS), including ROS, MAPKs (ERK, JNK, p38 MAPK), and NF-κB, and thereby reducing the production of inflammatory cytokines and chemokines. Phloretin also effectively suppressed the activation of DCs treated with different dosages of LPS or various TLR agonists. The LPS-induced DC maturation was attenuated by phloretin because the expression levels of the MHC class II and the co-stimulatory molecules were down-regulated, which then inhibited the LPS-stimulating DCs and the subsequent naïve T cell activation in a mixed lymphocyte reaction. Moreover, in vivo administration of phloretin suppressed the phenotypic maturation of the LPS-challenged splenic DCs and decreased the IFN-γ production from the activated CD4 T cells. Thus, we suggest that phloretin may potentially be an immunomodulator by impairing the activation and function of DCs and phloretin-contained fruits may be helpful in the improvement of inflammation and autoimmune diseases. PMID:24651121

  5. Analysis of proteomic profiles and functional properties of human peripheral blood myeloid dendritic cells, monocyte-derived dendritic cells and the dendritic cell-like KG-1 cells reveals distinct characteristics

    PubMed Central

    2007-01-01

    Background Dendritic cells (DCs) are specialized antigen presenting cells that play a pivotal role in bridging innate and adaptive immune responses. Given the scarcity of peripheral blood myeloid dendritic cells (mDCs) investigators have used different model systems for studying DC biology. Monocyte-derived dendritic cells (moDCs) and KG-1 cells are routinely used as mDC models, but a thorough comparison of these cells has not yet been carried out, particularly in relation to their proteomes. We therefore sought to run a comparative study of the proteomes and functional properties of these cells. Results Despite general similarities between mDCs and the model systems, moDCs and KG-1 cells, our findings identified some significant differences in the proteomes of these cells, and the findings were confirmed by ELISA detection of a selection of proteins. This was particularly noticeable with proteins involved in cell growth and maintenance (for example, fibrinogen γ chain (FGG) and ubiquinol cytochrome c) and cell-cell interaction and integrity (for example, fascin and actin). We then examined the surface phenotype, cytokine profile, endocytic and T-cell-activation ability of these cells in support of the proteomic data, and obtained confirmatory evidence for differences in the maturation status and functional attributes between mDCs and the two DC models. Conclusion We have identified important proteomic and functional differences between mDCs and two DC model systems. These differences could have major functional implications, particularly in relation to DC-T cell interactions, the so-called immunological synapse, and, therefore, need to be considered when interpreting data obtained from model DC systems. PMID:17331236

  6. Dendritic branching angles of pyramidal cells across layers of the juvenile rat somatosensory cortex.

    PubMed

    Leguey, Ignacio; Bielza, Concha; Larrañaga, Pedro; Kastanauskaite, Asta; Rojo, Concepción; Benavides-Piccione, Ruth; DeFelipe, Javier

    2016-09-01

    The characterization of the structural design of cortical microcircuits is essential for understanding how they contribute to function in both health and disease. Since pyramidal neurons represent the most abundant neuronal type and their dendritic spines constitute the major postsynaptic elements of cortical excitatory synapses, our understanding of the synaptic organization of the neocortex largely depends on the available knowledge regarding the structure of pyramidal cells. Previous studies have identified several apparently common rules in dendritic geometry. We study the dendritic branching angles of pyramidal cells across layers to further shed light on the principles that determine the geometric shapes of these cells. We find that the dendritic branching angles of pyramidal cells from layers II-VI of the juvenile rat somatosensory cortex suggest common design principles, despite the particular morphological and functional features that are characteristic of pyramidal cells in each cortical layer. J. Comp. Neurol. 524:2567-2576, 2016. © 2016 Wiley Periodicals, Inc. PMID:26850576

  7. Paraneoplastic pemphigus associated with follicular dendritic cell sarcoma: report of a case and review of literature

    PubMed Central

    Su, Zheng; Liu, Gaojie; Liu, Jianping; Fang, Tingfeng; Zeng, Yunjie; Zhang, Huayao; Yang, Shanglin; Wang, Yang; Zhang, Junmin; Wei, Jinxing; Li, Yingru; Guo, Youfeng

    2015-01-01

    Follicular dendritic cell sarcoma (FDCS) is a rare tumor associated with paraneoplastic pemphigus. It is Blame drenchs auxiliary cell tumor which is derived from the peripheral lymphoid tissues. Throughout the world, several patients of paraneoplastic pemphigus associated follicular dendritic cell sarcoma were reported in the literature, but mostly originated from the neck lymph nodes, and extranodal origin of follicular dendritic sarcoma was rarely reported. Also, so far we have found that the malignant degree of all patients diagnosed with malignant tumors have been reported were low and after combined treatment of surgery, radiotherapy and chemotherapy, most of the prognosis was good. However, here we present a patient of paraneoplastic pemphigus associated with follicular dendritic cell sarcoma origined from outside of the lymph nodes and had high tumor malignant degree for its unclear cell boundaries, obvious atypia and mitoses and the patient’s state became progressively deteriorate after operation. PMID:26722384

  8. Exploiting the Role of Endogenous Lymphoid-Resident Dendritic Cells in the Priming of NKT Cells and CD8+ T Cells to Dendritic Cell-Based Vaccines

    PubMed Central

    Petersen, Troels R.; Sika-Paotonu, Dianne; Knight, Deborah A.; Simkins, Helen M. A.; Hermans, Ian F.

    2011-01-01

    Transfer of antigen between antigen-presenting cells (APCs) is potentially a physiologically relevant mechanism to spread antigen to cells with specialized stimulatory functions. Here we show that specific CD8+ T cell responses induced in response to intravenous administration of antigen-loaded bone marrow-derived dendritic cells (BM-DCs), were ablated in mice selectively depleted of endogenous lymphoid-resident langerin+ CD8α+ dendritic cells (DCs), suggesting that the antigen is transferred from the injected cells to resident APCs. In contrast, antigen-specific CD4+ T cells were primed predominantly by the injected BM-DCs, with only very weak contribution of resident APCs. Crucially, resident langerin+ CD8α+ DCs only contributed to the priming of CD8+ T cells in the presence of maturation stimuli such as intravenous injection of TLR ligands, or by loading the BM-DCs with the glycolipid α-galactosylceramide (α-GalCer) to recruit the adjuvant activity of activated invariant natural killer-like T (iNKT) cells. In fact, injection of α-GalCer-loaded CD1d−/− BM-DCs resulted in potent iNKT cell activation, suggesting that this glycolipid antigen can also be transferred to resident CD1d+ APCs. While iNKT cell activation per se was independent of langerin+ CD8α+ DCs, some iNKT cell-mediated activities were reduced, notably release of IL-12p70 and transactivation of NK cells. We conclude that both protein and glycolipid antigens can be exchanged between distinct DC species. These data suggest that the efficacy of DC-based vaccination strategies may be improved by the incorporation of a systemic maturation signal aimed to engage resident APCs in CD8+ T cell priming, and α-GalCer may be particularly well suited to this purpose. PMID:21483862

  9. Mitochondrial fission protein Drp1 regulates mitochondrial transport and dendritic arborization in cerebellar Purkinje cells.

    PubMed

    Fukumitsu, Kansai; Hatsukano, Tetsu; Yoshimura, Azumi; Heuser, John; Fujishima, Kazuto; Kengaku, Mineko

    2016-03-01

    Mitochondria dynamically change their shape by repeated fission and fusion in response to physiological and pathological conditions. Recent studies have uncovered significant roles of mitochondrial fission and fusion in neuronal functions, such as neurotransmission and spine formation. However, the contribution of mitochondrial fission to the development of dendrites remains controversial. We analyzed the function of the mitochondrial fission GTPase Drp1 in dendritic arborization in cerebellar Purkinje cells. Overexpression of a dominant-negative mutant of Drp1 in postmitotic Purkinje cells enlarged and clustered mitochondria, which failed to exit from the soma into the dendrites. The emerging dendrites lacking mitochondrial transport remained short and unstable in culture and in vivo. The dominant-negative Drp1 affected neither the basal respiratory function of mitochondria nor the survival of Purkinje cells. Enhanced ATP supply by creatine treatment, but not reduced ROS production by antioxidant treatment, restored the hypomorphic dendrites caused by inhibition of Drp1 function. Collectively, our results suggest that Drp1 is required for dendritic distribution of mitochondria and thereby regulates energy supply in growing dendritic branches in developing Purkinje cells. PMID:26689905

  10. Completely resected follicular dendritic cell sarcoma of the posterior mediastinum: report of a case.

    PubMed

    Miyoshi, Ryo; Sonobe, Makoto; Miyamoto, Ei; Date, Hiroshi

    2016-12-01

    Follicular dendritic cell sarcoma is a rare malignant neoplasm originating from follicular dendritic cells, and most of them develop in lymph nodes of the head and neck. One third of follicular dendritic cell sarcomas occur in the extranodal sites such as the tonsils, mesentery, and retroperitoneal organs, but those of mediastinal origin are rare. Here, we present the case of a 16-year-old female with a large follicular dendritic cell sarcoma of posterior mediastinal origin. The tumor was found by a chest X-ray mass examination at her high school, and she had no subjective symptoms or significant past medical history. The tumor was diagnosed as a follicular dendritic cell sarcoma by computed tomography-guided needle biopsy. Although the tumor compressed the mediastinal organs and showed moderate uptake in 18-fluorodeoxyglucose positron emission tomography imaging, it was completely resected through posterolateral incision. Histological examination revealed that spindle-shaped tumor cells formed fascicular or storiform pattern with cellular pleomorphism. By immunohistochemical examination, the tumor cells were found to be positive for CD21 and follicular dendritic cell antigen. Two years after surgery, the patient remains alive with no signs of tumor recurrence. PMID:27001632

  11. Dendritic cells and B cells: unexpected partners in Th2 development.

    PubMed

    León, Beatriz; Ballesteros-Tato, André; Lund, Frances E

    2014-08-15

    Although we have known for decades that B cells contribute to immune responses by secreting Ab, it is now clear that they are more than simply factories for Ig production, and they also play key roles as modulators of T cell-dependent immunity. Indeed, the evidence showing that Ag-presenting and cytokine-producing B cells can alter the magnitude and quality of CD4 T cell responses continues to grow. In this article, we review the data showing that B cells, working in partnership with dendritic cells, regulate the development of Th2 cells and the subsequent allergic response. PMID:25086176

  12. Glycan Sulfation Modulates Dendritic Cell Biology and Tumor Growth.

    PubMed

    El Ghazal, Roland; Yin, Xin; Johns, Scott C; Swanson, Lee; Macal, Monica; Ghosh, Pradipta; Zuniga, Elina I; Fuster, Mark M

    2016-05-01

    In cancer, proteoglycans have been found to play roles in facilitating the actions of growth factors, and effecting matrix invasion and remodeling. However, little is known regarding the genetic and functional importance of glycan chains displayed by proteoglycans on dendritic cells (DCs) in cancer immunity. In lung carcinoma, among other solid tumors, tumor-associated DCs play largely subversive/suppressive roles, promoting tumor growth and progression. Herein, we show that targeting of DC glycan sulfation through mutation in the heparan sulfate biosynthetic enzyme N-deacetylase/N-sulfotransferase-1 (Ndst1) in mice increased DC maturation and inhibited trafficking of DCs to draining lymph nodes. Lymphatic-driven DC migration and chemokine (CCL21)-dependent activation of a major signaling pathway required for DC migration (as measured by phospho-Akt) were sensitive to Ndst1 mutation in DCs. Lewis lung carcinoma tumors in mice deficient in Ndst1 were reduced in size. Purified CD11c+ cells from the tumors, which contain the tumor-infiltrating DC population, showed a similar phenotype in mutant cells. These features were replicated in mice deficient in syndecan-4, the major heparan sulfate proteoglycan expressed on the DC surface: Tumors were growth-impaired in syndecan-4-deficient mice and were characterized by increased infiltration by mature DCs. Tumors on the mutant background also showed greater infiltration by NK cells and NKT cells. These findings indicate the genetic importance of DC heparan sulfate proteoglycans in tumor growth and may guide therapeutic development of novel strategies to target syndecan-4 and heparan sulfate in cancer. PMID:27237321

  13. Diesel-Enriched Particulate Matter Functionally Activates Human Dendritic Cells

    PubMed Central

    Porter, Michael; Karp, Matthew; Killedar, Smruti; Bauer, Stephen M.; Guo, Jia; Williams, D'Ann; Breysse, Patrick; Georas, Steve N.; Williams, Marc A.

    2007-01-01

    Epidemiologic studies have associated exposure to airborne particulate matter (PM) with exacerbations of asthma. It is unknown how different sources of PM affect innate immunity. We sought to determine how car- and diesel exhaust–derived PM affects dendritic cell (DC) activation. DC development was modeled using CD34+ hematopoietic progenitors. Airborne PM was collected from exhaust plenums of Fort McHenry Tunnel providing car-enriched particles (CEP) and diesel-enriched particles (DEP). DC were stimulated for 48 hours with CEP, DEP, CD40-ligand, or lipopolysaccharide. DC activation was assessed by flow cytometry, enzyme-linked immunosorbent assay, and standard culture techniques. DEP increased uptake of fluorescein isothiocyanate–dextran (a model antigen) by DC. Diesel particles enhanced cell-surface expression of co-stimulatory molecules (e.g., CD40 [P < 0.01] and MHC class II [P < 0.01]). By contrast, CEP poorly affected antigen uptake and expression of cell surface molecules, and did not greatly affect cytokine secretion by DC. However, DEP increased production of TNF, IL-6, and IFN-γ (P < 0.01), IL-12 (P < 0.05), and vascular endothelial growth factor (P < 0.001). In co-stimulation assays of PM-exposed DC and alloreactive CD4+ T cells, both CEP and DEP directed a Th2-like pattern of cytokine production (e.g., enhanced IL-13 and IL-18 and suppressed IFN-γ production). CD4+ T cells were not functionally activated on exposure to either DEP or CEP. Car- and diesel-enriched particles exert a differential effect on DC activation. Our data support the hypothesis that DEP (and to a lesser extent CEP) regulate important functional aspects of human DC, supporting an adjuvant role for this material. PMID:17630318

  14. Effects of TCDD on the Fate of Naive Dendritic Cells

    PubMed Central

    Bankoti, Jaishree; Burnett, Andrea; Navarro, Severine; Miller, Andrea K.; Rase, Ben; Shepherd, David M.

    2010-01-01

    The environmental contaminant, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), causes immune suppression via activation of the aryl hydrocarbon receptor. Dendritic cells (DCs), the professional antigen-presenting cells in the immune system, are adversely affected by TCDD. We hypothesized that TCDD alters DC homeostasis, resulting in a loss of DCs in naive mice. To test this hypothesis, C57Bl/6 mice were gavaged with either vehicle or an immunosuppressive dose of TCDD (15 μg/kg). TCDD exposure decreased the frequency and number of splenic CD11chigh DCs on day 7 when compared with vehicle-treated controls. TCDD increased the expression of CD86 and CD54, while decreasing the frequency of splenic CD11chigh DCs expressing CD11a and major histocompatibility complex (MHC) class II. Moreover, TCDD selectively decreased the CD11chighCD8α−33D1+ splenic DCs specialized at activating CD4+ T cells but did not affect the regulatory CD11chighCD8α+DEC205+ splenic DCs. TCDD did not alter the number or frequency of CD11clow splenic DCs but decreased their MHC class II and CD11a expression. Loss of splenic CD11chigh DCs was independent of Fas-mediated apoptosis and was not due to alterations in the numbers of common DC precursors in the bone marrow or their ability to generate steady-state DCs in vitro. Instead, increased CCR7 expression on CD11chigh DCs suggested involvement of a migratory event. Popliteal and brachial lymph node CD11c+ cells showed elevated levels of MHC class II and CD40 following TCDD exposure. Collectively, this study shows the presence of a TCDD-sensitive splenic DC subpopulation in naive mice, suggesting that TCDD may induce suppression of T-cell-mediated immunity by disrupting DC homeostasis. PMID:20211938

  15. Biotin deficiency enhances the inflammatory response of human dendritic cells.

    PubMed

    Agrawal, Sudhanshu; Agrawal, Anshu; Said, Hamid M

    2016-09-01

    The water-soluble biotin (vitamin B7) is indispensable for normal human health. The vitamin acts as a cofactor for five carboxylases that are critical for fatty acid, glucose, and amino acid metabolism. Biotin deficiency is associated with various diseases, and mice deficient in this vitamin display enhanced inflammation. Previous studies have shown that biotin affects the functions of adaptive immune T and NK cells, but its effect(s) on innate immune cells is not known. Because of that and because vitamins such as vitamins A and D have a profound effect on dendritic cell (DC) function, we investigated the effect of biotin levels on the functions of human monocyte-derived DCs. Culture of DCs in a biotin-deficient medium (BDM) and subsequent activation with LPS resulted in enhanced secretion of the proinflammatory cytokines TNF-α, IL-12p40, IL-23, and IL-1β compared with LPS-activated DCs cultured in biotin-sufficient (control) and biotin-oversupplemented media. Furthermore, LPS-activated DCs cultured in BDM displayed a significantly higher induction of IFN-γ and IL-17 indicating Th1/Th17 bias in T cells compared with cells maintained in biotin control or biotin-oversupplemented media. Investigations into the mechanisms suggested that impaired activation of AMP kinase in DCs cultured in BDM may be responsible for the observed increase in inflammatory responses. In summary, these results demonstrate for the first time that biotin deficiency enhances the inflammatory responses of DCs. This may therefore be one of the mechanism(s) that mediates the observed inflammation that occurs in biotin deficiency. PMID:27413170

  16. Impaired dendritic cell function in a spontaneous autoimmune polyneuropathy.

    PubMed

    Quan, Songhua; Kim, Hye-Jung; Dukala, Danuta; Sheng, Jian Rong; Soliven, Betty

    2015-05-01

    Spontaneous autoimmune polyneuropathy (SAP) in B7-2 knockout NOD mice mimics the progressive form of chronic inflammatory demyelinating polyradiculoneuropathy, and is mediated by myelin protein zero (P0)-reactive Th1 cells. In this study, we focused on the effect of B7-2 deletion on the function of dendritic cells (DCs) within the context of SAP. We found that development of SAP was associated with a preponderance or increase of CD11b(+) DCs in peripheral lymph nodes and sciatic nerves. B7-2 deletion led to altered immunophenotypic properties that differ between CD11b(+) DCs and CD8α(+) DCs. Both DC subsets from B7-2 knockout NOD mice exhibited impaired capacity to capture fluorophore-labeled myelin P0, but diminished Ag-presenting function was observed only in CD11b(+) DCs. Clinical assessment, electrophysiologic studies, and splenocyte proliferation studies revealed that absence of B7-2 on DCs was sufficient to cause impaired ability to induce tolerance to P0, which could be overcome by preconditioning with IL-10. Tolerance induction by Ag-pulsed wild-type NOD DCs was dependent on IL-10 and was associated with increased CD4(+) regulatory T cells, whereas tolerance induction by IL-10-conditioned B7-2-deficient DCs was associated with increased percentages of both regulatory T cells and B10 cells in the spleen. We conclude that B7-2 deletion has an impact on the distribution of DC subsets in lymphoid organs and alters the expression of costimulatory molecules, but functional consequences are not uniform across DC subsets. Defective tolerance induction in the absence of B7-2 can be restored by preconditioning of DCs with IL-10. PMID:25825437

  17. A multi-laboratory comparison of blood dendritic cell populations

    PubMed Central

    Fromm, Phillip Dieter; Kupresanin, Fiona; Brooks, Anna Elizabeth Stella; Dunbar, Peter Rodney; Haniffa, Muzifilla; Hart, Derek Nigel John; Clark, Georgina Jane

    2016-01-01

    HLDA10 collated a panel of monoclonal antibodies (mAbs) that primarily recognised molecules on human myeloid cell and dendritic cell (DC) populations. As part of the studies, we validated a backbone of mAbs to delineate monocyte and DC populations from peripheral blood. The mAb backbone allowed identification of monocyte and DC subsets using fluorochromes that were compatible with most ‘off the shelf' or routine flow cytometers. Three laboratories used this mAb backbone to assess the HLDA10 panel on blood monocytes and DCs. Each laboratory was provided with enough mAbs to perform five repeat experiments. The data were collated and analysed using Spanning-tree Progression Analysis of Density-normalised Events (SPADE). The data were interrogated for inter- and intra-laboratory variability. The results highlight the definition of DC populations using current readily available reagents. This collaborative process provides the broader scientific community with an invaluable data set that validates mAbs to leucocyte surface molecules. PMID:27195111

  18. Dendritic Cells and Multiple Sclerosis: Disease, Tolerance and Therapy

    PubMed Central

    Mohammad, Mohammad G.; Hassanpour, Masoud; Tsai, Vicky W. W.; Li, Hui; Ruitenberg, Marc J.; Booth, David R.; Serrats, Jordi; Hart, Prue H.; Symonds, Geoffrey P.; Sawchenko, Paul E.; Breit, Samuel N.; Brown, David A.

    2013-01-01

    Multiple sclerosis (MS) is a devastating neurological disease that predominantly affects young adults resulting in severe personal and economic impact. The majority of therapies for this disease were developed in, or are beneficial in experimental autoimmune encephalomyelitis (EAE), the animal model of MS. While known to target adaptive anti-CNS immune responses, they also target, the innate immune arm. This mini-review focuses on the role of dendritic cells (DCs), the professional antigen presenting cells of the innate immune system. The evidence for a role for DCs in the appropriate regulation of anti-CNS autoimmune responses and their role in MS disease susceptibility and possible therapeutic utility are discussed. Additionally, the current controversy regarding the evidence for the presence of functional DCs in the normal CNS is reviewed. Furthermore, the role of CNS DCs and potential routes of their intercourse between the CNS and cervical lymph nodes are considered. Finally, the future role that this nexus between the CNS and the cervical lymph nodes might play in site directed molecular and cellular therapy for MS is outlined. PMID:23271370

  19. Dendritic cell-based vaccines: barriers and opportunities

    PubMed Central

    Cintolo, Jessica A; Datta, Jashodeep; Mathew, Sarah J; Czerniecki, Brian J

    2014-01-01

    Dendritic cells (DCs) have several characteristics that make them an ideal vehicle for tumor vaccines, and with the first US FDA-approved DC-based vaccine in use for the treatment of prostate cancer, this technology has become a promising new therapeutic option. However, DC-based vaccines face several barriers that have limited their effectiveness in clinical trials. A major barrier includes the activation state of the DC. Both DC lineage and maturation signals must be selected to optimize the antitumor response and overcome immunosuppressive effects of the tumor microenvironment. Another barrier to successful vaccination is the selection of target antigens that will activate both CD8+ and CD4+ T cells in a potent, immune-specific manner. Finally, tumor progression and immune dysfunction limit vaccine efficacy in advanced stages, which may make DC-based vaccines more efficacious in treating early-stage disease. This review underscores the scientific basis and advances in the development of DC-based vaccines, focuses on current barriers to success and highlights new research opportunities to address these obstacles. PMID:23130928

  20. Trial watch: Dendritic cell-based anticancer therapy

    PubMed Central

    Bloy, Norma; Pol, Jonathan; Aranda, Fernando; Eggermont, Alexander; Cremer, Isabelle; Fridman, Wolf Hervé; Fučíková, Jitka; Galon, Jérôme; Tartour, Eric; Spisek, Radek; Dhodapkar, Madhav V.; Zitvogel, Laurence; Kroemer, Guido; Galluzzi, Lorenzo

    2014-01-01

    The use of patient-derived dendritic cells (DCs) as a means to elicit therapeutically relevant immune responses in cancer patients has been extensively investigated throughout the past decade. In this context, DCs are generally expanded, exposed to autologous tumor cell lysates or loaded with specific tumor-associated antigens (TAAs), and then reintroduced into patients, often in combination with one or more immunostimulatory agents. As an alternative, TAAs are targeted to DCs in vivo by means of monoclonal antibodies, carbohydrate moieties or viral vectors specific for DC receptors. All these approaches have been shown to (re)activate tumor-specific immune responses in mice, often mediating robust therapeutic effects. In 2010, the first DC-based preparation (sipuleucel-T, also known as Provenge®) has been approved by the US Food and Drug Administration (FDA) for use in humans. Reflecting the central position occupied by DCs in the regulation of immunological tolerance and adaptive immunity, the interest in harnessing them for the development of novel immunotherapeutic anticancer regimens remains high. Here, we summarize recent advances in the preclinical and clinical development of DC-based anticancer therapeutics. PMID:25941593

  1. CD83 and GRASP55 interact in human dendritic cells.

    PubMed

    Stein, Marcello F; Blume, Katja; Heilingloh, Christiane S; Kummer, Mirko; Biesinger, Brigitte; Sticht, Heinrich; Steinkasserer, Alexander

    2015-03-27

    CD83 is one of the best known surface markers for mature human dendritic cells (DCs). The full-length 45 kDa type-I membrane-bound form (mbCD83) is strongly glycosylated upon DCs maturation. As co-stimulatory properties of CD83 are attributed to mbCD83 surface expression is required for efficient T-cell stimulation by mature DCs. By yeast two-hybrid screening, we were able to identify GRASP55 as interaction partner of CD83. DCs maturation induces endogenous CD83 protein expression with simultaneous regulation of CD83 glycosylation, interaction and co-localization with GRASP55 and CD83 surface exposure. GRASP55 is especially known for its role in maintaining Golgi architecture, but also plays a role in Golgi transport of specific cargo proteins bearing a C-terminal valine residue. Here we additionally demonstrate that binding of CD83 and GRASP55 rely on the C-terminal TELV-motif of CD83. Mutation of this TELV-motif not only disrupted binding to GRASP55, but also altered the glycosylation pattern of CD83 and reduced its membrane expression. Here we show for the first time that GRASP55 interacts with CD83 shortly after induction of DC maturation and that this interaction plays a role in CD83 glycosylation as well as in surface expression of CD83 on DCs. PMID:25701785

  2. Evidence of dysregulation of dendritic cells in primary HIV infection

    PubMed Central

    Sabado, Rachel Lubong; O'Brien, Meagan; Subedi, Abhignya; Qin, Li; Hu, Nan; Taylor, Elizabeth; Dibben, Oliver; Stacey, Andrea; Fellay, Jacques; Shianna, Kevin V.; Siegal, Frederick; Shodell, Michael; Shah, Kokila; Larsson, Marie; Lifson, Jeffrey; Nadas, Arthur; Marmor, Michael; Hutt, Richard; Margolis, David; Garmon, Donald; Markowitz, Martin; Valentine, Fred; Borrow, Persephone

    2010-01-01

    Myeloid and plasmacytoid dendritic cells (DCs) are important mediators of both innate and adaptive immunity against pathogens such as HIV. During the course of HIV infection, blood DC numbers fall substantially. In the present study, we sought to determine how early in HIV infection the reduction occurs and whether the remaining DC subsets maintain functional capacity. We find that both myeloid DC and plasmacytoid DC levels decline very early during acute HIV in-fection. Despite the initial reduction in numbers, those DCs that remain in circulation retain their function and are able to stimulate allogeneic T-cell responses, and up-regulate maturation markers plus produce cytokines/chemokines in response to stimulation with TLR7/8 agonists. Notably, DCs from HIV-infected subjects produced significantly higher levels of cytokines/chemokines in response to stimulation with TLR7/8 agonists than DCs from uninfected controls. Further examination of gene expression profiles indicated in vivo activation, either directly or indirectly, of DCs during HIV infection. Taken together, our data demonstrate that despite the reduction in circulating DC numbers, those that remain in the blood display hyperfunctionality and implicates a possible role for DCs in promoting chronic immune activation. PMID:20693428

  3. Sirt6 regulates dendritic cell differentiation, maturation, and function

    PubMed Central

    Lasigliè, Denise; Boero, Silvia; Bauer, Inga; Morando, Sara; Damonte, Patrizia; Cea, Michele; Monacelli, Fiammetta; Odetti, Paizio; Ballestrero, Alberto; Uccelli, Antonio; Mostoslavsky, Raul; Poggi, Alessandro; Nencioni, Alessio

    2016-01-01

    Dendritic cells (DCs) are antigen-presenting cells that critically influence decisions about immune activation or tolerance. Impaired DC function is at the core of common chronic disorders and contributes to reduce immunocompetence during aging. Knowledge on the mechanisms regulating DC generation and function is necessary to understand the immune system and to prevent disease and immunosenescence. Here we show that the sirtuin Sirt6, which was previously linked to healthspan promotion, stimulates the development of myeloid, conventional DCs (cDCs). Sirt6-knockout (Sirt6KO) mice exhibit low frequencies of bone marrow cDC precursors and low yields of bone marrow-derived cDCs compared to wild-type (WT) animals. Sirt6KO cDCs express lower levels of class II MHC, of costimulatory molecules, and of the chemokine receptor CCR7, and are less immunostimulatory compared to WT cDCs. Similar effects in terms of differentiation and immunostimulatory capacity were observed in human monocyte-derived DCs in response to SIRT6 inhibition. Finally, while Sirt6KO cDCs show an overall reduction in their ability to produce IL-12, TNF-α and IL-6 secretion varies dependent on the stimulus, being reduced in response to CpG, but increased in response to other Toll-like receptor ligands. In conclusion, Sirt6 plays a crucial role in cDC differentiation and function and reduced Sirt6 activity may contribute to immunosenescence. PMID:26761436

  4. Dendritic Cell-Based Vaccine Against Fungal Infection.

    PubMed

    Ueno, Keigo; Urai, Makoto; Ohkouchi, Kayo; Miyazaki, Yoshitsugu; Kinjo, Yuki

    2016-01-01

    Several pathogenic fungi, including Cryptococcus gattii, Histoplasma capsulatum, Coccidioides immitis, and Penicillium marneffei, cause serious infectious diseases in immunocompetent humans. However, currently, prophylactic and therapeutic vaccines are not clinically used. In particular, C. gattii is an emerging pathogen and thus far protective immunity against this pathogen has not been well characterized. Experimental vaccines such as component and attenuated live vaccines have been used as tools to study protective immunity against fungal infection. Recently, we developed a dendritic cell (DC)-based vaccine to study protective immunity against pulmonary infection by highly virulent C. gattii strain R265 that was clinically isolated from bronchial washings of infected patients during the Vancouver Island outbreak. In this approach, bone marrow-derived DCs (BMDCs) are pulsed with heat-killed C. gattii and then transferred into mice prior to intratracheal infection. This DC vaccine significantly increases interleukin 17A (IL-17A)-, interferon gamma (IFN-γ)-, and tumor necrosis factor alpha (TNF-α)-producing T cells in the lungs and spleen and ameliorates the pathology, fungal burden, and mortality following C. gattii infection. This approach may result in the development of a new means of controlling lethal fungal infections. In this chapter, we describe the procedures of DC vaccine preparation and murine pulmonary infection model for analysis of immune response against C. gattii. PMID:27076152

  5. Immunity to Pathogens Taught by Specialized Human Dendritic Cell Subsets

    PubMed Central

    Geginat, Jens; Nizzoli, Giulia; Paroni, Moira; Maglie, Stefano; Larghi, Paola; Pascolo, Steve; Abrignani, Sergio

    2015-01-01

    Dendritic cells (DCs) are specialized antigen-presenting cells (APCs) that have a key role in immune responses because they bridge the innate and adaptive arms of the immune system. They mature upon recognition of pathogens and upregulate MHC molecules and costimulatory receptors to activate antigen-specific CD4+ and CD8+ T cells. It is now well established that DCs are not a homogeneous population but are composed of different subsets with specialized functions in immune responses to specific pathogens. Upon viral infections, plasmacytoid DCs (pDCs) rapidly produce large amounts of IFN-α, which has potent antiviral functions and activates several other immune cells. However, pDCs are not particularly potent APCs and induce the tolerogenic cytokine IL-10 in CD4+ T cells. In contrast, myeloid DCs (mDCs) are very potent APCs and possess the unique capacity to prime naive T cells and consequently to initiate a primary adaptive immune response. Different subsets of mDCs with specialized functions have been identified. In mice, CD8α+ mDCs capture antigenic material from necrotic cells, secrete high levels of IL-12, and prime Th1 and cytotoxic T-cell responses to control intracellular pathogens. Conversely, CD8α− mDCs preferentially prime CD4+ T cells and promote Th2 or Th17 differentiation. BDCA-3+ mDC2 are the human homologue of CD8α+ mDCs, since they share the expression of several key molecules, the capacity to cross-present antigens to CD8+ T-cells and to produce IFN-λ. However, although several features of the DC network are conserved between humans and mice, the expression of several toll-like receptors as well as the production of cytokines that regulate T-cell differentiation are different. Intriguingly, recent data suggest specific roles for human DC subsets in immune responses against individual pathogens. The biology of human DC subsets holds the promise to be exploitable in translational medicine, in particular for the development of vaccines against

  6. Immunity to Pathogens Taught by Specialized Human Dendritic Cell Subsets.

    PubMed

    Geginat, Jens; Nizzoli, Giulia; Paroni, Moira; Maglie, Stefano; Larghi, Paola; Pascolo, Steve; Abrignani, Sergio

    2015-01-01

    Dendritic cells (DCs) are specialized antigen-presenting cells (APCs) that have a key role in immune responses because they bridge the innate and adaptive arms of the immune system. They mature upon recognition of pathogens and upregulate MHC molecules and costimulatory receptors to activate antigen-specific CD4(+) and CD8(+) T cells. It is now well established that DCs are not a homogeneous population but are composed of different subsets with specialized functions in immune responses to specific pathogens. Upon viral infections, plasmacytoid DCs (pDCs) rapidly produce large amounts of IFN-α, which has potent antiviral functions and activates several other immune cells. However, pDCs are not particularly potent APCs and induce the tolerogenic cytokine IL-10 in CD4(+) T cells. In contrast, myeloid DCs (mDCs) are very potent APCs and possess the unique capacity to prime naive T cells and consequently to initiate a primary adaptive immune response. Different subsets of mDCs with specialized functions have been identified. In mice, CD8α(+) mDCs capture antigenic material from necrotic cells, secrete high levels of IL-12, and prime Th1 and cytotoxic T-cell responses to control intracellular pathogens. Conversely, CD8α(-) mDCs preferentially prime CD4(+) T cells and promote Th2 or Th17 differentiation. BDCA-3(+) mDC2 are the human homologue of CD8α(+) mDCs, since they share the expression of several key molecules, the capacity to cross-present antigens to CD8(+) T-cells and to produce IFN-λ. However, although several features of the DC network are conserved between humans and mice, the expression of several toll-like receptors as well as the production of cytokines that regulate T-cell differentiation are different. Intriguingly, recent data suggest specific roles for human DC subsets in immune responses against individual pathogens. The biology of human DC subsets holds the promise to be exploitable in translational medicine, in particular for the development of

  7. Dendritic Cells in Esophageal Adenocarcinoma: The Currently Available Information and Possibilities to use Dendritic Cells for Immunotherapeutic Approaches.

    PubMed

    Chistiakov, Dimitry A; Orekhov, Alexander N; Bobryshev, Yuri V

    2016-01-01

    Esophageal adenocarcinoma (EAC) is the second frequent cancer of the esophagus. Barrett's esophagus (BE) takes precedence over EAC. BE is a metaplastic change of the stratified squamous epithelium to the intestinal columnar epithelium due to the acidic gastrointestinal reflux. Further, the disease takes the hyperplastic stage followed by EAC. An initial immune response is an essential reaction of a body to an occurrence of alien/modified cells to be removed. It has been appreciated that an inflammatory reaction occurs in the early stages of EAC or even in BE. Dendritic cells (DCs) play a key role in a frontier of an immune response due to their advanced ability to recognize foreign antigens and mobilize naive T cells to effectors. However, in a cancer condition, tumor-delivered immunosuppression occurs in a variety of mechanisms that alter/switch the functionality of DCs from immune activating to immune suppressive cells. In this brief review, we consider tumor-induced paths of a capacity of tumor cells to down-regulate DCs, with a focus on EAC, and also discuss a possibility to use DCs for immunotherapeutic approaches. Indeed, DCs represent a promising tool for developing new immunotherapeutic approaches for cancer treatment including EAC. It has been reported to achieve effective DC-mediated immune responses by raising anti-tumor cytotoxic T cell responses against multiple cancer antigens through loading DCs with total tumor RNA. However, more studies should be performed in order to understand a precise role in tumor-induced mechanisms of DC suppression in BE/EAC. Likely, these mechanisms should involve general carcinogenic and EAC-specific pathways. PMID:26561054

  8. Distinct Cytokine Profiles of Neonatal Natural Killer T Cells after Expansion with Subsets of Dendritic Cells

    PubMed Central

    Kadowaki, Norimitsu; Antonenko, Svetlana; Ho, Stephen; Rissoan, Marie-Clotilde; Soumelis, Vassili; Porcelli, Steven A.; Lanier, Lewis L.; Liu, Yong-Jun

    2001-01-01

    Natural killer T (NKT) cells are a highly conserved subset of T cells that have been shown to play a critical role in suppressing T helper cell type 1–mediated autoimmune diseases and graft versus host disease in an interleukin (IL)-4–dependent manner. Thus, it is important to understand how the development of IL-4– versus interferon (IFN)-γ–producing NKT cells is regulated. Here, we show that NKT cells from adult blood and those from cord blood undergo massive expansion in cell numbers (500–70,000-fold) during a 4-wk culture with IL-2, IL-7, phytohemagglutinin, anti-CD3, and anti-CD28 mAbs. Unlike adult NKT cells that preferentially produce both IL-4 and IFN-γ, neonatal NKT cells preferentially produce IL-4 after polyclonal activation. Addition of type 2 dendritic cells (DC2) enhances the development of neonatal NKT cells into IL-4+IFN-γ− NKT2 cells, whereas addition of type 1 dendritic cells (DC1) induces polarization towards IL-4−IFN-γ+ NKT1 cells. Adult NKT cells display limited plasticity for polarization induced by DC1 or DC2. Thus, newly generated NKT cells may possess the potent ability to develop into IL-4+IFN-γ− NKT2 cells in response to appropriate stimuli and may thereafter acquire the tendency to produce both IL-4 and IFN-γ. PMID:11369793

  9. Modulation of respiratory dendritic cells during Klebsiella pneumonia infection

    PubMed Central

    2013-01-01

    Background Klebsiella pneumoniae is a leading cause of severe hospital-acquired respiratory tract infections and death but little is known regarding the modulation of respiratory dendritic cell (DC) subsets. Plasmacytoid DC (pDC) are specialized type 1 interferon producing cells and considered to be classical mediators of antiviral immunity. Method By using multiparameter flow cytometry analysis we have analysed the modulation of respiratory DC subsets after intratracheal Klebsiella pneumonia infection. Results Data indicate that pDCs and MoDC were markedly elevated in the post acute pneumonia phase when compared to mock-infected controls. Analysis of draining mediastinal lymph nodes revealed a rapid increase of activated CD103+ DC, CD11b+ DC and MoDC within 48 h post infection. Lung pDC identification during bacterial pneumonia was confirmed by extended phenotyping for 120G8, mPDCA-1 and Siglec-H expression and by demonstration of high Interferon-alpha producing capacity after cell sorting. Cytokine expression analysis of ex vivo-sorted respiratory DC subpopulations from infected animals revealed elevated Interferon-alpha in pDC, elevated IFN-gamma, IL-4 and IL-13 in CD103+ DC and IL-19 and IL-12p35 in CD11b+ DC subsets in comparison to CD11c+ MHC-class IIlow cells indicating distinct functional roles. Antigen-specific naive CD4+ T cell stimulatory capacity of purified respiratory DC subsets was analysed in a model system with purified ovalbumin T cell receptor transgenic naive CD4+ responder T cells and respiratory DC subsets, pulsed with ovalbumin and matured with Klebsiella pneumoniae lysate. CD103+ DC and CD11b+ DC subsets represented the most potent naive CD4+ T helper cell activators. Conclusion These results provide novel insight into the activation of respiratory DC subsets during Klebsiella pneumonia infection. The detection of increased respiratory pDC numbers in bacterial pneumonia may indicate possible novel pDC functions with respect to lung repair

  10. Peripheral CD103+ dendritic cells form a unified subset developmentally related to CD8α+ conventional dendritic cells

    PubMed Central

    Edelson, Brian T.; KC, Wumesh; Juang, Richard; Kohyama, Masako; Benoit, Loralyn A.; Klekotka, Paul A.; Moon, Clara; Albring, Jörn C.; Ise, Wataru; Michael, Drew G.; Bhattacharya, Deepta; Stappenbeck, Thaddeus S.; Holtzman, Michael J.; Sung, Sun-Sang J.; Murphy, Theresa L.; Hildner, Kai

    2010-01-01

    Although CD103-expressing dendritic cells (DCs) are widely present in nonlymphoid tissues, the transcription factors controlling their development and their relationship to other DC subsets remain unclear. Mice lacking the transcription factor Batf3 have a defect in the development of CD8α+ conventional DCs (cDCs) within lymphoid tissues. We demonstrate that Batf3−/− mice also lack CD103+CD11b− DCs in the lung, intestine, mesenteric lymph nodes (MLNs), dermis, and skin-draining lymph nodes. Notably, Batf3−/− mice displayed reduced priming of CD8 T cells after pulmonary Sendai virus infection, with increased pulmonary inflammation. In the MLNs and intestine, Batf3 deficiency resulted in the specific lack of CD103+CD11b− DCs, with the population of CD103+CD11b+ DCs remaining intact. Batf3−/− mice showed no evidence of spontaneous gastrointestinal inflammation and had a normal contact hypersensitivity (CHS) response, despite previous suggestions that CD103+ DCs were required for immune homeostasis in the gut and CHS. The relationship between CD8α+ cDCs and nonlymphoid CD103+ DCs implied by their shared dependence on Batf3 was further supported by similar patterns of gene expression and their shared developmental dependence on the transcription factor Irf8. These data provide evidence for a developmental relationship between lymphoid organ–resident CD8α+ cDCs and nonlymphoid CD103+ DCs. PMID:20351058

  11. Transcriptional and functional characterization of CD137L-dendritic cells identifies a novel dendritic cell phenotype

    PubMed Central

    Harfuddin, Zulkarnain; Dharmadhikari, Bhushan; Wong, Siew Cheng; Duan, Kaibo; Poidinger, Michael; Kwajah, Shaqireen; Schwarz, Herbert

    2016-01-01

    The importance of monocyte-derived dendritic cells (DCs) is evidenced by the fact that they are essential for the elimination of pathogens. Although in vitro DCs can be generated by treatment of monocytes with GM-CSF and IL-4, it is unknown what stimuli induce differentiation of DCs in vivo. CD137L-DCs are human monocyte-derived DC that are generated by CD137 ligand (CD137L) signaling. We demonstrate that the gene signature of in vitro generated CD137L-DCs is most similar to those of GM-CSF and IL-4-generated immature DCs and of macrophages. This is reminiscent of in vivo inflammatory DC which also have been reported to share gene signatures with monocyte-derived DCs and macrophages. Performing direct comparison of deposited human gene expression data with a CD137L-DC dataset revealed a significant enrichment of CD137L-DC signature genes in inflammatory in vivo DCs. In addition, surface marker expression and cytokine secretion by CD137L-DCs resemble closely those of inflammatory DCs. Further, CD137L-DCs express high levels of adhesion molecules, display strong attachment, and employ the adhesion molecule ALCAM to stimulate T cell proliferation. This study characterizes the gene expression profile of CD137L-DCs, and identifies significant similarities of CD137L-DCs with in vivo inflammatory monocyte-derived DCs and macrophages. PMID:27431276

  12. Regulation of Dendritic Cell Function by Dietary Polyphenols.

    PubMed

    Del Cornò, Manuela; Scazzocchio, Beatrice; Masella, Roberta; Gessani, Sandra

    2016-04-01

    Marked changes in socioeconomic status, cultural traditions, population growth, and agriculture have been affecting diets worldwide. Nutrition is known to play a pivotal role in the pathogenesis of several chronic diseases, and the use of bioactive food compounds at pharmacologic doses is emerging as a preventive and/or therapeutic approach to target metabolic dysregulations occurring in aging, obesity-related chronic diseases, and cancer. Only recently have data on the effects of specific nutrients or food on the immune system become available, and studies regarding the human immune system are still in their infancy. Beyond providing essential nutrients, diet can actively influence the immune system. Understanding how diet and nutritional status influence the innate and adaptive arms of our immune system represents an area of scientific need, opportunity, and challenge. The insights gleaned should help to address several pressing global health problems. Recently, biologically active polyphenols, which are widespread constituents of fruit and vegetables, have gained importance as complex regulators of various cellular processes, critically involved in the maintenance of body homeostasis. This review outlines the potential effects of polyphenols on the function of dendritic cells (DCs), key players in the orchestration of the immune response. Their effects on different aspects of DC biology including differentiation, maturation, and DC capacity to shift immune response toward tolerance or immune activation will be outlined. PMID:24941314

  13. Plasmacytoid dendritic cells in skin lesions of classic Kaposi's sarcoma.

    PubMed

    Karouni, Mirna; Kurban, Mazen; Abbas, Ossama

    2016-09-01

    Plasmacytoid dendritic cells (pDCs) are the most potent producers of type I interferons (IFNs), which allows them to provide anti-viral resistance and to link the innate and adaptive immunity by controlling the function of myeloid DCs, lymphocytes, and natural killer cells. pDCs are involved in the pathogenesis of several infectious [especially viral, such as Molluscum contagiosum (MC)], inflammatory/autoimmune, and neoplastic entities. Kaposi's sarcoma (KS) is a multifocal, systemic lympho-angioproliferative tumor associated with Kaposi's sarcoma-associated herpesvirus (KSHV) infection. Microscopy typically exhibits a chronic inflammatory lymphoplasmacytic infiltrate in addition to the vascular changes and spindle cell proliferation. Despite the extensive research done on the immune evasion strategies employed by KSHV, pDCs role in relation to KS has only rarely been investigated. Given this, we intend to investigate pDC occurrence and activity in the skin lesions of KS. Immunohistochemical staining for BDCA-2 (specific pDC marker) and MxA (surrogate marker for local type I IFN production) was performed on classic KS (n = 20) with the control group comprising inflamed MC (n = 20). As expected, BDCA-2+ pDCs were present in abundance with diffuse and intense MxA expression (indicative of local type I IFN production) in all inflamed MC cases (20 of 20, 100 %). Though present in all the KS cases, pDCs were significantly less abundant in KS than in inflamed MC cases, and MxA expression was patchy/weak in most KS cases. In summary, pDCs are part of the inflammatory host response in KS; however, they were generally low in number with decreased type I IFN production which is probably related to KSHV's ability to evade the immune system through the production of different viral proteins capable of suppressing IFN production as well as pDC function. PMID:27372661

  14. Follicular dendritic cell networks of primary follicles and germinal centers: phenotype and function

    PubMed Central

    Allen, Christopher D C; Cyster, Jason G

    2008-01-01

    Follicular dendritic cells (FDCs) were identified decades ago by their ability to retain immune complexes and more recent findings indicate that they are a source of B cell attractants and trophic factors. New imaging studies have shown that B cells closely associate with their dendritic processes during migration. Here we will review the properties of these specialized follicular stromal cells and provide an update on the requirements for their maturation into phenotypically distinct cells within germinal center light and dark zones. We will then discuss current understanding of how they help support the B cell immune response. PMID:18261920

  15. Mapping the accumulation of co-infiltrating CNS dendritic cells and encephalitogenic T cells during EAE

    PubMed Central

    Clarkson, Benjamin D; Walker, Alec; Harris, Melissa; Rayasam, Aditya; Sandor, Matyas; Fabry, Zsuzsanna

    2014-01-01

    Evidence from experimental autoimmune encephalomyelitis (EAE) suggests that CNS-infiltrating dendritic cells (DCs) are crucial for restimulation of coinfiltrating T cells. Here we systematically quantified and visualized the distribution and interaction of CNS DCs and T cells during EAE. We report marked periventricular accumulation of DCs and myelin-specific T cells during EAE disease onset prior to accumulation in the spinal cord, indicating that the choroid plexus-CSF axis is a CNS entry portal. Moreover, despite emphasis on spinal cord inflammation in EAE and in correspondence with MS pathology, inflammatory lesions containing interacting DCs and T cells are present in specific brain regions. PMID:25288303

  16. Empowering gamma delta T cells with antitumor immunity by dendritic cell-based immunotherapy

    PubMed Central

    Van Acker, Heleen H; Anguille, Sébastien; Van Tendeloo, Viggo F; Lion, Eva

    2015-01-01

    Gamma delta (γδ) T cells are the all-rounders of our immune-system with their major histocompatibility complex-unrestricted cytotoxicity, capacity to secrete immunosti-mulatory cytokines and ability to promote the generation of tumor antigen-specific CD8+ and CD4+ T cell responses. Dendritic cell (DC)-based vaccine therapy has the prospective to harness these unique features of the γδ T cells in the fight against cancer. In this review, we will discuss our current knowledge on DC-mediated γδ T cell activation and related opportunities for tumor immunologists. PMID:26405575

  17. BAFF and APRIL from Activin A-Treated Dendritic Cells Upregulate the Antitumor Efficacy of Dendritic Cells In Vivo.

    PubMed

    Shurin, Michael R; Ma, Yang; Keskinov, Anton A; Zhao, Ruijing; Lokshin, Anna; Agassandian, Marianna; Shurin, Galina V

    2016-09-01

    The members of the TGFβ superfamily play a key role in regulating developmental and homeostasis programs by controlling differentiation, proliferation, polarization, and survival of different cell types. Although the role of TGFβ1 in inflammation and immunity is well evident, the contribution of other TGFβ family cytokines in the modulation of the antitumor immune response remains less documented. Here we show that activin A triggers SMAD2 and ERK1/2 pathways in dendritic cells (DC) expressing type I and II activin receptors, and upregulates production of the TNFα family cytokines BAFF (TALL-1, TNFSF13B) and APRIL (TALL-2, TNFSF13A), which is blocked by SMAD2 and ERK1/2 inhibitors, respectively. BAFF and APRIL derived from activin A-treated DCs upregulate proliferation and survival of T cells expressing the corresponding receptors, BAFF-R and TACI. In vivo, activin A-stimulated DCs demonstrate a significantly increased ability to induce tumor-specific CTLs and inhibit the growth of melanoma and lung carcinoma, which relies on DC-derived BAFF and APRIL, as knockdown of the BAFF and APRIL gene expression in activin A-treated DCs blocks augmentation of their antitumor potential. Although systemic administration of activin A, BAFF, or APRIL for the therapeutic purposes is not likely due to the pluripotent effects on malignant and nonmalignant cells, our data open a novel opportunity for improving the efficacy of DC vaccines. In fact, a significant augmentation of the antitumor activity of DC pretreated with activin A and the proven role of DC-derived BAFF and APRIL in the induction of antitumor immunity in vivo support this direction. Cancer Res; 76(17); 4959-69. ©2016 AACR. PMID:27364554

  18. The microRNA bantam functions in epithelial cells to regulate scaling growth of dendrite arbors in Drosophila sensory neurons

    PubMed Central

    Parrish, Jay Z.; Xu, Peizhang; Kim, Charles C.; Jan, Lily Yeh; Jan, Yuh Nung

    2009-01-01

    Summary In addition to establishing dendritic coverage of the receptive field, neurons need to adjust their dendritic arbors to match changes of the receptive field. Here we show that dendrite arborization (da) sensory neurons establish dendritic coverage of the body wall early in Drosophila larval development and then grow in precise proportion to their substrate, the underlying body wall epithelium, as the larva more than triples in length. This phenomenon, referred to as scaling growth of dendrites, requires the function of the microRNA (miRNA) bantam (ban) in the epithelial cells rather than the da neurons themselves. We further show that ban in epithelial cells dampens Akt kinase activity in adjacent neurons to influence dendrite growth. This signaling between epithelial cells and neurons receiving sensory input from the body wall synchronizes their growth to ensure proper dendritic coverage of the receptive field. PMID:19778508

  19. Natural Killer Cells as Helper Cells in Dendritic Cell Cancer Vaccines

    PubMed Central

    Pampena, María Betina; Levy, Estrella Mariel

    2015-01-01

    Vaccine-based cancer immunotherapy has generated highly variable clinical results due to differing methods of vaccine preparation and variation in patient populations among other lesser factors. Moreover, these clinical responses do not necessarily correspond with the induction of tumor-specific cytotoxic lymphocytes. Here, we review the participation of natural killer (NK) cells as alternative immune components that could cooperate in successful vaccination treatment. NK cells have been described as helper cells in dendritic cell-based cancer vaccines, but the role in other kinds of vaccination strategies (whole cells, peptide, or DNA-based vaccines) is poorly understood. In this article, we address the following issues regarding the role of NK cells in cancer vaccines: NK cell anti-tumor action sites, and the loci of NK cell interaction with other immune cells; descriptions of new data on the memory characteristics of NK cells described in infectious diseases; and finally phenotypical and functional changes after vaccination measured by immunomonitoring in preclinical and clinical settings. PMID:25674087

  20. Human Liver Stem Cells Suppress T-Cell Proliferation, NK Activity, and Dendritic Cell Differentiation

    PubMed Central

    Bruno, Stefania; Grange, Cristina; Tapparo, Marta; Pasquino, Chiara; Romagnoli, Renato; Dametto, Ennia; Amoroso, Antonio; Tetta, Ciro; Camussi, Giovanni

    2016-01-01

    Human liver stem cells (HLSCs) are a mesenchymal stromal cell-like population resident in the adult liver. Preclinical studies indicate that HLSCs could be a good candidate for cell therapy. The aim of the present study was to evaluate the immunogenicity and the immunomodulatory properties of HLSCs on T-lymphocytes, natural killer cells (NKs), and dendritic cells (DCs) in allogeneic experimental settings. We found that HLSCs inhibited T-cell proliferation by a mechanism independent of cell contact and dependent on the release of prostaglandin E2 (PGE2) and on indoleamine 2,3-dioxygenase activity. When compared with mesenchymal stromal cells (MSCs), HLSCs were more efficient in inhibiting T-cell proliferation. At variance with MSCs, HLSCs did not elicit NK degranulation. Moreover, HLSCs inhibited NK degranulation against K562, a NK-sensitive target, by a mechanism dependent on HLA-G release. When tested on DC generation from monocytes, HLSCs were found to impair DC differentiation and DCs ability to induce T-cell proliferation through PGE2. This study shows that HLSCs have immunomodulatory properties similar to MSCs, but, at variance with MSCs, they do not elicit a NK response. PMID:27127520

  1. Frequency-dependent signal processing in apical dendrites of hippocampal CA1 pyramidal cells.

    PubMed

    Watanabe, H; Tsubokawa, H; Tsukada, M; Aihara, T

    2014-10-10

    Depending on an animal's behavioral state, hippocampal CA1 pyramidal cells receive distinct patterns of excitatory and inhibitory synaptic inputs. The time-dependent changes in the frequencies of these inputs and the nonuniform distribution of voltage-gated channels lead to dynamic fluctuations in membrane conductance. In this study, using a whole-cell patch-clamp method, we attempted to record and analyze the frequency dependencies of membrane responsiveness in Wistar rat hippocampal CA1 pyramidal cells following noise current injection directly into dendrites and somata under pharmacological blockade of all synaptic inputs. To estimate the frequency-dependent properties of membrane potential, membrane impedance was determined from the voltage response divided by the input current in the frequency domain. The cell membrane of most neurons showed low-pass filtering properties in all regions. In particular, the properties were strongly expressed in the somata or proximal dendrites. Moreover, the data revealed nonuniform distribution of dendritic impedance, which was high in the intermediate segment of the apical dendritic shaft (∼220-260μm from the soma). The low-pass filtering properties in the apical dendrites were more enhanced by membrane depolarization than those in the somata. Coherence spectral analysis revealed high coherence between the input signal and the output voltage response in the theta-gamma frequency range, and large lags emerged in the distal dendrites in the gamma frequency range. Our results suggest that apical dendrites of hippocampal CA1 pyramidal cells integrate synaptic inputs according to the frequency components of the input signal along the dendritic segments receiving the inputs. PMID:25135353

  2. Molecular Factors in Dendritic Cell Responses to Adsorbed Glycoconjugates

    PubMed Central

    Hotaling, Nathan A.; Cummings, Richard D.; Ratner, Daniel M.; Babensee, Julia E.

    2014-01-01

    Carbohydrates and glycoconjugates have been shown to exert pro-inflammatory effects on the dendritic cell (DC), supporting pathogen-induced innate immunity and antigen processing, as well as immunosuppressive effects in the tolerance to self-proteins. Additionally, the innate inflammatory response to implanted biomaterials has been hypothesized to be mediated by inflammatory cells interacting with adsorbed proteins, many of which are glycosylated. However, the molecular factors relevant for surface displayed glycoconjugate modulation of DC phenotype are unknown. Thus, in this study, a model system was developed to establish the role of glycan composition, density, and carrier cationization state on DC response. Thiol modified glycans were covalently bound to a model protein carrier, maleimide functionalized bovine serum albumin (BSA), and the number of glycans per BSA modulated. Additionally, the carrier isoelectric point was scaled from a pI of ~4.0 to ~10.0 using ethylenediamine (EDA). The DC response to the neoglycoconjugates adsorbed to wells of a 384 well plate was determined via a high throughput assay. The underlying trends in DC phenotype in relation to conjugate properties were elucidated via multivariate general linear models. It was found that glycoconjugates with more than 20 glycans per carrier had the greatest impact on the pro-inflammatory response from DCs, followed by conjugates having an isoelectric point above 9.5. Surfaces displaying terminal α1–2 linked mannose structures were able to increase the inflammatory DC response to a greater extent than did any other terminal glycan structure. The results herein can be applied to inform the design of the next generation of combination products and biomaterials for use in future vaccines and implanted materials. PMID:24746228

  3. Circulating Dendritic Cells, Farm Exposure and Asthma at Early Age.

    PubMed

    Kääriö, H; Nieminen, J K; Karvonen, A M; Huttunen, K; Schröder, P C; Vaarala, O; von Mutius, E; Pfefferle, P I; Schaub, B; Pekkanen, J; Hirvonen, M-R; Roponen, M

    2016-01-01

    Farm environment has been shown to protect from childhood asthma. Underlying immunological mechanisms are not clear yet, including the role of dendritic cells (DCs). The aim was to explore whether asthma and farm exposures are associated with the proportions and functional properties of DCs from 4.5-year-old children in a subgroup of the Finnish PASTURE birth cohort study. Myeloid DCs (mDCs), plasmacytoid DCs (pDCs) and CD86 expression on mDCs ex vivo (n = 100) identified from peripheral blood mononuclear cells (PBMCs) were analysed using flow cytometry. MDCs and production of interleukin (IL)-6 and tumour necrosis factor alpha (TNF-α) by mDCs were analysed after 5 h in vitro stimulation with lipopolysaccharide (LPS) (n = 88). Prenatal and current farm exposures (farming, stables, hay barn and farm milk) were assessed from questionnaires. Asthma at age 6 years was defined as a doctor's diagnosis and symptoms; atopic sensitization was defined by antigen-specific IgE measurements. Asthma was positively associated with CD86 expression on mDCs ex vivo [adjusted odds ratio (aOR) 4.83, 95% confidence interval (CI) 1.51-15.4] and inversely with IL-6 production in mDCs after in vitro stimulation with LPS (aOR 0.19, 95% CI 0.04-0.82). In vitro stimulation with LPS resulted in lower percentage of mDCs in the farm PBMC cultures as compared to non-farm PBMC cultures. Our results suggest an association between childhood asthma and functional properties of DCs. Farm exposure may have immunomodulatory effects by decreasing mDC proportions. PMID:26368653

  4. Lung dendritic cells facilitate extrapulmonary bacterial dissemination during pneumococcal pneumonia

    PubMed Central

    Rosendahl, Alva; Bergmann, Simone; Hammerschmidt, Sven; Goldmann, Oliver; Medina, Eva

    2013-01-01

    Streptococcus pneumoniae is a leading cause of bacterial pneumonia worldwide. Given the critical role of dendritic cells (DCs) in regulating and modulating the immune response to pathogens, we investigated here the role of DCs in S. pneumoniae lung infections. Using a well-established transgenic mouse line which allows the conditional transient depletion of DCs, we showed that ablation of DCs resulted in enhanced resistance to intranasal challenge with S. pneumoniae. DCs-depleted mice exhibited delayed bacterial systemic dissemination, significantly reduced bacterial loads in the infected organs and lower levels of serum inflammatory mediators than non-depleted animals. The increased resistance of DCs-depleted mice to S. pneumoniae was associated with a better capacity to restrict pneumococci extrapulmonary dissemination. Furthermore, we demonstrated that S. pneumoniae disseminated from the lungs into the regional lymph nodes in a cell-independent manner and that this direct way of dissemination was much more efficient in the presence of DCs. We also provide evidence that S. pneumoniae induces expression and activation of matrix metalloproteinase-9 (MMP-9) in cultured bone marrow-derived DCs. MMP-9 is a protease involved in the breakdown of extracellular matrix proteins and is critical for DC trafficking across extracellular matrix and basement membranes during the migration from the periphery to the lymph nodes. MMP-9 was also significantly up-regulated in the lungs of mice after intranasal infection with S. pneumoniae. Notably, the expression levels of MMP-9 in the infected lungs were significantly decreased after depletion of DCs suggesting the involvement of DCs in MMP-9 production during pneumococcal pneumonia. Thus, we propose that S. pneumoniae can exploit the DC-derived proteolysis to open tissue barriers thereby facilitating its own dissemination from the local site of infection. PMID:23802100

  5. HIV-1-derived lentiviral vectors directly activate plasmacytoid dendritic cells, which in turn induce the maturation of myeloid dendritic cells.

    PubMed

    Rossetti, Maura; Gregori, Silvia; Hauben, Ehud; Brown, Brian D; Sergi, Lucia Sergi; Naldini, Luigi; Roncarolo, Maria-Grazia

    2011-02-01

    Lentiviral vectors (LV) can induce type I interferon (IFN I) production from murine plasmacytoid dendritic cells (pDC), but not myeloid (my)DC. Here, we investigated whether this mechanism is conserved in human DC. MyDC and pDC were isolated from peripheral blood and transduced with increasing vector concentrations. Compared with in vitro differentiated monocyte-derived DC, the transduction efficiency of peripheral blood DC was low (ranging from <1% to 45%), with pDC showing the lowest susceptibility to LV transduction. Phenotype and function of myDC were not directly modified by LV transduction; by contrast, pDC produced significant levels of IFN-α and tumor necrosis factor-α. pDC activation was dependent on functional vector particles and was mediated by Toll-like receptor 7/9 triggering. Coculture of myDC with pDC in the presence of LV resulted in myDC activation, with CD86 up-regulation and interleukin-6 secretion. These findings demonstrate that the induction of transgene-specific immunity is triggered by an innate immune response with pDC activation and consequent myDC maturation, a response that closely resembles the one induced by functional viruses. This information is important to design strategies aimed at using LV in humans for gene therapy, where adverse immune responses must be avoided, or for cancer immunotherapy, where inducing immunity is the goal. PMID:20825284

  6. PHENOTYPE AND POLARIZATION OF AUTOLOGOUS T CELLS BY BIOMATERIAL-TREATED DENDRITIC CELLS

    PubMed Central

    Park, Jaehyung; Gerber, Michael H.; Babensee, Julia E.

    2014-01-01

    Given the central role of dendritic cells (DCs) in directing T cell phenotypes, the ability of biomaterial-treated DCs to dictate autologous T cell phenotype was investigated. Here, we demonstrate that differentially biomaterial-treated DCs differentially directed autologous T cell phenotype and polarization, depending on the biomaterial used to pre-treat the DCs. Immature DCs (iDCs) were derived from human peripheral blood monocytes, and treated with biomaterial films of alginate, agarose, chitosan, hyaluronic acid, or 75:25 poly(lactic-co-glycolic acid) (PLGA), followed by co-culture of these biomaterial-treated DCs and autologous T cells. When autologous T cells were co-cultured with DCs treated with biomaterial film/antigen (ovalbumin, OVA) combinations, different biomaterial films induced differential levels of T cell marker (CD4, CD8, CD25, CD69) expression, as well as differential cytokine profiles [interferon (IFN)-γ, interleukin (IL)-12p70, IL-10, IL-4] in the polarization of T helper types. Dendritic cells treated with agarose films/OVA induced CD4+CD25+FoxP3+ (T regulatory cells) expression, comparable to untreated iDCs, on autologous T cells in the DC-T co-culture system. Furthermore, in this co-culture, agarose treatment induced release of IL-12p70 and IL-10 at higher levels, as compared to DC treatment with other biomaterial films/OVA, suggesting Th1 and Th2 polarization, respectively. Dendritic cells treated with PLGA film/OVA treatment induced release of IFN-γ at higher levels compared to that observed for co-cultures with iDCs or DCs treated with all other biomaterial films. These results indicate that DC treatment with different biomaterial films has potential as a tool for immunomodulation by directing autologous T cell responses. PMID:24616366

  7. Cimetidine modulates the antigen presenting capacity of dendritic cells from colorectal cancer patients.

    PubMed

    Kubota, T; Fujiwara, H; Ueda, Y; Itoh, T; Yamashita, T; Yoshimura, T; Okugawa, K; Yamamoto, Y; Yano, Y; Yamagishi, H

    2002-04-22

    Cimetidine, a H(2) receptor antagonist, has been reported to improve survival in gastrointestinal cancer patients. These effects have largely been attributed to the enhancing effects of cimetidine on the host's antitumour cell-mediated immune response, such as inhibition of suppressor T lymphocyte activity, stimulation of natural killer cell activity and increase of interleukin-2 production from helper T lymphocytes. We conducted an in vitro study on the effects of cimetidine on differentiation and antigen presenting capacity of monocyte-derived dendritic cells from advanced colorectal cancer patients and normal controls. As a result, an investigation of expression of surface molecules associated with dendritic cells by flow cytometric analyses showed that cimetidine had no enhancing effect on differentiation of dendritic cells from cancer patients and normal controls. An investigation of [(3)H]thymidine incorporation by allogeneic mixed lymphocyte reactions revealed that cimetidine increased the antigen presenting capacity of dendritic cells from both materials. Moreover, a higher antigen presenting capacity was observed in advanced cancer patients compared to normal controls. These effects might be mediated via specific action of cimetidine and not via H(2) receptors because famotidine did not show similar effects. Our results suggest that cimetidine may enhance the host's antitumour cell-mediated immunity by improving the suppressed dendritic cells function of advanced cancer patients. PMID:11953882

  8. Corticotropin-releasing factor secretion from dendritic cells stimulated by commensal bacteria

    PubMed Central

    Hojo, Mariko; Ohkusa, Toshifumi; Tomeoku, Harumi; Koido, Shigeo; Asaoka, Daisuke; Nagahara, Akihito; Watanabe, Sumio

    2011-01-01

    AIM: To study the production and secretion of corticotropin-releasing factor (CRF) by dendritic cells and the influence of commensal bacteria. METHODS: JAWSII cells (ATCC CRL-11904), a mouse dendritic cell line, were seeded into 24-well culture plates and grown for 3 d. Commensal bacterial strains of Clostridium clostrodiiforme (JCM1291), Bacteroides vulgatus (B. vulgatus) (JCM5856), Escherichia coli (JCM1649), or Fusobacterium varium (F. varium) (ATCC8501) were added to the cells except for the control well, and incubated for 2 h. After incubation, we performed enzyme-linked immunosorbent assay for the cultured medium and reverse transcription polymerase chain reaction for the dendritic cells, and compared these values with controls. RESULTS: The level of CRF secretion by control dendritic cells was 40.4 ± 6.2 pg/mL. The CRF levels for cells incubated with F. varium and B. vulgatus were significantly higher than that of the control (P < 0.0001). CRF mRNA was present in the control sample without bacteria, and CRF mRNA levels in all samples treated with bacteria were above that of the control sample. F. varium caused the greatest increase in CRF mRNA expression. CONCLUSION: Our results suggest that dendritic cells produce CRF, a process augmented by commensal bacteria. PMID:22046091

  9. Human monocyte-derived dendritic cells turn into foamy dendritic cells with IL-17A1[S

    PubMed Central

    Salvatore, Giulia; Bernoud-Hubac, Nathalie; Bissay, Nathalie; Debard, Cyrille; Daira, Patricia; Meugnier, Emmanuelle; Proamer, Fabienne; Hanau, Daniel; Vidal, Hubert; Aricò, Maurizio; Delprat, Christine; Mahtouk, Karène

    2015-01-01

    Interleukin 17A (IL-17A) is a proinflammatory cytokine involved in the pathogenesis of chronic inflammatory diseases. In the field of immunometabolism, we have studied the impact of IL-17A on the lipid metabolism of human in vitro-generated monocyte-derived dendritic cells (DCs). Microarrays and lipidomic analysis revealed an intense remodeling of lipid metabolism induced by IL-17A in DCs. IL-17A increased 2–12 times the amounts of phospholipids, cholesterol, triglycerides, and cholesteryl esters in DCs. Palmitic (16:0), stearic (18:0), and oleic (18:ln-9c) acid were the main fatty acid chains present in DCs. They were strongly increased in response to IL-17A while their relative proportion remained unchanged. Capture of extracellular lipids was the major mechanism of lipid droplet accumulation, visualized by electron microscopy and Oil Red O staining. Besides this foamy phenotype, IL-17A induced a mixed macrophage-DC phenotype and expression of the nuclear receptor NR1H3/liver X receptor-α, previously identified in the context of atherosclerosis as the master regulator of cholesterol homeostasis in macrophages. These IL-17A-treated DCs were as competent as untreated DCs to stimulate allogeneic naive T-cell proliferation. Following this first characterization of lipid-rich DCs, we propose to call these IL-17A-dependent cells “foamy DCs” and discuss the possible existence of foamy DCs in atherosclerosis, a metabolic and inflammatory disorder involving IL-17A. PMID:25833686

  10. Activation of antitumor cytotoxic T lymphocytes by fusions of human dendritic cells and breast carcinoma cells

    PubMed Central

    Gong, Jianlin; Avigan, David; Chen, Dongshu; Wu, Zekui; Koido, Shigeo; Kashiwaba, Masahiro; Kufe, Donald

    2000-01-01

    We have reported that fusions of murine dendritic cells (DCs) and murine carcinoma cells reverse unresponsiveness to tumor-associated antigens and induce the rejection of established metastases. In the present study, fusions were generated with primary human breast carcinoma cells and autologous DCs. Fusion cells coexpressed tumor-associated antigens and DC-derived costimulatory molecules. The fusion cells also retained the functional potency of DCs and stimulated autologous T cell proliferation. Significantly, the results show that autologous T cells are primed by the fusion cells to induce MHC class I-dependent lysis of autologous breast tumor cells. These findings demonstrate that fusions of human breast cancer cells and DCs activate T cell responses against autologous tumors. PMID:10688917

  11. Tenascin‐C Aggravates Autoimmune Myocarditis via Dendritic Cell Activation and Th17 Cell Differentiation

    PubMed Central

    Machino‐Ohtsuka, Tomoko; Tajiri, Kazuko; Kimura, Taizo; Sakai, Satoshi; Sato, Akira; Yoshida, Toshimichi; Hiroe, Michiaki; Yasutomi, Yasuhiro; Aonuma, Kazutaka; Imanaka‐Yoshida, Kyoko

    2014-01-01

    Background Tenascin‐C (TN‐C), an extracellular matrix glycoprotein, appears at several important steps of cardiac development in the embryo, but is sparse in the normal adult heart. TN‐C re‐expresses under pathological conditions including myocarditis, and is closely associated with tissue injury and inflammation in both experimental and clinical settings. However, the pathophysiological role of TN‐C in the development of myocarditis is not clear. We examined how TN‐C affects the initiation of experimental autoimmune myocarditis, immunologically. Methods and Results A model of experimental autoimmune myocarditis was established in BALB/c mice by immunization with murine α‐myosin heavy chains. We found that TN‐C knockout mice were protected from severe myocarditis compared to wild‐type mice. TN‐C induced synthesis of proinflammatory cytokines, including interleukin (IL)‐6, in dendritic cells via activation of a Toll‐like receptor 4, which led to T‐helper (Th)17 cell differentiation and exacerbated the myocardial inflammation. In the transfer experiment, dendritic cells loaded with cardiac myosin peptide acquired the functional capacity to induce myocarditis when stimulated with TN‐C; however, TN‐C‐stimulated dendritic cells generated from Toll‐like receptor 4 knockout mice did not induce myocarditis in recipients. Conclusions Our results demonstrated that TN‐C aggravates autoimmune myocarditis by driving the dendritic cell activation and Th17 differentiation via Toll‐like receptor 4. The blockade of Toll‐like receptor 4‐mediated signaling to inhibit the proinflammatory effects of TN‐C could be a promising therapeutic strategy against autoimmune myocarditis. PMID:25376187

  12. Plasmacytoid dendritic cells in allogeneic hematopoietic cell transplantation: benefit or burden?

    PubMed Central

    Auletta, JJ; Devine, SM; Waller, EK

    2016-01-01

    Plasmacytoid dendritic cells (pDCs) bridge innate and adaptive immune responses and have important roles in hematopoietic engraftment, GvHD and graft-versus-leukemia responses following allogeneic hematopoietic cell transplantation (HCT). In addition, pDCs mediate antiviral immunity, particularly as they are the body’s primary cellular source of type I interferon. Given their pleiotropic roles, pDCs have emerged as cells that critically impact transplant outcomes, including overall survival. In this article, we will review the pre-clinical and clinical literature, supporting the crucial roles that pDCs assume as key immune effector cells during HCT. PMID:26642333

  13. Plasmacytoid Dendritic Cells Are Crucial in Bifidobacterium adolescentis-Mediated Inhibition of Yersinia enterocolitica Infection

    PubMed Central

    Wittmann, Alexandra; Autenrieth, Ingo B.; Frick, Julia-Stefanie

    2013-01-01

    In industrialized countries bacterial intestinal infections are commonly caused by enteropathogenic Enterobacteriaceae. The interaction of the microbiota with the host immune system determines the adequacy of an appropriate response against pathogens. In this study we addressed whether the probiotic Bifidobacterium adolescentis is protective during intestinal Yersinia enterocolitica infection. Female C57BL/6 mice were fed with B. adolescentis, infected with Yersinia enterocolitica, or B. adolescentis fed and subsequently infected with Yersinia enterocolitica. B. adolescentis fed and Yersinia infected mice were protected from Yersinia infection as indicated by a significantly reduced weight loss and splenic Yersinia load when compared to Yersinia infected mice. Moreover, protection from infection was associated with increased intestinal plasmacytoid dendritic cell and regulatory T-cell frequencies. Plasmacytoid dendritic cell function was investigated using depletion experiments by injecting B. adolescentis fed, Yersinia infected C57BL/6 mice with anti-mouse PDCA-1 antibody, to deplete plasmacytoid dendritic cells, or respective isotype control. The B. adolescentis-mediated protection from Yersinia dissemination to the spleen was abrogated after plasmacytoid dendritic cell depletion indicating a crucial function for pDC in control of intestinal Yersinia infection. We suggest that feeding of B. adolescentis modulates the intestinal immune system in terms of increased plasmacytoid dendritic cell and regulatory T-cell frequencies, which might account for the B. adolescentis-mediated protection from Yersinia enterocolitica infection. PMID:23977019

  14. Maturation of dendritic cells with lipopeptides that represent vaccine candidates for hepatitis C virus.

    PubMed

    Chua, Brendon Y; Healy, Anne; Cameron, Paul U; Stock, Owen; Rizkalla, Michael; Zeng, Weiguang; Torresi, Joseph; Brown, Lorena E; Fowler, Nina L; Gowans, Eric J; Jackson, David C

    2003-02-01

    The ability of antigens to elicit immune responses depends upon their initial recognition, uptake, processing and presentation by dendritic cells. This fact has been recognized by many workers and dendritic cells are now regarded as natural 'adjuvants' in the business of vaccine design. One way of persuading dendritic cells to become interested in foreign material is to decorate it with lipid moieties found in bacteria. This approach has been used in the context of synthetic peptide-based immunogens and depending on the nature of the epitopes included, can provide highly immunogenic structures capable of eliciting antibody or cytotoxic T cell responses. In this paper we describe the results of experiments in which the stimulatory effects of peptide-based vaccine candidates on human dendritic cells are examined. Our findings indicate that lipidated structures comprising vaccine target sequences of viral origin coupled to the synthetic lipid groups of bacteria are able to induce the maturation of dendritic cells, as measured by the expression of cell surface MHC class II molecules. PMID:12534949

  15. Influenza virus-infected dendritic cells stimulate strong proliferative and cytolytic responses from human CD8+ T cells.

    PubMed Central

    Bhardwaj, N; Bender, A; Gonzalez, N; Bui, L K; Garrett, M C; Steinman, R M

    1994-01-01

    Antigen-specific, CD8+, cytolytic T lymphocytes (CTLs) could potentially provide resistance to several infectious and malignant diseases. However, the cellular requirements for the generation of specific CTLs in human lymphocyte cultures are not well defined, and repetitive stimulation with antigen is often required. We find that strong CD8+ CTL responses to influenza virus can be generated from freshly isolated blood T cells, as long as dendritic cells are used as antigen presenting cells (APCs). Small numbers of dendritic cells (APC:T cell ratio of 1:50-1:100) induce these CTL responses from most donors in 7 d of culture, but monocytes are weak or inactive. Whereas both dendritic cells and monocytes are infected with influenza virus, the former serve as effective APCs for the induction of CD8+ T cells while the latter act as targets for the CTLs that are induced. The strong CD8+ response to influenza virus-infected dendritic cells is accompanied by extensive proliferation of the CD8+ T cells, but the response can develop in the apparent absence of CD4+ helpers or exogenous lymphokines. CD4+ influenza virus-specific CTLs can also be induced by dendritic cells, but the cultures initially must be depleted of CD8+ cells. These findings should make it possible to use dendritic cells to generate human, antigen-specific, CD8+ CTLs to other targets. The results illustrate the principle that efficient T cell-mediated responses develop in two stages: an afferent limb in which dendritic cells are specialized APCs and an efferent limb in which the primed T cells carry out an immune response to many types of presenting cells. Images PMID:8040335

  16. Pathogen-Associated Molecular Patterns Induced Crosstalk between Dendritic Cells, T Helper Cells, and Natural Killer Helper Cells Can Improve Dendritic Cell Vaccination

    PubMed Central

    Oth, Tammy; Vanderlocht, Joris; Van Elssen, Catharina H. M. J.; Bos, Gerard M. J.; Germeraad, Wilfred T. V.

    2016-01-01

    A coordinated cellular interplay is of crucial importance in both host defense against pathogens and malignantly transformed cells. The various interactions of Dendritic Cells (DC), Natural Killer (NK) cells, and T helper (Th) cells can be influenced by a variety of pathogen-associated molecular patterns (PAMPs) and will lead to enhanced CD8+ effector T cell responses. Specific Pattern Recognition Receptor (PRR) triggering during maturation enables DC to enhance Th1 as well as NK helper cell responses. This effect is correlated with the amount of IL-12p70 released by DC. Activated NK cells are able to amplify the proinflammatory cytokine profile of DC via the release of IFN-γ. The knowledge on how PAMP recognition can modulate the DC is of importance for the design and definition of appropriate therapeutic cancer vaccines. In this review we will discuss the potential role of specific PAMP-matured DC in optimizing therapeutic DC-based vaccines, as some of these DC are efficiently activating Th1, NK cells, and cytotoxic T cells. Moreover, to optimize these vaccines, also the inhibitory effects of tumor-derived suppressive factors, for example, on the NK-DC crosstalk, should be taken into account. Finally, the suppressive role of the tumor microenvironment in vaccination efficacy and some proposals to overcome this by using combination therapies will be described. PMID:26980946

  17. Activation-Induced Cell Death of Dendritic Cells Is Dependent on Sphingosine Kinase 1

    PubMed Central

    Schwiebs, Anja; Friesen, Olga; Katzy, Elisabeth; Ferreirós, Nerea; Pfeilschifter, Josef M.; Radeke, Heinfried H.

    2016-01-01

    Sphingosine 1-phosphate (S1P) is an immune modulatory lipid mediator and has been implicated in numerous pathophysiological processes. S1P is produced by sphingosine kinase 1 (Sphk1) and Sphk2. Dendritic cells (DCs) are central for the direction of immune responses and crucially involved in autoimmunity and cancerogenesis. In this study we examined the function and survival of bone marrow-derived DCs under long-term inflammatory stimulation. We observed that differentiated cells undergo activation-induced cell death (AICD) upon LPS stimulation with an increased metabolic activity shortly after stimulation, followed by a rapid activation of caspase 3 and subsequent augmented apoptosis. Importantly, we highlight a profound role of Sphk1 in secretion of inflammatory cytokines and survival of dendritic cells that might be mediated by a change in sphingolipid levels as well as by a change in STAT3 expression. Cell growth during differentiation of Sphk1-deficient cells treated with the functional S1P receptor antagonist FTYP was reduced. Importantly, in dendritic cells we did not observe a compensatory regulation of Sphk2 mRNA in Sphk1-deficient cells. Instead, we discovered a massive increase in Sphk1 mRNA concentration upon long-term stimulation with LPS in wild type cells that might function as an attempt to rescue from inflammation-caused cell death. Taken together, in this investigation we describe details of a crucial involvement of sphingolipids and Sphk1 in AICD during long-term immunogenic activity of DCs that might play an important role in autoimmunity and might explain the differences in immune response observed in in vivo studies of Sphk1 modulation. PMID:27148053

  18. Dendritic cell-based vaccine for pancreatic cancer in Japan

    PubMed Central

    Okamoto, Masato; Kobayashi, Masanori; Yonemitsu, Yoshikazu; Koido, Shigeo; Homma, Sadamu

    2016-01-01

    “Vaccell” is a dendritic cell (DC)-based cancer vaccine which has been established in Japan. The DCs play central roles in deciding the direction of host immune reactions as well as antigen presentation. We have demonstrated that DCs treated with a streptococcal immune adjuvant OK-432, produce interleukin-12, induce Th1-dominant state, and elicit anti-tumor effects, more powerful than those treated with the known DC-maturating factors. We therefore decided to mature DCs by the OK-432 for making an effective DC vaccine, Vaccell. The 255 patients with inoperable pancreatic cancer who received standard chemotherapy combined with DC vaccines, were analyzed retrospectively. Survival time of the patients with positive delayed type hypersensitivity (DTH) skin reaction was significantly prolonged as compared with that of the patients with negative DTH. The findings strongly suggest that there may be “Responders” for the DC vaccine in advanced pancreatic cancer patients. We next conducted a small-scale prospective clinical study. In this trial, we pulsed HLA class II-restricted WT1 peptide (WT1-II) in addition to HLA class I-restricted peptide (WT1-I) into the DCs. Survival of the patients received WT1-I and -II pulsed DC vaccine was significantly extended as compared to that of the patients received DCs pulsed with WT1-I or WT1-II alone. Furthermore, WT1-specific DTH positive patients showed significantly improved the overall survival as well as progression-free survival as compared to the DTH negative patients. The activation of antigen-specific immune responses by DC vaccine in combination with standard chemotherapy may be associated with a good clinical outcome in advanced pancreatic cancer. We are now planning a pivotal study of the Vaccell in appropriate protocols in Japan. PMID:26855819

  19. Dendritic cell-based vaccine for pancreatic cancer in Japan.

    PubMed

    Okamoto, Masato; Kobayashi, Masanori; Yonemitsu, Yoshikazu; Koido, Shigeo; Homma, Sadamu

    2016-02-01

    "Vaccell" is a dendritic cell (DC)-based cancer vaccine which has been established in Japan. The DCs play central roles in deciding the direction of host immune reactions as well as antigen presentation. We have demonstrated that DCs treated with a streptococcal immune adjuvant OK-432, produce interleukin-12, induce Th1-dominant state, and elicit anti-tumor effects, more powerful than those treated with the known DC-maturating factors. We therefore decided to mature DCs by the OK-432 for making an effective DC vaccine, Vaccell. The 255 patients with inoperable pancreatic cancer who received standard chemotherapy combined with DC vaccines, were analyzed retrospectively. Survival time of the patients with positive delayed type hypersensitivity (DTH) skin reaction was significantly prolonged as compared with that of the patients with negative DTH. The findings strongly suggest that there may be "Responders" for the DC vaccine in advanced pancreatic cancer patients. We next conducted a small-scale prospective clinical study. In this trial, we pulsed HLA class II-restricted WT1 peptide (WT1-II) in addition to HLA class I-restricted peptide (WT1-I) into the DCs. Survival of the patients received WT1-I and -II pulsed DC vaccine was significantly extended as compared to that of the patients received DCs pulsed with WT1-I or WT1-II alone. Furthermore, WT1-specific DTH positive patients showed significantly improved the overall survival as well as progression-free survival as compared to the DTH negative patients. The activation of antigen-specific immune responses by DC vaccine in combination with standard chemotherapy may be associated with a good clinical outcome in advanced pancreatic cancer. We are now planning a pivotal study of the Vaccell in appropriate protocols in Japan. PMID:26855819

  20. Cigarette Smoke Decreases the Maturation of Lung Myeloid Dendritic Cells

    PubMed Central

    Calero-Acuña, Carmen; Moreno-Mata, Nicolás; Gómez-Izquierdo, Lourdes; Sánchez-López, Verónica; López-Ramírez, Cecilia; Tobar, Daniela; López-Villalobos, José Luis; Gutiérrez, Cesar; Blanco-Orozco, Ana; López-Campos, José Luis

    2016-01-01

    Background Conflicting data exist on the role of pulmonary dendritic cells (DCs) and their maturation in patients with chronic obstructive pulmonary disease (COPD). Herein, we investigated whether disease severity and smoking status could affect the distribution and maturation of DCs in lung tissues of patients undergoing elective pneumectomy or lobectomy for suspected primary lung cancer. Materials and Methods A total of 75 consecutive patients were included. Spirometry testing was used to identify COPD. Lung parenchyma sections anatomically distant from the primary lesion were examined. We used flow cytometry to identify different DCs subtypes—including BDCA1-positive myeloid DCs (mDCs), BDCA3-positive mDCs, and plasmacytoid DCs (pDCs)—and determine their maturation markers (CD40, CD80, CD83, and CD86) in all participants. We also identified follicular DCs (fDCs), Langerhans DCs (LDCs), and pDCs in 42 patients by immunohistochemistry. Results COPD was diagnosed in 43 patients (16 current smokers and 27 former smokers), whereas the remaining 32 subjects were classified as non-COPD (11 current smokers, 13 former smokers, and 8 never smokers). The number and maturation of DCs did not differ significantly between COPD and non-COPD patients. However, the results of flow cytometry indicated that maturation markers CD40 and CD83 of BDCA1-positive mDCs were significantly decreased in smokers than in non-smokers (P = 0.023 and 0.013, respectively). Immunohistochemistry also revealed a lower number of LDCs in COPD patients than in non-COPD subjects. Conclusions Cigarette smoke, rather than airflow limitation, is the main determinant of impaired DCs maturation in the lung. PMID:27058955

  1. Dendritic cells and myeloid leukaemias: plasticity and commitment in cell differentiation.

    PubMed

    Rasaiyaah, Jane; Yong, Kwee; Katz, David R; Kellam, Paul; Chain, Benjamin M

    2007-08-01

    Dendritic cells (DCs) are key antigen-presenting cells (APCs), which link innate and adaptive immunity, ultimately activating antigen-specific T cells. This review examines the relationship between the acute and chronic myeloid leukaemias and cells with DC properties. DCs are non-dividing terminally differentiated cells, and ex vivo leukaemic cells or cell lines show little similarity to DCs. However, many leukaemias differentiate further in response to defined stimuli, and retain a degree of lineage plasticity. Therefore, several studies have explored the response of leukaemic cells to the in vitro regimens used to differentiate ex vivo primary DCs. Recent data suggest that the most 'dendritic-like' cells can be derived from more undifferentiated myeloid leukaemias, such as the myelomonocytic Mutz-3 cell line. These findings have important implications for understanding the developmental origins of DCs, for harnessing the APC properties of this class of tumour to stimulate the therapeutic anti-tumour immunity, and for developing useful models for the study of human DC physiology and pathology. There is a strong rationale for further exploration of this class of tumour and its relationship to the normal DC. PMID:17614817

  2. IPC: professional type 1 interferon-producing cells and plasmacytoid dendritic cell precursors.

    PubMed

    Liu, Yong-Jun

    2005-01-01

    Type 1 interferon-(alpha, beta, omega)-producing cells (IPCs), also known as plasmacytoid dendritic cell precursors (pDCs), represent 0.2%-0.8% of peripheral blood mononuclear cells in both humans and mice. IPCs display plasma cell morphology, selectively express Toll-like receptor (TLR)-7 and TLR9, and are specialized in rapidly secreting massive amounts of type 1 interferon following viral stimulation. IPCs can promote the function of natural killer cells, B cells, T cells, and myeloid DCs through type 1 interferons during an antiviral immune response. At a later stage of viral infection, IPCs differentiate into a unique type of mature dendritic cell, which directly regulates the function of T cells and thus links innate and adaptive immune responses. After more than two decades of effort by researchers, IPCs finally claim their place in the hematopoietic chart as the most important cell type in antiviral innate immunity. Understanding IPC biology holds future promise for developing cures for infectious diseases, cancer, and autoimmune diseases. PMID:15771572

  3. Clinical trials of dendritic cell-based cancer vaccines in hematologic malignancies

    PubMed Central

    Pyzer, Athalia R; Avigan, David E; Rosenblatt, Jacalyn

    2015-01-01

    The potential for the immune system to target hematological malignancies is demonstrated in the allogeneic transplant setting, where durable responses can be achieved. However, allogeneic transplantation is associated with significant morbidity and mortality related to graft versus host disease. Cancer immunotherapy has the capacity to direct a specific cytotoxic immune response against cancer cells, particularly residual cancer cells, in order to reduce the likelihood of disease relapse in a more targeted and tolerated manner. Ex vivo dendritic cells can be primed in various ways to present tumor associated antigen to the immune system, in the context of co-stimulatory molecules, eliciting a tumor specific cytotoxic response in patients. Several approaches to prime dendritic cells and overcome the immunosuppressive microenvironment have been evaluated in pre-clinical and early clinical trials with promising results. In this review, we summarize the clinical data evaluating dendritic cell based vaccines for the treatment of hematological malignancies. PMID:25625926

  4. Differential dendritic Ca2+ signalling in young and mature hippocampal granule cells

    PubMed Central

    Stocca, Gabriella; Schmidt-Hieber, Christoph; Bischofberger, Josef

    2008-01-01

    Neuronal activity is critically important for development and plasticity of dendrites, axons and synaptic connections. Although Ca2+ is an important signal molecule for these processes, not much is known about the regulation of the dendritic Ca2+ concentration in developing neurons. Here we used confocal Ca2+ imaging to investigate dendritic Ca2+ signalling in young and mature hippocampal granule cells, identified by the expression of the immature neuronal marker polysialated neural cell adhesion molecule (PSA-NCAM). Using the Ca2+-sensitive fluorescent dye OGB-5N, we found that both young and mature granule cells showed large action-potential evoked dendritic Ca2+ transients with similar amplitude of ∼200 nm, indicating active backpropagation of action potentials. However, the decay of the dendritic Ca2+ concentration back to baseline values was substantially different with a decay time constant of 550 ms in young versus 130 ms in mature cells, leading to a more efficient temporal summation of Ca2+ signals during theta-frequency stimulation in the young neurons. Comparison of the peak Ca2+ concentration and the decay measured with different Ca2+ indicators (OGB-5N, OGB-1) in the two populations of neurons revealed that the young cells had an ∼3 times smaller endogenous Ca2+-binding ratio (∼75 versus∼220) and an ∼10 times slower Ca2+ extrusion rate (∼170 s−1versus∼1800 s−1). These data suggest that the large dendritic Ca2+ signals due to low buffer capacity and slow extrusion rates in young granule cells may contribute to the activity-dependent growth and plasticity of dendrites and new synaptic connections. This will finally support differentiation and integration of young neurons into the hippocampal network. PMID:18591186

  5. Effects of human mesenchymal stem cells on the differentiation of dendritic cells from CD34+ cells.

    PubMed

    Chen, Lei; Zhang, Wei; Yue, Han; Han, Qin; Chen, Bin; Shi, Mingxia; Li, Jing; Li, Binzong; You, Shengguo; Shi, Yufang; Zhao, Robert Chunhua

    2007-10-01

    Mesenchymal stem cells (MSCs) have profound immunomodulatory functions both in vitro and in vivo. However, their effects on the differentiation of dendritic cells (DCs) are unknown. In this study, we employed an in vitro model to investigate the effects of human MSCs on the development of DCs. CD34(+) cells isolated from cord blood were cultured under conventional DC(cDC) or plasmacytoid DC (pDC) differentiation conditions, in the presence or absence of MSCs or their conditioned medium. Here we show that both MSCs and their conditioned medium dramatically increased the numbers of cells generated under either condition. The percentage of cells with the cDC phenotype is significantly reduced in the presence of MSCs or their conditioned medium, whereas the percentage of pDC increased. The capacity of cDCs from MSCs or their conditioned medium-treated CD34(+) cells to stimulate allogeneic T cells was weakened. Furthermore, MSCs can skew the DC function from cDC to pDC, thus biasing the immune system toward Th2 and away from Th1 responses. Blocking the prostaglandin E(2) (PGE(2)) synthesis of MSCs can reverse most of these influences of MSCs on DCs differentiation and function. Therefore, MSCs can significantly influence DC development through PGE(2) production. PMID:17999594

  6. Lactotransferrin-Cre reporter mice trace neutrophils, monocytes/macrophages and distinct subtypes of dendritic cells.

    PubMed

    Kovacic, Boris; Hoelbl-Kovacic, Andrea; Fischhuber, Katrin M; Leitner, Nicole R; Gotthardt, Dagmar; Casanova, Emilio; Sexl, Veronika; Müller, Mathias

    2014-06-01

    Considerable effort has been expended to identify genes that account for myeloid lineage commitment and development. However, currently available non-invasive mouse models utilize myeloid-specific reporters that are significantly expressed in hematopoietic stem cells as well as lymphoid compartments. Here, we describe a myeloid-specific marker that is not shared by any other lineage. We show that lactotransferrin mRNA is expressed by Gr-1(+)/CD11b(+) cells in the bone marrow, as opposed to hematopoietic stem cells or any peripheral cell population. To follow the progeny of lactotransferrin-expressing bone marrow cells, we generated a mouse model in which a reporter gene is irreversibly activated from the lactotransferrin-promoter. We found that lactotransferrin-reporter labels a majority of neutrophils, monocytes, macrophages and distinct subtypes of dendritic cells, while excluding T, B, natural killer cells, interferon-producing killer dendritic cells, plasmacytoid dendritic cells, erythrocytes and eosinophils. Lactotransferrin-reporter(-) bone marrow cells retain lymphoid, erythroid and long-term repopulating potential, while lactotransferrin-reporter(+) bone marrow cells confer only myeloid, but not lymphoid potential. We conclude that lactotransferrin represents a late stage differentiation marker of neutrophils, macrophages and distinct subtypes of dendritic cells. PMID:24561791

  7. Lactotransferrin-Cre reporter mice trace neutrophils, monocytes/macrophages and distinct subtypes of dendritic cells

    PubMed Central

    Kovacic, Boris; Hoelbl-Kovacic, Andrea; Fischhuber, Katrin M.; Leitner, Nicole R.; Gotthardt, Dagmar; Casanova, Emilio; Sexl, Veronika; Müller, Mathias

    2014-01-01

    Considerable effort has been expended to identify genes that account for myeloid lineage commitment and development. However, currently available non-invasive mouse models utilize myeloid-specific reporters that are significantly expressed in hematopoietic stem cells as well as lymphoid compartments. Here, we describe a myeloid-specific marker that is not shared by any other lineage. We show that lactotransferrin mRNA is expressed by Gr-1+/CD11b+ cells in the bone marrow, as opposed to hematopoietic stem cells or any peripheral cell population. To follow the progeny of lactotransferrin-expressing bone marrow cells, we generated a mouse model in which a reporter gene is irreversibly activated from the lactotransferrin-promoter. We found that lactotransferrin-reporter labels a majority of neutrophils, monocytes, macrophages and distinct subtypes of dendritic cells, while excluding T, B, natural killer cells, interferon-producing killer dendritic cells, plasmacytoid dendritic cells, erythrocytes and eosinophils. Lactotransferrin-reporter− bone marrow cells retain lymphoid, erythroid and long-term repopulating potential, while lactotransferrin-reporter+ bone marrow cells confer only myeloid, but not lymphoid potential. We conclude that lactotransferrin represents a late stage differentiation marker of neutrophils, macrophages and distinct subtypes of dendritic cells. PMID:24561791

  8. Nanostructured lipid carriers loaded with resveratrol modulate human dendritic cells

    PubMed Central

    Barbosa, João P; Neves, Ana R; Silva, Andreia M; Barbosa, Mário A; Reis, M Salette; Santos, Susana G

    2016-01-01

    Dendritic cells (DCs) are promising targets for drug delivery, as they can induce immunity or tolerance. The current study aims to examine the potential of using nanostructured lipid carriers (NLC) as delivery systems for human DC by evaluating nanoparticle internalization, cell labeling, and drug activity. NLC were formulated incorporating the fluorochrome fluorescein isothiocyanate (FITC-NLC) or the natural anti-inflammatory molecule resveratrol (rsv-NLC). Primary human DCs were differentiated from peripheral blood monocytes, and the innovative imaging flow cytometry technique was used to examine FITC-NLC internalization. The capacity of rsv-NLC to inhibit DC activation in response to proinflammatory cytokine tumor necrosis factor-α (TNF- α) was investigated by conventional flow cytometry. A combination of imaging and conventional flow cytometry was used to assess NLC cytotoxicity. The results obtained indicate that both NLC formulations were stable over time, with mean diameter <200 nm and highly negative zeta potential (about −30 mV). When DCs were placed in contact with NLC, imaging flow cytometry clearly showed that DCs efficiently internalized FITC-NLC, with nearly 100% of cells internalizing nanoparticles upon 1 hour of incubation. Both immature and mature DCs internalized NLC to high and comparable levels, and without cytotoxicity. Stimulating DC with TNF-α in the presence of rsv-NLC revealed that, using these nanoparticles, very small concentrations of rsv were sufficient to significantly decrease surface expression of activation marker CD83 (5 µM) and major histocompatibility complex-class II molecule human leukocyte antigen – antigen D related (10 µM), both upregulated in response to TNF-α stimulation. Rsv-NLC were compared with free rsv; at 5 µM, rsv-NLC were able to inhibit nuclear factor κ beta phosphorylation and significantly decrease the level of interleukin-12/23, both upregulated in response to TNF-α, while 10 µM free rsv were

  9. Nanostructured lipid carriers loaded with resveratrol modulate human dendritic cells.

    PubMed

    Barbosa, João P; Neves, Ana R; Silva, Andreia M; Barbosa, Mário A; Reis, M Salette; Santos, Susana G

    2016-01-01

    Dendritic cells (DCs) are promising targets for drug delivery, as they can induce immunity or tolerance. The current study aims to examine the potential of using nanostructured lipid carriers (NLC) as delivery systems for human DC by evaluating nanoparticle internalization, cell labeling, and drug activity. NLC were formulated incorporating the fluorochrome fluorescein isothiocyanate (FITC-NLC) or the natural anti-inflammatory molecule resveratrol (rsv-NLC). Primary human DCs were differentiated from peripheral blood monocytes, and the innovative imaging flow cytometry technique was used to examine FITC-NLC internalization. The capacity of rsv-NLC to inhibit DC activation in response to proinflammatory cytokine tumor necrosis factor-α (TNF- α) was investigated by conventional flow cytometry. A combination of imaging and conventional flow cytometry was used to assess NLC cytotoxicity. The results obtained indicate that both NLC formulations were stable over time, with mean diameter <200 nm and highly negative zeta potential (about -30 mV). When DCs were placed in contact with NLC, imaging flow cytometry clearly showed that DCs efficiently internalized FITC-NLC, with nearly 100% of cells internalizing nanoparticles upon 1 hour of incubation. Both immature and mature DCs internalized NLC to high and comparable levels, and without cytotoxicity. Stimulating DC with TNF-α in the presence of rsv-NLC revealed that, using these nanoparticles, very small concentrations of rsv were sufficient to significantly decrease surface expression of activation marker CD83 (5 µM) and major histocompatibility complex-class II molecule human leukocyte antigen - antigen D related (10 µM), both upregulated in response to TNF-α stimulation. Rsv-NLC were compared with free rsv; at 5 µM, rsv-NLC were able to inhibit nuclear factor κ beta phosphorylation and significantly decrease the level of interleukin-12/23, both upregulated in response to TNF-α, while 10 µM free rsv were needed

  10. T cells kill bacteria captured by transinfection from dendritic cells and confer protection in mice.

    PubMed

    Cruz-Adalia, Aránzazu; Ramirez-Santiago, Guillermo; Calabia-Linares, Carmen; Torres-Torresano, Mónica; Feo, Lidia; Galán-Díez, Marta; Fernández-Ruiz, Elena; Pereiro, Eva; Guttmann, Peter; Chiappi, Michele; Schneider, Gerd; Carrascosa, José López; Chichón, Francisco Javier; Martínez Del Hoyo, Gloria; Sánchez-Madrid, Francisco; Veiga, Esteban

    2014-05-14

    Dendritic cells (DCs) phagocytose, process, and present bacterial antigens to T lymphocytes to trigger adaptive immunity. In vivo, bacteria can also be found inside T lymphocytes. However, T cells are refractory to direct bacterial infection, leaving the mechanisms by which bacteria invade T cells unclear. We show that T cells take up bacteria from infected DCs by the process of transinfection, which requires direct contact between the two cells and is enhanced by antigen recognition. Prior to transfer, bacteria localize to the immunological synapse, an intimate DC/T cell contact structure that activates T cells. Strikingly, T cells efficiently eliminate the transinfecting bacteria within the first hours after infection. Transinfected T cells produced high levels of proinflammatory cytokines and were able to protect mice from bacterial challenge following adoptive transfer. Thus, T lymphocytes can capture and kill bacteria in a manner reminiscent of innate immunity. PMID:24832455

  11. Dengue tropism for macrophages and dendritic cells: the host cell effect.

    PubMed

    Flipse, Jacky; Torres, Silvia; Diosa-Toro, Mayra; van der Ende-Metselaar, Heidi; Herrera-Rodriguez, José; Urcuqui-Inchima, Silvio; Huckriede, Anke; Rodenhuis-Zybert, Izabela A; Smit, Jolanda M

    2016-07-01

    Dengue virus infects immune cells, including monocytes, macrophages and dendritic cells (DC). We compared virus infectivity in macrophages and DC, and found that the virus origin determined the cell tropism of progeny virus. The highest efficiency of re-infection was seen for macrophage-derived dengue virus. Furthermore, in the presence of enhancing antibodies, macrophage-derived virus gave greater enhancement of infection compared with immature DC-derived virus. Taken together, our results highlight the importance of macrophages in dengue infection. PMID:27046075

  12. The yin and yang of intestinal epithelial cells in controlling dendritic cell function

    PubMed Central

    Iliev, Iliyan D.; Matteoli, Gianluca; Rescigno, Maria

    2007-01-01

    Recent work suggests that dendritic cells (DCs) in mucosal tissues are “educated” by intestinal epithelial cells (IECs) to suppress inflammation and promote immunological tolerance. After attack by pathogenic microorganisms, however, “non-educated” DCs are recruited from nearby areas, such as the dome of Peyer's patches (PPs) and the blood, to initiate inflammation and the ensuing immune response to the invader. Differential epithelial cell (EC) responses to commensals and pathogens may control these two tolorogenic and immunogenic functions of DCs. PMID:17893197

  13. Migration of Langerhans cells and gammadelta dendritic cells from UV-B-irradiated sheep skin.

    PubMed

    Dandie, G W; Clydesdale, G J; Radcliff, F J; Muller, H K

    2001-02-01

    Depletion of dendritic cells from UV-B-irradiated sheep skin was investigated by monitoring migration of these cells towards regional lymph nodes. By creating and cannulating pseudoafferent lymphatic vessels draining a defined region of skin, migrating cells were collected and enumerated throughout the response to UV-B irradiation. In the present study, the effects of exposing sheep flank skin to UV-B radiation clearly demonstrated a dose-dependent increase in the migration of Langerhans cells (LC) from the UV-B-exposed area to the draining lymph node. The range of UV-B doses assessed in this study included 2.7 kJ/m2, a suberythemal dose; 8 kJ/m2, 1 minimal erythemal dose (MED); 20.1 kJ/m2; 40.2 kJ/m2; and 80.4 kJ/m2, 10 MED. The LC were the cells most sensitive to UV-B treatment, with exposure to 8 kJ/m2 or greater reproducibly causing a significant increase in migration. Migration of gammadelta+ dendritic cells (gammadelta+ DC) from irradiated skin was also triggered by exposure to UV-B radiation, but dose dependency was not evident within the range of UV-B doses examined. This, in conjunction with the lack of any consistent correlation between either the timing or magnitude of migration peaks of these two cell types, suggests that different mechanisms govern the egress of LC and gammadelta+ DC from the skin. It is concluded that the depression of normal immune function in the skin after exposure to erythemal doses of UV-B radiation is associated with changes in the migration patterns of epidermal dendritic cells to local lymph nodes. PMID:11168622

  14. Functional and transcriptional profiling of MUTZ-3, a myeloid cell line acting as a model for dendritic cells

    PubMed Central

    Larsson, Kristina; Lindstedt, Malin; Borrebaeck, Carl A K

    2006-01-01

    The incidence of allergy is steadily increasing, but the molecular mechanisms involved in the allergic immune response are still not fully understood. In particular, further investigations focusing on dendritic cells, which are central in orchestrating the immune response, are needed. The objective of this study was to investigate the ability of myeloid leukaemia-derived cell lines, such as KG-1, THP-1 and MUTZ-3, to serve as in vitro models for dendritic cells. The ability of these cell lines to mature into functional dendritic cells, expressing costimulatory molecules, was assessed by functional and transcriptional profiling and compared with that of monocyte-derived dendritic cells, which are now used as a standard source of dendritic cells. High-density microarray analysis was utilized to study the transcriptional activity and kinetics of activation of the differentiated MUTZ-3 cell line, in response to a cocktail of inflammatory cytokines. The data obtained clearly demonstrate that MUTZ-3 cells have the ability to induce antigen-independent proliferation in CD4+ CD45RA+ T cells, whereas KG-1 and THP-1 only induced a marginal response. Furthermore, MUTZ-3 displayed the phenotypic and transcriptional profiles of immature dendritic cells, after differentiation with granulocyte–macrophage colony-stimulating factor and interleukin-4. Upon activation with inflammatory cytokines, MUTZ-3 matured phenotypically and exhibited a gene induction similar to that of monocyte-derived dendritic cells. This delineation of the cellular and transcriptional activity of MUTZ-3, in response to maturational stimuli, demonstrates the significance of this cell line as a model for functional studies of inflammatory responses. PMID:16423051

  15. Stromal fibroblasts support dendritic cells to maintain IL-23/Th17 responses after exposure to ionizing radiation.

    PubMed

    Malecka, Anna; Wang, Qunwei; Shah, Sabaria; Sutavani, Ruhcha V; Spendlove, Ian; Ramage, Judith M; Greensmith, Julie; Franks, Hester A; Gough, Michael J; Saalbach, Anja; Patel, Poulam M; Jackson, Andrew M

    2016-08-01

    Dendritic cell function is modulated by stromal cells, including fibroblasts. Although poorly understood, the signals delivered through this crosstalk substantially alter dendritic cell biology. This is well illustrated with release of TNF-α/IL-1β from activated dendritic cells, promoting PGE2 secretion from stromal fibroblasts. This instructs dendritic cells to up-regulate IL-23, a key Th17-polarizing cytokine. We previously showed that ionizing radiation inhibited IL-23 production by human dendritic cells in vitro. In the present study, we investigated the hypothesis that dendritic cell-fibroblast crosstalk overcomes the suppressive effect of ionizing radiation to support appropriately polarized Th17 responses. Radiation (1-6 Gy) markedly suppressed IL-23 secretion by activated dendritic cells (P < 0.0001) without adversely impacting their viability and consequently, inhibited the generation of Th17 responses. Cytokine suppression by ionizing radiation was selective, as there was no effect on IL-1β, -6, -10, and -27 or TNF-α and only a modest (11%) decrease in IL-12p70 secretion. Coculture with fibroblasts augmented IL-23 secretion by irradiated dendritic cells and increased Th17 responses. Importantly, in contrast to dendritic cells, irradiated fibroblasts maintained their capacity to respond to TNF-α/IL-1β and produce PGE2, thus providing the key intermediary signals for successful dendritic cell-fibroblasts crosstalk. In summary, stromal fibroblasts support Th17-polarizing cytokine production by dendritic cells that would otherwise be suppressed in an irradiated microenvironment. This has potential ramifications for understanding the immune response to local radiotherapy. These findings underscore the need to account for the impact of microenvironmental factors, including stromal cells, in understanding the control of immunity. PMID:27049023

  16. Role of dendritic cells in the induction of regulatory T cells

    PubMed Central

    2011-01-01

    Dendritic cells (DCs) play a key role in initiating immune responses and maintaining immune tolerance. In addition to playing a role in thymic selection, DCs play an active role in tolerance under steady state conditions through several mechanisms which are dependent on IL-10, TGF-β, retinoic acid, indoleamine-2,3,-dioxygenase along with vitamin D. Several of these mechanisms are employed by DCs in induction of regulatory T cells which are comprised of Tr1 regulatory T cells, natural and inducible foxp3+ regulatory T cells, Th3 regulatory T cells and double negative regulatory T cells. It appears that certain DC subsets are highly specialized in inducing regulatory T cell differentiation and in some tissues the local microenvironment plays a role in driving DCs towards a tolerogenic response. In this review we discuss the recent advances in our understanding of the mechanisms underlying DC driven regulatory T cell induction. PMID:21711933

  17. Control of regulatory T cells and airway tolerance by lung macrophages and dendritic cells.

    PubMed

    Duan, Wei; Croft, Michael

    2014-12-01

    Airway tolerance, a state of immunological surveillance, suppresses the development of lung inflammatory disorders that are driven by various pathological effector cells of the immune system. Tolerance in the lung to inhaled antigens is primarily mediated by regulatory T cells (Treg cells) that can inhibit effector T cells via a myriad of mechanisms. Accumulating evidence suggests that regulatory antigen-presenting cells are critical for generating Treg cells and/or maintaining the suppressive environment in the lung. This review focuses on the control of airway tolerance by Treg cells and the role of regulatory lung tissue and alveolar macrophages, and lung and lymph node dendritic cells, in contributing to airway tolerance that is associated with suppression of allergic asthmatic disease. PMID:25525738

  18. MHC Class II Antigen Presentation by Dendritic Cells Regulated through Endosomal Sorting

    PubMed Central

    ten Broeke, Toine; Wubbolts, Richard; Stoorvogel, Willem

    2013-01-01

    For the initiation of adaptive immune responses, dendritic cells present antigenic peptides in association with major histocompatibility complex class II (MHCII) to naïve CD4+ T lymphocytes. In this review, we discuss how antigen presentation is regulated through intracellular processing and trafficking of MHCII. Newly synthesized MHCII is chaperoned by the invariant chain to endosomes, where peptides from endocytosed pathogens can bind. In nonactivated dendritic cells, peptide-loaded MHCII is ubiquitinated and consequently sorted by the ESCRT machinery to intraluminal vesicles of multivesicular bodies, ultimately leading to lysosomal degradation. Ubiquitination of newly synthesized MHCII is blocked when dendritic cells are activated, now allowing its transfer to the cell surface. This mode of regulation for MHCII is a prime example of how molecular processing and sorting at multivesicular bodies can determine the expression of signaling receptors at the plasma membrane. PMID:24296169

  19. Chronic alcohol exposure affects the cell components involved in membrane traffic in neuronal dendrites.

    PubMed

    Romero, Ana M; Renau-Piqueras, Jaime; Marín, M Pilar; Esteban-Pretel, Guillermo

    2015-01-01

    The specific traffic of the membrane components in neurons is a major requirement to establish and maintain neuronal domains-the axonal and the somatodendritic domains-and their polarized morphology. Unlike axons, dendrites contain membranous organelles, which are involved in the secretory pathway, including the endoplasmic reticulum, the Golgi apparatus and post-Golgi apparatus carriers, the cytoskeleton, and plasma membrane. A variety of molecules and factors are also involved in this process. Previous studies have shown that chronic alcohol exposure negatively affects several of these cell components, such as the Golgi apparatus or cytoskeleton in neurons. Yet very little information is available on the possible effects of this exposure on the remaining cell elements involved in intracellular trafficking in neurons, particularly in dendrites. By qualitative and quantitative electron microscopy, immunofluorescence and immunoblotting, we herein show that chronic exposure to moderate levels (30 mM) of ethanol in cultured neurons reduces the volume and surface density of the rough endoplasmic reticulum, and increases the levels of GRP78, a chaperone involved in endoplasmic reticulum stress. Ethanol also significantly diminishes the proportion of neurons that show an extension of Golgi into dendrites and dendritic Golgi outposts, a structure present exclusively in longer, thicker apical dendrites. Both Golgi apparatus types were also fragmented into a large number of cells. We also investigated the effect of alcohol on the levels of microtubule-based motor proteins KIF5, KIF17, KIFC2, dynein, and myosin IIb, responsible for transporting different cargoes in dendrites. Of these, alcohol differently affects several of them by lowering dynein and raising KIF5, KIFC2, and myosin IIb. These results, together with other previously published ones, suggest that practically all the protein trafficking steps in dendrites are altered to a greater or lesser extent by chronic

  20. Mast cells and dendritic cells form synapses that facilitate antigen transfer for T cell activation

    PubMed Central

    Carroll-Portillo, Amanda; Cannon, Judy L.; te Riet, Joost; Holmes, Anna; Kawakami, Yuko; Kawakami, Toshiaki; Cambi, Alessandra

    2015-01-01

    Mast cells (MCs) produce soluble mediators such as histamine and prostaglandins that are known to influence dendritic cell (DC) function by stimulating maturation and antigen processing. Whether direct cell–cell interactions are important in modulating MC/DC function is unclear. In this paper, we show that direct contact between MCs and DCs occurs and plays an important role in modulating the immune response. Activation of MCs through FcεRI cross-linking triggers the formation of stable cell–cell interactions with immature DCs that are reminiscent of the immunological synapse. Direct cellular contact differentially regulates the secreted cytokine profile, indicating that MC modulation of DC populations is influenced by the nature of their interaction. Synapse formation requires integrin engagement and facilitates the transfer of internalized MC-specific antigen from MCs to DCs. The transferred material is ultimately processed and presented by DCs and can activate T cells. The physiological outcomes of the MC–DC synapse suggest a new role for intercellular crosstalk in defining the immune response. PMID:26304724

  1. Prominent role for plasmacytoid dendritic cells in mucosal T cell-independent IgA induction.

    PubMed

    Tezuka, Hiroyuki; Abe, Yukiko; Asano, Jumpei; Sato, Taku; Liu, Jiajia; Iwata, Makoto; Ohteki, Toshiaki

    2011-02-25

    Although both conventional dendritic cells (cDCs) and plasmacytoid dendritic cells (pDCs) are present in the gut-associated lymphoid tissues (GALT), the roles of pDCs in the gut remain largely unknown. Here we show a critical role for pDCs in T cell-independent (TI) IgA production by B cells in the GALT. When pDCs of the mesenteric lymph nodes (MLNs) and Peyer's patches (PPs) (which are representative GALT) were cultured with naive B cells to induce TI IgA class switch recombination (CSR), IgA production was substantially higher than in cocultures of these cells with cDCs. IgA production was dependent on APRIL and BAFF production by pDCs. Importantly, pDC expression of APRIL and BAFF was dependent on stromal cell-derived type I IFN signaling under steady-state conditions. Our findings provide insight into the molecular basis of pDC conditioning to induce mucosal TI IgA production, which may lead to improvements in vaccination strategies and treatment for mucosal-related disorders. PMID:21333555

  2. Role of cellular prion proteins in the function of macrophages and dendritic cells.

    PubMed

    Nitta, Kayako; Sakudo, Akikazu; Masuyama, Jun; Xue, Guangai; Sugiura, Katsuaki; Onodera, Takashi

    2009-01-01

    The cellular isoform of prion proteins (PrPC) is expressed in hematopoietic stem cells, granulocytes, T and B lymphocyte natural killer cells, platelets, monocytes, dendritic cells, and follicular dendritic cells, which may act as carrier cells for the spread of its abnormal isoform (PrPSc) before manifesting transmissible spongiform encephalopathies (TSEs). In particular, macrophages and dendritic cells seem to be involved in the replication of PrPSc after ingestion. In addition, information on the role of PrPC during phagocytotic activity in these cells has been obtained. A recent study showed that resident macrophages from ZrchI PrP gene (Prnp)-deficient (Prnp-/-) mice show augmented phagocytotic activity compared to Prnp+/+ counterparts. In contrast, our study suggests that Rikn Prnp-/- peritoneal macrophages show pseudopodium extension arrest and up-regulation of phagocytotic activity compared to Prnp+/+ cells. Although reports regarding phagocytotic activity in resident and peritoneal macrophages are inconsistent between ZrchI and Rikn Prnp-/- mice, it seems plausible that PrPC in macrophages could contribute to maintain the immunological environment. This review will introduce the recent progress in understanding the functions of PrPC in macrophages and dendritic cells under physiological conditions and its involvement in the pathogenesis of prion diseases. PMID:19275736

  3. Olfactory nerve stimulation-induced calcium signaling in the mitral cell distal dendritic tuft.

    PubMed

    Yuan, Q; Knöpfel, T

    2006-04-01

    Olfactory receptor neuron axons form the olfactory nerve (ON) and project to the glomerular layer of the olfactory bulb, where they form excitatory synapses with terminal arborizations of the mitral cell (MC) tufted primary dendrite. Clusters of MC dendritic tufts define olfactory glomeruli, where they involve in complex synaptic interactions. The computational function of these cellular interactions is not clear. We used patch-clamp electrophysiology combined with whole field or two-photon Ca2+ imaging to study ON stimulation-induced Ca2+ signaling at the level of individual terminal branches of the MC primary dendrite in mice. ON-evoked subthreshold excitatory postsnaptic potentials induced Ca2+ transients in the MC tuft dendrites that were spatially inhomogeneous, exhibiting discrete "hot spots." In contrast, Ca2+ transients induced by backpropagating action potentials occurred throughout the dendritic tuft, being larger in the thin terminal dendrites than in the base of the tuft. Single ON stimulation-induced Ca2+ transients were depressed by the NMDA receptor antagonist D-aminophosphonovaleric acid (D-APV), increased with increasing stimulation intensity, and typically showed a prolonged rising phase. The synaptically induced Ca2+ signals reflect, at least in part, dendrodendritic interactions that support intraglomerular coupling of MCs and generation of an output that is common to all MCs associated with one glomerulus. PMID:16319202

  4. Brain-derived neurotrophic factor prevents dendritic retraction of adult mouse retinal ganglion cells.

    PubMed

    Binley, Kate E; Ng, Wai S; Barde, Yves-Alain; Song, Bing; Morgan, James E

    2016-08-01

    We used cultured adult mouse retinae as a model system to follow and quantify the retraction of dendrites using diolistic labelling of retinal ganglion cells (RGCs) following explantation. Cell death was monitored in parallel by nuclear staining as 'labelling' with RGC and apoptotic markers was inconsistent and exceedingly difficult to quantify reliably. Nuclear staining allowed us to delineate a lengthy time window during which dendrite retraction can be monitored in the absence of RGC death. The addition of brain-derived neurotrophic factor (BDNF) produced a marked reduction in dendritic degeneration, even when application was delayed for 3 days after retinal explantation. These results suggest that the delayed addition of trophic factors may be functionally beneficial before the loss of cell bodies in the course of conditions such as glaucoma. PMID:27285957

  5. Preconditioning Vaccine Sites for mRNA-Transfected Dendritic Cell Therapy and Antitumor Efficacy.

    PubMed

    Batich, Kristen A; Swartz, Adam M; Sampson, John H

    2016-01-01

    Messenger RNA (mRNA)-transfected dendritic cell (DC) vaccines have been shown to be a powerful modality for eliciting antitumor immune responses in mice and humans; however, their application has not been fully optimized since many of the factors that contribute to their efficacy remain poorly understood. Work stemming from our laboratory has recently demonstrated that preconditioning the vaccine site with a recall antigen prior to the administration of a dendritic cell vaccine creates systemic recall responses and resultantly enhances dendritic cell migration to the lymph nodes with improved antitumor efficacy. This chapter describes the generation of murine mRNA-transfected DC vaccines, as well as a method for vaccine site preconditioning with protein antigen formulations that create potent recall responses. PMID:27076169

  6. Orf virus IL-10 reduces monocyte, dendritic cell and mast cell recruitment to inflamed skin.

    PubMed

    Bennett, Jared R; Lateef, Zabeen; Fleming, Stephen B; Mercer, Andrew A; Wise, Lyn M

    2016-02-01

    Orf virus (ORFV) is a zoonotic parapoxvirus that causes pustular dermatitis of sheep, and occasionally humans. Despite causing sustained infections, ORFV induces only a transient increase in pro-inflammatory signalling and the trafficking of innate immune cells within the skin seems to be impaired. An explanation for this tempered response to ORFV infection may lie in its expression of a homolog of the anti-inflammatory cytokine, interleukin (IL)-10. Using a murine model in which inflammation was induced by bacterial lipopolysaccharide, we examined the effects of the ORFV-IL-10 protein on immune cell trafficking to and from the skin. ORFV-IL-10 limited the recruitment of blood-derived Gr-1(int)/CD11b(int) monocytes, CD11c(+ve)/MHC-II(+ve) dendritic cells and c-kit(+ve)/FcεR1(+ve) mature mast cells into inflamed skin. ORFV-IL-10 also suppressed the activation of CD11c(+ve)/MHC-II(+ve) dendritic cells within the skin, reducing their trafficking to the draining lymph node. These findings suggest that expression of IL-10 by ORFV may contribute to the impaired trafficking of innate immune cells within infected skin. PMID:26732486

  7. Interleukin 15 Skews Monocyte Differentiation into Dendritic Cells with Features of Langerhans Cells

    PubMed Central

    Mohamadzadeh, Mansour; Berard, Frederic; Essert, Gregory; Chalouni, Cecile; Pulendran, Bali; Davoust, Jean; Bridges, George; Palucka, A. Karolina; Banchereau, Jacques

    2001-01-01

    Langerhans cells (LCs) represent a subset of immature dendritic cells (DCs) specifically localized in the epidermis and other mucosal epithelia. As surrounding keratinocytes can produce interleukin (IL)-15, a cytokine that utilizes IL-2Rγ chain, we analyzed whether IL-15 could skew monocyte differentiation into LCs. Monocytes cultured for 6 d with granulocyte/macrophage colony-stimulating factor (GM-CSF) and IL-15 differentiate into CD1a+HLA-DR+CD14−DCs (IL15-DCs). Agents such as lipopolysaccharide (LPS), tumor necrosis factor (TNF)α, and CD40L induce maturation of IL15-DCs to CD83+, DC-LAMP+ cells. IL15-DCs are potent antigen-presenting cells able to induce the primary (mixed lymphocyte reaction [MLR]) and secondary (recall responses to flu-matrix peptide) immune responses. As opposed to cultures made with GM-CSF/IL-4 (IL4-DCs), a proportion of IL15-DCs expresses LC markers: E-Cadherin, Langerin, and CC chemokine receptor (CCR)6. Accordingly, IL15-DCs, but not IL4-DCs, migrate in response to macrophage inflammatory protein (MIP)-3α/CCL20. However, IL15-DCs cannot be qualified as “genuine” Langerhans cells because, despite the presence of the 43-kD Langerin, they do not express bona fide Birbeck granules. Thus, our results demonstrate a novel pathway in monocyte differentiation into dendritic cells. PMID:11581322

  8. Phenotypic, ultra-structural and functional characterization of bovine peripheral blood dendritic cell subsets

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Dendritic cells (DC) are multifunctional cells that bridge the gap between innate and adaptive immune systems. In bovine, significant information is lacking on the precise identity and role of peripheral blood DC subsets. In this study, we identify and characterize bovine peripheral blood DC subsets...

  9. Suppression of Th1-Mediated Autoimmunity by Embryonic Stem Cell-Derived Dendritic Cells

    PubMed Central

    Ikeda, Tokunori; Hirata, Shinya; Takamatsu, Koutaro; Haruta, Miwa; Tsukamoto, Hirotake; Ito, Takaaki; Uchino, Makoto; Ando, Yukio; Nagafuchi, Seiho; Nishimura, Yasuharu; Senju, Satoru

    2014-01-01

    We herein demonstrate the immune-regulatory effect of embryonic stem cell-derived dendritic cells (ES-DCs) using two models of autoimmune disease, namely non-obese diabetic (NOD) mice and experimental autoimmune encephalomyelitis (EAE). Treatment of pre-diabetic NOD mice with ES-DCs exerted almost complete suppression of diabetes development during the observation period for more than 40 weeks. The prevention of diabetes by ES-DCs was accompanied with significant reduction of insulitis and decreased number of Th1 and Th17 cells in the spleen. Development of EAE was also inhibited by the treatment with ES-DCs, and the therapeutic effect was obtained even if ES-DCs were administrated after the onset of clinical symptoms. Treatment of EAE-induced mice with ES-DCs reduced the infiltration of inflammatory cells into the spinal cord and suppressed the T cell response to the myelin antigen. Importantly, the ES-DC treatment did not affect T cell response to an exogenous antigen. As the mechanisms underlying the reduction of the number of infiltrating Th1 cells, we observed the inhibition of differentiation and proliferation of Th1 cells by ES-DCs. Furthermore, the expression of VLA-4α on Th1 cells was significantly inhibited by ES-DCs. Considering the recent advances in human induced pluripotent stem cell-related technologies, these results suggest a clinical application for pluripotent stem cell-derived dendritic cells as a therapy for T cell-mediated autoimmune diseases. PMID:25522369

  10. Suppression of Th1-mediated autoimmunity by embryonic stem cell-derived dendritic cells.

    PubMed

    Ikeda, Tokunori; Hirata, Shinya; Takamatsu, Koutaro; Haruta, Miwa; Tsukamoto, Hirotake; Ito, Takaaki; Uchino, Makoto; Ando, Yukio; Nagafuchi, Seiho; Nishimura, Yasuharu; Senju, Satoru

    2014-01-01

    We herein demonstrate the immune-regulatory effect of embryonic stem cell-derived dendritic cells (ES-DCs) using two models of autoimmune disease, namely non-obese diabetic (NOD) mice and experimental autoimmune encephalomyelitis (EAE). Treatment of pre-diabetic NOD mice with ES-DCs exerted almost complete suppression of diabetes development during the observation period for more than 40 weeks. The prevention of diabetes by ES-DCs was accompanied with significant reduction of insulitis and decreased number of Th1 and Th17 cells in the spleen. Development of EAE was also inhibited by the treatment with ES-DCs, and the therapeutic effect was obtained even if ES-DCs were administrated after the onset of clinical symptoms. Treatment of EAE-induced mice with ES-DCs reduced the infiltration of inflammatory cells into the spinal cord and suppressed the T cell response to the myelin antigen. Importantly, the ES-DC treatment did not affect T cell response to an exogenous antigen. As the mechanisms underlying the reduction of the number of infiltrating Th1 cells, we observed the inhibition of differentiation and proliferation of Th1 cells by ES-DCs. Furthermore, the expression of VLA-4α on Th1 cells was significantly inhibited by ES-DCs. Considering the recent advances in human induced pluripotent stem cell-related technologies, these results suggest a clinical application for pluripotent stem cell-derived dendritic cells as a therapy for T cell-mediated autoimmune diseases. PMID:25522369

  11. Ion efflux and influenza infection trigger NLRP3 inflammasome signaling in human dendritic cells.

    PubMed

    Fernandez, Melissa Victoria; Miller, Elizabeth; Krammer, Florian; Gopal, Ramya; Greenbaum, Benjamin D; Bhardwaj, Nina

    2016-05-01

    The nucleotide-binding oligomerization domain-like receptor protein 3 inflammasome, a multiprotein complex, is an essential intracellular mediator of antiviral immunity. In murine dendritic cells, this complex responds to a wide array of signals, including ion efflux and influenza A virus infection, to activate caspase-1-mediated proteolysis of IL-1β and IL-18 into biologically active cytokines. However, the presence and function of the nucleotide-binding oligomerization domain-like receptor protein 3 inflammasome in human dendritic cells, in response to various triggers, including viral infection, has not been defined clearly. Here, we delineate the contribution of the nucleotide-binding oligomerization domain-like receptor protein 3 inflammasome to the secretion of IL-1β, IL-18, and IL-1α by human dendritic cells (monocyte-derived and primary conventional dendritic cells). Activation of the nucleotide-binding oligomerization domain-like receptor protein 3 inflammasome in human dendritic cells by various synthetic activators resulted in the secretion of bioactive IL-1β, IL-18, and IL-1α and induction of pyroptotic cell death. Cellular IL-1β release depended on potassium efflux and the activity of proteins nucleotide-binding oligomerization domain-like receptor protein 3 and caspase-1. Likewise, influenza A virus infection of dendritic cells resulted in priming and activation of the nucleotide-binding oligomerization domain-like receptor protein 3 inflammasome and secretion of IL-1β and IL-18 in an M2- and nucleotide-binding oligomerization domain-like receptor protein 3-dependent manner. The magnitude of priming by influenza A virus varied among different strains and inversely corresponded to type I IFN production. To our knowledge, this is the first report describing the existence and function of the nucleotide-binding oligomerization domain-like receptor protein 3 inflammasome in human dendritic cells and the ability of influenza A virus to prime and

  12. Modulation of Dendritic Cell Immunobiology via Inhibition of 3-Hydroxy-3-Methylglutaryl-CoA (HMG-CoA) Reductase

    PubMed Central

    Luessi, Felix; Bendix, Ivo; Paterka, Magdalena; Prozorovski, Timour; Treue, Denise; Luenstedt, Sarah; Herz, Josephine; Siffrin, Volker; Infante-Duarte, Carmen; Zipp, Frauke; Waiczies, Sonia

    2014-01-01

    The maturation status of dendritic cells determines whether interacting T cells are activated or if they become tolerant. Previously we could induce T cell tolerance by applying a 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitor (HMGCRI) atorvastatin, which also modulates MHC class II expression and has therapeutic potential in autoimmune disease. Here, we aimed at elucidating the impact of this therapeutic strategy on T cell differentiation as a consequence of alterations in dendritic cell function. We investigated the effect of HMGCRI during differentiation of peripheral human monocytes and murine bone marrow precursors to immature DC in vitro and assessed their phenotype. To examine the stimulatory and tolerogenic capacity of these modulated immature dendritic cells, we measured proliferation and suppressive function of CD4+ T cells after stimulation with the modulated immature dendritic cells. We found that an HMGCRI, atorvastatin, prevents dendrite formation during the generation of immature dendritic cells. The modulated immature dendritic cells had a diminished capacity to take up and present antigen as well as to induce an immune response. Of note, the consequence was an increased capacity to differentiate naïve T cells towards a suppressor phenotype that is less sensitive to proinflammatory stimuli and can effectively inhibit the proliferation of T effector cells in vitro. Thus, manipulation of antigen-presenting cells by HMGCRI contributes to an attenuated immune response as shown by promotion of T cells with suppressive capacities. PMID:25013913

  13. Cross-Presentation of Cell-Associated Antigens by MHC Class I in Dendritic Cell Subsets

    PubMed Central

    Gutiérrez-Martínez, Enric; Planès, Remi; Anselmi, Giorgio; Reynolds, Matthew; Menezes, Shinelle; Adiko, Aimé Cézaire; Saveanu, Loredana; Guermonprez, Pierre

    2015-01-01

    Dendritic cells (DCs) have the unique ability to pick up dead cells carrying antigens in tissue and migrate to the lymph nodes where they can cross-present cell-associated antigens by MHC class I to CD8+ T cells. There is strong in vivo evidence that the mouse XCR1+ DCs subset acts as a key player in this process. The intracellular processes underlying cross-presentation remain controversial and several pathways have been proposed. Indeed, a wide number of studies have addressed the cellular process of cross-presentation in vitro using a variety of sources of antigen and antigen-presenting cells. Here, we review the in vivo and in vitro evidence supporting the current mechanistic models and disscuss their physiological relevance to the cross-presentation of cell-associated antigens by DCs subsets. PMID:26236315

  14. IgA production requires B cell interaction with subepithelial dendritic cells in Peyer's patches.

    PubMed

    Reboldi, Andrea; Arnon, Tal I; Rodda, Lauren B; Atakilit, Amha; Sheppard, Dean; Cyster, Jason G

    2016-05-13

    Immunoglobulin A (IgA) induction primarily occurs in intestinal Peyer's patches (PPs). However, the cellular interactions necessary for IgA class switching are poorly defined. Here we show that in mice, activated B cells use the chemokine receptor CCR6 to access the subepithelial dome (SED) of PPs. There, B cells undergo prolonged interactions with SED dendritic cells (DCs). PP IgA class switching requires innate lymphoid cells, which promote lymphotoxin-β receptor (LTβR)-dependent maintenance of DCs. PP DCs augment IgA production by integrin αvβ8-mediated activation of transforming growth factor-β (TGFβ). In mice where B cells cannot access the SED, IgA responses against oral antigen and gut commensals are impaired. These studies establish the PP SED as a niche supporting DC-B cell interactions needed for TGFβ activation and induction of mucosal IgA responses. PMID:27174992

  15. Presence and regulation of the endocannabinoid system in human dendritic cells.

    PubMed

    Matias, Isabel; Pochard, Pierre; Orlando, Pierangelo; Salzet, Michel; Pestel, Joel; Di Marzo, Vincenzo

    2002-08-01

    Cannabinoid receptors and their endogenous ligands, the endocannabinoids, have been detected in several blood immune cells, including monocytes/macrophages, basophils and lymphocytes. However, their presence in dendritic cells, which play a key role in the initiation and development of the immune response, has never been investigated. Here we have analyzed human dendritic cells for the presence of the endocannabinoids, anandamide and 2-arachidonoylglycerol (2-AG), the cannabinoid CB1 and CB2 receptors, and one of the enzymes mostly responsible for endocannabinoid hydrolysis, the fatty acid amide hydrolase (FAAH). By using a very sensitive liquid chromatography-atmospheric pressure chemical ionization-mass spectrometric (LC-APCI-MS) method, lipids extracted from immature dendritic cells were shown to contain 2-AG, anandamide and the anti-inflammatory anandamide congener, N-palmitoylethanolamine (PalEtn) (2.1 +/- 1.0, 0.14 +/- 0.02 and 8.2 +/- 3.9 pmol x 10(-7) cells, respectively). The amounts of 2-AG, but not anandamide or PalEtn, were significantly increased following cell maturation induced by bacterial lipopolysaccharide (LPS) or the allergen Der p 1 (2.8- and 1.9-fold, respectively). By using both RT-PCR and Western immunoblotting, dendritic cells were also found to express measurable amounts of CB1 and CB2 receptors and of FAAH. Cell maturation did not consistently modify the expression of these proteins, although in some cell preparations a decrease of the levels of both CB1 and CB2 mRNA transcripts was observed after LPS stimulation. These findings demonstrate for the first time that the endogenous cannabinoid system is present in human dendritic cells and can be regulated by cell activation. PMID:12153574

  16. Identification of TTP mRNA targets in human dendritic cells reveals TTP as a critical regulator of dendritic cell maturation.

    PubMed

    Emmons, Jillian; Townley-Tilson, W H Davin; Deleault, Kristen M; Skinner, Stephen J; Gross, Robert H; Whitfield, Michael L; Brooks, Seth A

    2008-05-01

    Dendritic cells provide a critical link between innate and adaptive immunity and are essential to prime a naive T-cell response. The transition from immature dendritic cells to mature dendritic cells involves numerous changes in gene expression; however, the role of post-transcriptional changes in this process has been largely ignored. Tristetraprolin is an AU-rich element mRNA-binding protein that has been shown to regulate the stability of a number of cytokines and chemokines of mRNAs. Using TTP immunoprecipitations and Affymetrix GeneChips, we identified 393 messages as putative TTP mRNA targets in human dendritic cells. Gene ontology analysis revealed that approximately 25% of the identified mRNAs are associated with protein synthesis. We also identified six MHC Class I alleles, five MHC Class II alleles, seven chemokine and chemokine receptor genes, indoleamine 2,3 dioxygenase, and CD86 as putative TTP ligands. Real-time PCR was used to validate the GeneChip data for 15 putative target genes and functional studies performed for six target genes. These data establish that TTP regulates the expression of DUSP1, IDO, SOD2, CD86, and MHC Class I-B and F via the 3'-untranslated region of each gene. A novel finding is the demonstration that TTP can interact with and regulate the expression of non-AU-rich element-containing messages. The data implicate TTP as having a broader role in regulating and limiting the immune response than previously suspected. PMID:18367721

  17. An efficient method that reveals both the dendrites and the soma mosaics of retinal ganglion cells.

    PubMed

    Zhan, X J; Troy, J B

    1997-03-01

    A method of using neurobiotin to stain both the dendrites and the soma mosaics of retinal ganglion cells in fresh retinae is described. This method is simple to use and efficient in revealing morphological details for a large number of retinal ganglion cells. It has five advantages over currently available staining methods. (1) It stains all ganglion cells in the whole retina or in a selected retinal area, permitting ganglion cell distributions across the retina to be obtained. (2) It reveals cell dendrites in great detail, especially in regions outside the area centralis. The dendritic field mosaics and, therefore the dendritic field coverage factors, of different ganglion cell types across the whole retina can be obtained easily. (3) It works reliably, efficiently, and does not require the expensive set-up or the pains-taking work needed when staining cells through intracellular injection. (4) It works under both in vivo and in vitro settings, permitting the use of retinae from animals sacrificed for other purposes and the use of postmortem human retinae. (5) The end product of the visualization process is optically dark and electron dense, permitting specimens to be examined under both light and electron microscopes. PMID:9128174

  18. Intraperitoneal Follicular Dendritic Cell Sarcoma: Role of Chemotherapy and Bone Marrow Allotransplantation in Locally Advanced Disease?

    PubMed Central

    Liberale, G; Keriakos, K; Azerad, MA; De Saint Aubain, N; El Nakadi, I

    2015-01-01

    We describe a case of a 44 year-old woman diagnosed with follicular dendritic cell sarcoma (FDCS). FDCS is a very rare disease affecting the dendritic antigen presenting cells and is often misdiagnosed. Surgery is considered the best treatment modality, followed by chemotherapy. In our case, surgical excision was not possible, therefore the patient received two lines of chemotherapy followed by bone marrow allotransplantation, then a third line of chemotherapy with a complete metabolic response seen on PET/computed tomography (CT) follow-up 29 months later. A review of the literature has been performed. PMID:25698886

  19. Paraneoplastic Pemphigus Associated with Follicular Dendritic Cell Tumor in the Mediastinum

    PubMed Central

    Velarasan, Kanmani; Ram, Thomas Samuel

    2016-01-01

    Paraneoplastic Pemphigus (PNP) is an autoimmune bullous disease characterized by severe stomatitis, polymorphous skin eruptions, and underlying neoplasms. Diagnosis of cutaneous paraneoplastic disorders requires high index of suspicion. We describe a patient with PNP associated with follicular dendritic cell (FDC) tumor in the mediastinum, a rare neoplasm originating from follicular dendritic cells. Its management requires identification of underlying malignancy and treatment of the same. Our patient showed remission of PNP upon excision of the tumor and remained disease-free for 8 years. PMID:27190659

  20. Paraneoplastic Pemphigus Associated with Follicular Dendritic Cell Tumor in the Mediastinum.

    PubMed

    Prakasan, Aparna Mullangath; Prabhu, Anne Jennifer; Velarasan, Kanmani; Backianathan, Selvamani; Ram, Thomas Samuel

    2016-01-01

    Paraneoplastic Pemphigus (PNP) is an autoimmune bullous disease characterized by severe stomatitis, polymorphous skin eruptions, and underlying neoplasms. Diagnosis of cutaneous paraneoplastic disorders requires high index of suspicion. We describe a patient with PNP associated with follicular dendritic cell (FDC) tumor in the mediastinum, a rare neoplasm originating from follicular dendritic cells. Its management requires identification of underlying malignancy and treatment of the same. Our patient showed remission of PNP upon excision of the tumor and remained disease-free for 8 years. PMID:27190659

  1. Distinct axo-somato-dendritic distributions of three potassium channels in CA1 hippocampal pyramidal cells

    PubMed Central

    Kirizs, Tekla; Kerti-Szigeti, Katalin; Lorincz, Andrea; Nusser, Zoltan

    2014-01-01

    Potassium channels comprise the most diverse family of ion channels and play critical roles in a large variety of physiological and pathological processes. In addition to their molecular diversity, variations in their distributions and densities on the axo-somato-dendritic surface of neurons are key parameters in determining their functional impact. Despite extensive electrophysiological and anatomical investigations, the exact location and densities of most K+ channels in small subcellular compartments are still unknown. Here we aimed at providing a quantitative surface map of two delayed-rectifier (Kv1.1 and Kv2.1) and one G-protein-gated inwardly rectifying (Kir3.2) K+ channel subunits on hippocampal CA1 pyramidal cells (PCs). Freeze-fracture replica immunogold labelling was employed to determine the relative densities of these K+ channel subunits in 18 axo-somato-dendritic compartments. Significant densities of the Kv1.1 subunit were detected on axon initial segments (AISs) and axon terminals, with an approximately eight-fold lower density in the latter compartment. The Kv2.1 subunit was found in somatic, proximal dendritic and AIS plasma membranes at approximately the same densities. This subunit has a non-uniform plasma membrane distribution; Kv2.1 clusters are frequently adjacent to, but never overlap with, GABAergic synapses. A quasi-linear increase in the Kir3.2 subunit density along the dendrites of PCs was detected, showing no significant difference between apical dendritic shafts, oblique dendrites or dendritic spines at the same distance from the soma. Our results demonstrate that each subunit has a unique cell-surface distribution pattern, and predict their differential involvement in synaptic integration and output generation at distinct subcellular compartments. PMID:24606584

  2. Can dendritic cells improve whole cancer cell vaccines based on immunogenically killed cancer cells?

    PubMed Central

    Cicchelero, Laetitia; Denies, Sofie; Devriendt, Bert; de Rooster, Hilde; Sanders, Niek N

    2015-01-01

    Immunogenic cell death (ICD) offers interesting opportunities in cancer cell (CC) vaccine manufacture, as it increases the immunogenicity of the dead CC. Furthermore, fusion of CCs with dendritic cells (DCs) is considered a superior method for generating whole CC vaccines. Therefore, in this work, we determined in naive mice whether immunogenically killed CCs per se (CC vaccine) elicit an antitumoral immune response different from the response observed when immunogenically killed CCs are associated with DCs through fusion (fusion vaccine) or through co-incubation (co-incubation vaccine). After tumor inoculation, the type of immune response in the prophylactically vaccinated mice differed between the groups. In more detail, fusion vaccines elicited a humoral anticancer response, whereas the co-incubation and CC vaccine mainly induced a cellular response. Despite these differences, all three approaches offered a prophylactic protection against tumor development in the murine mammary carcinoma model. In summary, it can be concluded that whole CC vaccines based on immunogenically killed CCs may not necessarily require association with DCs to elicit a protective anticancer immune response. If this finding can be endorsed in other cancer models, the manufacture of CC vaccines would greatly benefit from this new insight, as production of DC-based vaccines is laborious, time-consuming and expensive. PMID:26587315

  3. Visualizing Toll-like Receptor-dependent Phagosomal Dynamics in Murine Dendritic Cells Using Live Cell Microscopy

    PubMed Central

    Mantegazza, Adriana R.; Marks, Michael S.

    2015-01-01

    Dendritic cells are professional phagocytes that are highly specialized to process and present antigens from internalized particles to prime naïve T cells. To achieve their functions, the phagocytic machinery and membrane dynamics of these cells have been adapted to optimize presentation of antigens from phagocytosed particles that bear ligands of pattern recognition receptors, such as toll-like receptors (TLRs), and that are thus perceived of as “dangerous”. We have recently shown that phagosomes that are engaged in TLR signaling in dendritic cells emit numerous long tubules that facilitate content exchange with other signaling phagosomes and favor presentation of particle-derived antigens. This chapter describes the methods used to study the formation of these tubules, which we refer to as “phagotubules”, by live cell imaging of mouse dendritic cells after the phagocytosis of fluorescent latex beads. We also describe methods to assess the effect of TLR signaling on this process. PMID:25702119

  4. iPS-cell derived dendritic cells and macrophages for cancer therapy.

    PubMed

    Senju, Satoru

    2016-08-01

    Antibody-based anti-cancer immunotherapy was recently recognized as one of the truly effective therapies for cancer patients. Antibodies against cell surface cancer antigens, such as CD20, and also those against immune-inhibitory molecules called "immune checkpoint blockers", such as CTLA4 or PD1, have emerged. Large-scale clinical trials have confirmed that, in some cases, antibody-based drugs are superior to conventional chemotherapeutic agents. These antibody-based drugs are now being manufactured employing a mass-production system by pharmaceutical companies. Anti-cancer therapy by immune cells, i.e. cell-based immunotherapy, is expected to be more effective than antibody therapy, because immune cells can recognize, infiltrate, and act in cancer tissues more directly than antibodies. In order to achieve cell-based anti-cancer immunotherapy, it is necessary to develop manufacturing systems for mass-production of immune cells. Our group has been studying immunotherapy with myeloid cells derived from ES cells or iPS cells. These pluripotent stem cells can be readily propagated under constant culture conditions, with expansion into a large quantity. We consider these stem cells to be the most suitable cellular source for mass-production of immune cells. This review introduces our studies on anti-cancer therapy with iPS cell-derived dendritic cells and iPS cell-derived macrophages. PMID:27599426

  5. Intestinal dendritic cells survey circulatory antigens prior to induction of CD8+ T cells

    PubMed Central

    Chang, Sun Young; Song, Joo-Hye; Guleng, Bayasi; Cotoner, Carmen Alonso; Arihiro, Seiji; Zhao, Yun; Chiang, Hao-Sen; O'Keeffe, Michael; Liao, Gongxian; Karp, Christopher L.; Kweon, Mi-Na; Sharpe, Arlene H.; Bhan, Atul; Terhorst, Cox; Reinecker, Hans-Christian

    2013-01-01

    Circulatory antigens transit through the small intestine via the fenestrated capillaries in the lamina propria prior to entering into the draining lymphatics. But whether or how this process controls mucosal immune responses remains unknown. Here we demonstrate that dendritic cells (DCs) of the lamina propria can sample and process both circulatory and luminal antigens. Surprisingly, antigen cross-presentation by resident CX3CR1+ DCs induced differentiation of precursor cells into CD8+ T cells that expressed interleukin-10 (IL-10), IL-13 and IL-9 and could migrate into adjacent compartments. We conclude that lamina propria CX3CR1+ DCs facilitate the surveillance of circulatory antigens and act as a conduit for the processing of self- and intestinally-absorbed-antigens, leading to the induction of CD8+ T cells, that partake in the control of T cell activation during mucosal immune responses. PMID:23246312

  6. Clonal analysis of human dendritic cell progenitor using a stromal cell culture

    PubMed Central

    Lee, Jaeyop; Breton, Gaëlle; Aljoufi, Arafat; Zhou, Yu Jerry; Puhr, Sarah; Nussenzweig, Michel C.; Liu, Kang

    2015-01-01

    Different dendritic cell (DC) subsets co-exist in humans and coordinate the immune response. Having a short life, DCs must be constantly replenished from their progenitors in the bone marrow through hematopoiesis. Identification of a DC-restricted progenitor in mouse has improved our understanding of how DC lineage diverges from myeloid and lymphoid lineages. However, identification of the DC-restricted progenitor in humans has not been possible because a system that simultaneously nurtures differentiation of human DCs, myeloid and lymphoid cells, is lacking. Here we report a cytokine and stromal cell culture that allows evaluation of CD34+ progenitor potential to all three DC subsets as well as other myeloid and lymphoid cells, at a single cell level. Using this system, we show that human granulocyte–macrophage progenitors are heterogeneous and contain restricted progenitors to DCs. PMID:26056939

  7. Polarized Dendritic Cells as Cancer Vaccines: Directing Effector-type T Cells to Tumors

    PubMed Central

    Kalinski, Pawel; Okada, Hideho

    2010-01-01

    Ex-vivo-generation and antigen loading of dendritic cells (DCs) from cancer patients helps to bypass the dysfunction of endogenous DCs. It also allows to control the process of DC maturation and to imprint in maturing DCs several functions essential for induction of effective forms of cancer immunity. Recent reports from several groups including ours demonstrate that distinct conditions of DC generation and maturation can prime DCs for preferential interaction with different (effector versus regulatory) subsets of immune cells. Moreover, differentially-generated DCs have been shown to imprint different effector mechanisms in CD4+ and CD8+ T cells (delivery of “signal three”) and to induce their different homing properties (delivery of “signal four”). These developments allow for selective induction of tumor-specific T cells with desirable effector functions and tumor-relevant homing properties and to direct the desirable types of immune cells to tumors. PMID:20409732

  8. Dendritic cells and alveolar macrophages mediate IL-13–induced airway inflammation and chemokine production

    PubMed Central

    Crapster-Pregont, Margaret; Yeo, Janice; Sanchez, Raquel L.; Kuperman, Douglas A.

    2013-01-01

    Background IL-13 in the airway induces pathologies that are highly characteristic of asthma, including mucus metaplasia, airway hyperreactivity (AHR), and airway inflammation. As such, it is important to identify the IL-13–responding cell types that mediate each of the above pathologies. For example, IL-13’s effects on epithelium contribute to mucus metaplasia and AHR. IL-13’s effects on smooth muscle also contribute to AHR. However, it has been difficult to identify the cell types that mediate IL-13–induced airway inflammation. Objective We sought to determine which cell types mediate IL-13–induced airway inflammation. Methods We treated the airways of mice with IL-13 alone or in combination with IFN-γ. We associated the inhibitory effect of IFN-γ on IL-13–induced airway inflammation and chemokine production with cell types in the lung that coexpress IL-13 and IFN-γ receptors. We then evaluated IL-13–induced responses in CD11c promoter–directed diphtheria toxin receptor–expressing mice that were depleted of both dendritic cells and alveolar macrophages and in CD11b promoter–directed diphtheria toxin receptor– expressing mice that were depleted of dendritic cells. Results Dendritic cell and alveolar macrophage depletion protected mice from IL-13–induced airway inflammation and CCL11, CCL24, CCL22, and CCL17 chemokine production. Preferential depletion of dendritic cells protected mice from IL-13–induced airway inflammation and CCL22 and CCL17 chemokine production but not from IL-13–induced CCL11 and CCL24 chemokine production. In either case mice were not protected from IL-13–induced AHR and mucus metaplasia. Conclusions Pulmonary dendritic cells and alveolar macrophages mediate IL-13–induced airway inflammation and chemokine production. (J Allergy Clin Immunol 2012;129:1621-7.) PMID:22365581

  9. HIV is trapped and masked in the cytoplasm of lymph node follicular dendritic cells.

    PubMed Central

    Tacchetti, C.; Favre, A.; Moresco, L.; Meszaros, P.; Luzzi, P.; Truini, M.; Rizzo, F.; Grossi, C. E.; Ciccone, E.

    1997-01-01

    To gain further insight into the pathogenesis of human immunodeficiency virus (HIV) infection, lymph nodes from seven asymptomatic HIV+ subjects were analyzed during the latent phase of disease. Both ultrastructural and immunohistochemical analyses revealed that, in all of the cases, plasma cells producing IgM/gamma were present in germinal centers. Secreted immunoglobulins formed extracellular deposits mimicking the follicular dendritic cell network. Immunoglobulin produced by germinal center plasma cells are specific for HIV because they bind the HIV env protein gp 120. Plasma cells producing antibodies with the same specificity were also abundant in the extrafollicular regions of lymph nodes. During the latent phase of infection, the virus largely accumulates within the germinal centers. Therefore, extracellular immunoglobulin may form immune complexes, as shown by the presence of HIV-specific antibodies, HIV particles, and complement components C3c, C3d, and C1q in the interdendritic spaces. When the ultrastructural localization of HIV in germinal centers was analyzed, abundant virus particles were found in the interdendritic spaces. In addition to this extracellular localization of HIV, receptor-mediated endocytosis of viral particles by follicular dendritic cells was observed. Complete HIV particles were found within the endosomal compartment of the follicular dendritic cells and, as complete viral particles, free in the cytoplasm, indicating that the virus may escape from the endocytic compartment. As the virus is abundant in the cytoplasm, this event leads to formation of a hidden reservoir within follicular dendritic cells. In this location, HIV escapes recognition by cytotoxic T lymphocytes. In contrast, virus budding indicating a productive infection of follicular dendritic cells that would render them susceptible to T-cell-mediated lysis has been seldom observed. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 PMID:9033269

  10. BDNF over-expression increases olfactory bulb granule cell dendritic spine density in vivo.

    PubMed

    McDole, B; Isgor, C; Pare, C; Guthrie, K

    2015-09-24

    Olfactory bulb granule cells (GCs) are axon-less, inhibitory interneurons that regulate the activity of the excitatory output neurons, the mitral and tufted cells, through reciprocal dendrodendritic synapses located on GC spines. These contacts are established in the distal apical dendritic compartment, while GC basal dendrites and more proximal apical segments bear spines that receive glutamatergic inputs from the olfactory cortices. This synaptic connectivity is vital to olfactory circuit function and is remodeled during development, and in response to changes in sensory activity and lifelong GC neurogenesis. Manipulations that alter levels of the neurotrophin brain-derived neurotrophic factor (BDNF) in vivo have significant effects on dendritic spine morphology, maintenance and activity-dependent plasticity for a variety of CNS neurons, yet little is known regarding BDNF effects on bulb GC spine maturation or maintenance. Here we show that, in vivo, sustained bulbar over-expression of BDNF in transgenic mice produces a marked increase in GC spine density that includes an increase in mature spines on their apical dendrites. Morphometric analysis demonstrated that changes in spine density were most notable in the distal and proximal apical domains, indicating that multiple excitatory inputs are potentially modified by BDNF. Our results indicate that increased levels of endogenous BDNF can promote the maturation and/or maintenance of dendritic spines on GCs, suggesting a role for this factor in modulating GC functional connectivity within adult olfactory circuitry. PMID:26211445

  11. Systemic Control of Plasmacytoid Dendritic Cells by CD8+ T Cells and Commensal Microbiota1

    PubMed Central

    Fujiwara, Daisuke; Wei, Bo; Presley, Laura L.; Brewer, Sarah; McPherson, Michael; Lewinski, Michael A.; Borneman, James; Braun, Jonathan

    2012-01-01

    The composition of the intestinal microbial community is a distinctive individual trait that may divergently influence host biology. Because dendritic cells (DC) regulate the quality of the host response to microbiota, we evaluated DC in mice bearing distinct enteric microbial communities divergent for colitis susceptibility. Surprisingly, a selective, systemic reduction of plasmacytoid dendritic cells (pDC) was observed in isogenic mice with different microbiota: restricted flora (RF) vs specific pathogen free (SPF). This reduction was not observed in germfree mice, suggesting that the pDC deficiency was not simply due to a lack of intestinal microbial products. The microbial action was linked to cytotoxic CD8+ T cells, since pDC in RF mice were preserved in the CD8−/− and perforin−/− genotypes, partially restored by anti-CD8β Ab, and augmented in SPF mice bearing the TAP−/− genotype. Direct evidence for pDC cytolysis was obtained by rapid and selective pDC depletion in SPF mice transferred with RF CD8+ T cells. These data indicate that commensal microbiota, via CTL activation, functionally shape systemic immune regulation that may modify risk of inflammatory disease. PMID:18424703

  12. Chicken interleukin-21 is costimulatory for T cells and blocks maturation of dendritic cells.

    PubMed

    Rothwell, Lisa; Hu, Tuanjun; Wu, Zhiguang; Kaiser, Pete

    2012-02-01

    In mammals, interleukin-21 (IL-21) is an immunomodulatory cytokine with pleiotropic effects on the proliferation, differentiation and effector functions of T, B, NK and dendritic cells. A cDNA encoding the chicken orthologue of IL-21 (chIL-21) was cloned by RT-PCR from RNA isolated from activated chicken splenocytes and consists of 438 nucleotides, encoding an open reading frame of 145 amino acids (aa). Chicken IL-21 has 20-30% aa identity to its orthologues in mammals, Xenopus and fish, but is more highly conserved within Aves (50-80%). The four alpha-helical bundle structure of mammalian IL-21 appears to be conserved in the predicted chicken protein, as are the four cysteine residues required for the formation of two disulphide bridges. A glutamine residue in aa position 129, which has been implicated in the binding of IL-21 to the IL-2 receptor γ-chain in mammals, is also conserved. ChIL-21 is expressed in most lymphoid tissues, predominantly by CD4+ TCRαβ+ T cells. As in mammals, chIL-21 synergistically enhances T-cell proliferation and inhibits maturation of dendritic cells. PMID:21911004

  13. Adipose Tissue Dendritic Cells Enhances Inflammation by Prompting the Generation of Th17 Cells

    PubMed Central

    Tian, Xinyu; Tang, Xinyi; Rui, Ke; Tong, Jia; Lu, Liwei; Xu, Huaxi; Wang, Shengjun

    2014-01-01

    Background Obesity has become a global challenge for public health. It has been reported that obesity is associated with chronic inflammation. However, the mechanism for the chronic inflammation contributes to obesity remains elusive. Methodology/Principal Findings In our study, we found a novel CD11c+ dendritic cell subset existed in murine adipose tissues which was immature phenotype. Moreover, as compared to the lean controls, the number of CD11c+ DCs and CD4+IL-17+T cells were higher in adipose tissue of high fat diet (HFD) mice. Adipose tissues derived dendritic cells (ATDCs) displayed lower levels of CD40, CD80, CD86, MHCI and MHCII expression than splenic DCs (SPDCs). However, ATDCs showed higher levels of IL-6, TGF-β and IL-23 secretion. Moreover, our in vitro experiments demonstrated that ATDCs were capable of promoting Th17 cell generation. Conclusions/Significance Our results indicate the existence of CD11c+ DCs in adipose tissues, which displays an immature phenotype but possessing pro-inflammatory function. PMID:24642966

  14. Dendritic cells drive memory CD8 T-cell homeostasis via IL-15 transpresentation

    PubMed Central

    Stonier, Spencer W.; Ma, Lisa J.; Castillo, Eliseo F.

    2008-01-01

    Interleukin-15 (IL-15) is crucial for the development of naive and memory CD8 T cells and is delivered through a mechanism called transpresentation. Previous studies showed that memory CD8 T cells require IL-15 transpresentation by an as yet unknown cell of hematopoietic origin. We hypothesized that dendritic cells (DCs) transpresent IL-15 to CD8 T cells, and we examined this by developing a transgenic model that limits IL-15 transpresentation to DCs. In this study, IL-15 transpresentation by DCs had little effect on restoring naive CD8 T cells but contributed to the development of memory-phenotype CD8 T cells. The generation of virus-specific, memory CD8 T cells was partially supported by IL-15Rα+ DCs through the preferential enhancement of a subset of KLRG-1+CD27− CD8 T cells. In contrast, these DCs were largely sufficient in driving normal homeostatic proliferation of established memory CD8 T cells, suggesting that memory CD8 T cells grow more dependent on IL-15 transpresentation by DCs. Overall, our study clearly supports a role for DCs in memory CD8 T-cell homeostasis but also provides evidence that other hematopoietic cells are involved in this function. The identification of DCs fulfilling this role will enable future studies to better focus on mechanisms regulating T-cell homeostasis. PMID:18812469

  15. Generation of antitumor response by IL-2-transduced JAWS II dendritic cells.

    PubMed

    Rossowska, Joanna; Pajtasz-Piasecka, Elżbieta; Ryśnik, Oliwia; Wojas, Justyna; Krawczenko, Agnieszka; Szyda, Anna; Duś, Danuta

    2011-10-01

    Antigen-loaded dendritic cells (DCs) are a promising tool for inducing a tumor-specific immune response. It seems probable that co-administration of those cells together with cytokine-transduced DCs can further increase effectiveness of the antitumor vaccine. The local production of IL-2 by genetically modified DCs may result in alteration of the unfavorable tumor environment causing immune response dysfunction. In the presented study murine DCs of an established JAWS II cell line were transduced with a retroviral vector carrying murine IL-2 gene (JAWS II/IL-2). JAWS II/IL-2 cells demonstrated slightly decreased tumor antigen (TAg) uptake capacities. However, this modification resulted in enhanced ability of the cells to migrate in vivo. The multiple injection of vaccines containing JAWS II/IL-2 cells caused MC38 tumor growth delay and prolonged mice survival. The immunological response was manifested as cytotoxic natural killer (NK) and T cell activation and tumor tissue infiltration by CD8(+) and CD4(+) cells, accompanied by increased IFN-γ production by spleen cells. These observations suggest that repeated peritumoral administration of IL-2-producing dendritic cells can inhibit tumor growth by intensification of CD8(+) and CD4(+) cells' influx into tumor tissue and further activation of the systemic antitumor response. It can be concluded that IL-2 transduced dendritic cells may be used as a potent adjuvant in antitumor immunotherapy. PMID:21676487

  16. Characterization of Dendritic Cell Subsets Through Gene Expression Analysis.

    PubMed

    Vu Manh, Thien-Phong; Dalod, Marc

    2016-01-01

    Dendritic cells (DCs) are immune sentinels of the body and play a key role in the orchestration of the communication between the innate and the adaptive immune systems. DCs can polarize innate and adaptive immunity toward a variety of functions, sometimes with opposite roles in the overall control of immune responses (e.g., tolerance or immunosuppression versus immunity) or in the balance between various defense mechanisms promoting the control of different types of pathogens (e.g., antiviral versus antibacterial versus anti-worm immunity). These multiple DC functions result both from the plasticity of individual DC to exert different activities and from the existence of various DC subsets specialized in distinct functions. Functional genomics represents a powerful, unbiased, approach to better characterize these two levels of DC plasticity and to decipher its molecular regulation. Indeed, more and more experimental immunologists are generating high-throughput data in order to better characterize different states of DC based, for example, on their belonging to a specific subpopulation and/or on their exposure to specific stimuli and/or on their ability to exert a specific function. However, the interpretation of this wealth of data is severely hampered by the bottleneck of their bioinformatics analysis. Indeed, most experimental immunologists lack advanced computational or bioinformatics expertise and do not know how to translate raw gene expression data into potential biological meaning. Moreover, subcontracting such analyses is generally disappointing or financially not sustainable, since companies generally propose canonical analysis pipelines that are often unadapted for the structure of the data to analyze or for the precise type of questions asked. Hence, there is an important need of democratization of the bioinformatics analyses of gene expression profiling studies, in order to accelerate interpretation of the results by the researchers at the origin of the

  17. Oral bacteria induce a differential activation of human immunodeficiency virus-1 promoter in T cells, macrophages and dendritic cells

    PubMed Central

    Huang, C. B.; Emerson, K. A.; Gonzalez, O. A.; Ebersole, J. L.

    2014-01-01

    Introduction The human immunodeficiency virus (HIV) can integrate into T cells, macrophages and dendritic cells resulting in a latent infection. Reports have also demonstrated that various microbial and host cell factors can trigger HIV reactivation leading to HIV recrudescence, potentially undermining highly active antiretroviral therapies. Methods This study evaluated the capacity of oral bacteria associated with chronic periodontal infections to stimulate HIV promoter activation in various cell models of HIV latency. Results T cells (1G5) challenged with oral bacteria demonstrated a dose–response of HIV promoter activation with a subset of the bacteria, as well as kinetics that were generally similar irrespective of the stimuli. Direct bacterial challenge of the T cells resulted in increased activation of approximately 1.5- to 7-fold over controls. Challenge of macrophages (BF24) indicated different kinetics for individual bacteria and resulted in consistent increases in promoter activation of five fold to six fold over basal levels for all bacteria except Streptococcus mutans. Dendritic cells showed increases in HIV reactivation of 7- to 34-fold specific for individual species of bacteria. Conclusion These results suggested that oral bacteria have the capability to reactivate HIV from latently infected cells, showing a relationship of mature dendritic cells > immature dendritic cells > macrophages ≥ T cells. Expression of various pattern recognition receptors on these various cell types may provide insight into the primary receptors/signaling pathways used for reactivation by the bacteria. PMID:19702954

  18. [Prion diseases: what is the role of dendritic cells in the pathogenesis of transmissible prion diseases?].

    PubMed

    Bachy, Véronique; Aucouturier, Pierre

    2010-01-01

    Prion diseases are caused by the transconformation of a normal cellular protein, PrPc, into an infectious isoform, PrPsc, which ultimately triggers neuronal death. They are always fatal and, after transmission, they feature long incubation periods, during which prions accumulate in lymphoid tissues, infect nerves and progress to the central nervous system. In lymphoid organs, prions replicate and accumulate in follicular dendritic cells. Suppressing these cells slows down the neuro-invasion but does not totally abrogate it. This review examines the current knowledge in the roles of hematopoietic dendritic cells at different steps of the pathogenesis of prion diseases. Dendritic cells endocytose inoculated prions, permit their crossing of the intestinal epithelium and then migrate and transport them to lymphoid organs. They can carry prions to sites of neuroinvasion, and establish contacts with axons in peripheral lymph nodes or even after passage of the blood-brain barrier. However, results in the literature on the role of dendritic cells differ according to the host or the prion strain. PMID:20619164

  19. The Effect of Traditional Chinese Formula Danchaiheji on the Differentiation of Regulatory Dendritic Cells

    PubMed Central

    Wang, Xiaodong; Tong, Jingzhi; Li, Keqiu; Jing, Yaqing

    2016-01-01

    Recently, regulatory dendritic cells (DCregs), a newly described dendritic cell subset with potent immunomodulatory function, have attracted increased attention for their utility in treating immune response-related diseases, such as graft-versus-host disease, hypersensitivity, and autoimmune diseases. Danchaiheji (DCHJ) is a traditional Chinese formula that has been used for many years in the clinic. However, whether DCHJ can program dendritic cells towards a regulatory phenotype and the underlying mechanism behind this process remain unknown. Herein, we investigate the effects of traditional Chinese DCHJ on DCregs differentiation and a mouse model of skin transplantation. The current study demonstrates that DCHJ can induce dendritic cells to differentiate into DCregs, which are represented by high CD11b and low CD86 and HLA-DR expression as well as the secretion of IL-10 and TGF-β. In addition, DCHJ inhibited DC migration and T cell proliferation, which correlated with increased IDO expression. Furthermore, DCHJ significantly prolonged skin graft survival time in a mouse model of skin transplantation without any liver or kidney toxicity. The traditional Chinese formula DCHJ has the potential to be a potent immunosuppressive agent with high efficiency and nontoxicity. PMID:27525028

  20. Aire-Overexpressing Dendritic Cells Induce Peripheral CD4+ T Cell Tolerance

    PubMed Central

    Li, Dongbei; Li, Haijun; Fu, Haiying; Niu, Kunwei; Guo, Yantong; Guo, Chuan; Sun, Jitong; Li, Yi; Yang, Wei

    2015-01-01

    Autoimmune regulator (Aire) can promote the ectopic expression of peripheral tissue-restricted antigens (TRAs) in thymic medullary epithelial cells (mTECs), which leads to the deletion of autoreactive T cells and consequently prevents autoimmune diseases. However, the functions of Aire in the periphery, such as in dendritic cells (DCs), remain unclear. This study’s aim was to investigate the effect of Aire-overexpressing DCs (Aire cells) on the functions of CD4+ T cells and the treatment of type 1 diabetes (T1D). We demonstrated that Aire cells upregulated the mRNA levels of the tolerance-related molecules CD73, Lag3, and FR4 and the apoptosis of CD4+ T cells in STZ-T1D mouse-derived splenocytes. Furthermore, following insulin stimulation, Aire cells decreased the number of CD4+ IFN-γ+ T cells in both STZ-T1D and WT mouse-derived splenocytes and reduced the expression levels of TCR signaling molecules (Ca2+ and p-ERK) in CD4+ T cells. We observed that Aire cells-induced CD4+ T cells could delay the development of T1D. In summary, Aire-expressing DCs inhibited TCR signaling pathways and decreased the quantity of CD4+IFN-γ+ autoreactive T cells. These data suggest a mechanism for Aire in the maintenance of peripheral immune tolerance and provide a potential method to control autoimmunity by targeting Aire. PMID:26729097

  1. Interfaces between dendritic cells, other immune cells, and nerve fibres in mouse Peyer's patches: potential sites for neuroinvasion in prion diseases.

    PubMed

    Defaweux, Valérie; Dorban, Gauthier; Demonceau, Caroline; Piret, Joëlle; Jolois, Olivier; Thellin, Olivier; Thielen, Caroline; Heinen, Ernst; Antoine, Nadine

    2005-01-01

    In this study, we examined where immune cells and nerve fibres are located in mouse Peyer's patches, with a view to identifying potential sites for neuroinvasion by prions. Special attention was paid to dendritic cells, viewed as candidate transporters of infectious prion. Double immunofluorescence labellings with anti-CD11c antibody and marker for other immune cells (B cells, T cells, follicular dendritic cells) were carried out and analysed by confocal microscopy on Peyer's patch cryosections. To reveal the extensive ganglionated networks of the myenteric and submucosal plexi and the sparse meshworks of nerve strands, we used antibodies directed against different neurofilament subunits or against glial fibrillary acidic protein. In the suprafollicular dome, dendritic cells connect, via their cytoplasmic extensions, enterocytes with M cells of the follicle-associated epithelium. They are also close to B and T cells. Nerve fibres are detected in the suprafollicular dome, notably in contact with dendritic cells. Similar connections between dendritic cells, T cells, and nerve fibres are seen in the interfollicular region. Germinal centres are not innervated; inside them dendritic cells establish contacts with follicular dendritic cells and with B cells. After immunolabelling of normal prion protein, dendritic cells of the suprafollicular dome are intensely positive labelled. PMID:15816033

  2. Functional interaction of plasmacytoid dendritic cells with multiple myeloma cells: a therapeutic target.

    PubMed

    Chauhan, Dharminder; Singh, Ajita V; Brahmandam, Mohan; Carrasco, Ruben; Bandi, Madhavi; Hideshima, Teru; Bianchi, Giada; Podar, Klaus; Tai, Yu-Tzu; Mitsiades, Constantine; Raje, Noopur; Jaye, David L; Kumar, Shaji K; Richardson, Paul; Munshi, Nikhil; Anderson, Kenneth C

    2009-10-01

    Multiple myeloma (MM) remains incurable despite novel therapies, suggesting the need for further identification of factors mediating tumorigenesis and drug resistance. Using both in vitro and in vivo MM xenograft models, we show that plasmacytoid dendritic cells (pDCs) in the bone marrow (BM) microenvironment both mediate immune deficiency characteristic of MM and promote MM cell growth, survival, and drug resistance. Microarray, cell signaling, cytokine profile, and immunohistochemical analysis delineate the mechanisms mediating these sequelae. Although pDCs are resistant to novel therapies, targeting toll-like receptors with CpG oligodeoxynucleotides both restores pDC immune function and abrogates pDC-induced MM cell growth. Our study therefore validates targeting pDC-MM interactions as a therapeutic strategy to overcome drug resistance in MM. PMID:19800576

  3. Critical role of dendritic cells in T cell retention in the interfollicular region of Peyer's patches.

    PubMed

    Obata, Takashi; Shibata, Naoko; Goto, Yoshiyuki; Ishikawa, Izumi; Sato, Shintaro; Kunisawa, Jun; Kiyono, Hiroshi

    2013-07-15

    Peyer's patches (PPs) simultaneously initiate active and quiescent immune responses in the gut. The immunological function is achieved by the rigid regulation of cell distribution and trafficking, but how the cell distribution is maintained remains to be elucidated. In this study, we show that binding of stromal cell-derived lymphoid chemokines to conventional dendritic cells (cDCs) is essential for the retention of naive CD4(+) T cells in the interfollicular region (IFR) of PPs. Transitory depletion of CD11c(high) cDCs in mice rapidly impaired the IFR structure in the PPs without affecting B cell follicles or germinal centers, lymphoid chemokine production from stromal cells, or the immigration of naive T cells into the IFRs of PPs. The cDC-orchestrated retention of naive T cells was mediated by heparinase-sensitive molecules that were expressed on cDCs and bound the lymphoid chemokine CCL21 produced from stromal cells. These data collectively reveal that interactions among cDCs, stromal cells, and naive T cells are necessary for the formation of IFRs in the PPs. PMID:23772027

  4. The SNARE VAMP7 Regulates Exocytic Trafficking of Interleukin-12 in Dendritic Cells.

    PubMed

    Chiaruttini, Giulia; Piperno, Giulia M; Jouve, Mabel; De Nardi, Francesca; Larghi, Paola; Peden, Andrew A; Baj, Gabriele; Müller, Sabina; Valitutti, Salvatore; Galli, Thierry; Benvenuti, Federica

    2016-03-22

    Interleukin-12 (IL-12), produced by dendritic cells in response to activation, is central to pathogen eradication and tumor rejection. The trafficking pathways controlling spatial distribution and intracellular transport of IL-12 vesicles to the cell surface are still unknown. Here, we show that intracellular IL-12 localizes in late endocytic vesicles marked by the SNARE VAMP7. Dendritic cells (DCs) from VAMP7-deficient mice are partially impaired in the multidirectional release of IL-12. Upon encounter with antigen-specific T cells, IL-12-containing vesicles rapidly redistribute at the immune synapse and release IL-12 in a process entirely dependent on VAMP7 expression. Consistently, acquisition of effector functions is reduced in T cells stimulated by VAMP7-null DCs. These results provide insights into IL-12 intracellular trafficking pathways and show that VAMP7-mediated release of IL-12 at the immune synapse is a mechanism to transmit innate signals to T cells. PMID:26972013

  5. Branching angles of pyramidal cell dendrites follow common geometrical design principles in different cortical areas

    PubMed Central

    Bielza, Concha; Benavides-Piccione, Ruth; López-Cruz, Pedro; Larrañaga, Pedro; DeFelipe, Javier

    2014-01-01

    Unraveling pyramidal cell structure is crucial to understanding cortical circuit computations. Although it is well known that pyramidal cell branching structure differs in the various cortical areas, the principles that determine the geometric shapes of these cells are not fully understood. Here we analyzed and modeled with a von Mises distribution the branching angles in 3D reconstructed basal dendritic arbors of hundreds of intracellularly injected cortical pyramidal cells in seven different cortical regions of the frontal, parietal, and occipital cortex of the mouse. We found that, despite the differences in the structure of the pyramidal cells in these distinct functional and cytoarchitectonic cortical areas, there are common design principles that govern the geometry of dendritic branching angles of pyramidal cells in all cortical areas. PMID:25081193

  6. Branching angles of pyramidal cell dendrites follow common geometrical design principles in different cortical areas.

    PubMed

    Bielza, Concha; Benavides-Piccione, Ruth; López-Cruz, Pedro; Larrañaga, Pedro; DeFelipe, Javier

    2014-01-01

    Unraveling pyramidal cell structure is crucial to understanding cortical circuit computations. Although it is well known that pyramidal cell branching structure differs in the various cortical areas, the principles that determine the geometric shapes of these cells are not fully understood. Here we analyzed and modeled with a von Mises distribution the branching angles in 3D reconstructed basal dendritic arbors of hundreds of intracellularly injected cortical pyramidal cells in seven different cortical regions of the frontal, parietal, and occipital cortex of the mouse. We found that, despite the differences in the structure of the pyramidal cells in these distinct functional and cytoarchitectonic cortical areas, there are common design principles that govern the geometry of dendritic branching angles of pyramidal cells in all cortical areas. PMID:25081193

  7. The dynamic lives of macrophage and dendritic cell subsets in atherosclerosis

    PubMed Central

    Taghavie-Moghadam, Paresa L.; Butcher, Matthew J.; Galkina, Elena V.

    2014-01-01

    Atherosclerosis, the major pathological process through which arterial plaques are formed, is a dynamic chronic inflammatory disease of large and medium sized arteries in which the vasculature, lipid metabolism, and the immune system all play integral roles. Both the innate and adaptive immune systems are involved in the development and progression of atherosclerosis but myeloid cells represent the major component of the burgeoning atherosclerotic plaque. Various myeloid cells, including monocytes, macrophages, and dendritic cells can be found within the healthy and atherosclerotic arterial wall, where they can contribute to or regulate inflammation. However, the precise behaviors and functions of these cells in situ are still active areas of investigation that continue to yield exciting and surprising new data. Here, we review recent progress in understanding of the complex biology of macrophages and dendritic cells, focusing particularly on the dynamic regulation of these subsets in the arterial wall and novel, emerging functions of these cells during atherogenesis. PMID:24628328

  8. The SNARE VAMP7 Regulates Exocytic Trafficking of Interleukin-12 in Dendritic Cells

    PubMed Central

    Chiaruttini, Giulia; Piperno, Giulia M.; Jouve, Mabel; De Nardi, Francesca; Larghi, Paola; Peden, Andrew A.; Baj, Gabriele; Müller, Sabina; Valitutti, Salvatore; Galli, Thierry; Benvenuti, Federica

    2016-01-01

    Summary Interleukin-12 (IL-12), produced by dendritic cells in response to activation, is central to pathogen eradication and tumor rejection. The trafficking pathways controlling spatial distribution and intracellular transport of IL-12 vesicles to the cell surface are still unknown. Here, we show that intracellular IL-12 localizes in late endocytic vesicles marked by the SNARE VAMP7. Dendritic cells (DCs) from VAMP7-deficient mice are partially impaired in the multidirectional release of IL-12. Upon encounter with antigen-specific T cells, IL-12-containing vesicles rapidly redistribute at the immune synapse and release IL-12 in a process entirely dependent on VAMP7 expression. Consistently, acquisition of effector functions is reduced in T cells stimulated by VAMP7-null DCs. These results provide insights into IL-12 intracellular trafficking pathways and show that VAMP7-mediated release of IL-12 at the immune synapse is a mechanism to transmit innate signals to T cells. PMID:26972013

  9. Human dendritic cells and macrophages. In situ immunophenotypic definition of subsets that exhibit specific morphologic and microenvironmental characteristics.

    PubMed Central

    Wood, G. S.; Turner, R. R.; Shiurba, R. A.; Eng, L.; Warnke, R. A.

    1985-01-01

    Using a panel of monoclonal antibodies and antisera in situ, the authors have defined subsets of human dendritic cells and macrophages that exhibit specific morphologic and microenvironmental characteristics. All subsets contained cells that reacted with antibodies directed against HLA-A,B,C, HLA-Dr, leukocyte common, Leu-M3, and Leu-3(T4) antigens. R4/23 and anti-S100 defined three major subsets. R4/23+, S100- cells constituted the B-cell-related follicular dendritic cells, which were identified only within the germinal center/mantle microenvironment of lymphoid follicles. R4/23-, S100+ cells constituted the T-cell-related dendritic cell subset. Anti-Leu-6(T6) further subdivided this group into Leu-6(T6)- interdigitating cells within the T-cell microenvironments of lymphoid organs and Leu-6(T6)+ Langerhans cells found predominantly in epithelial microenvironments, especially the skin. R4/23-, S100- cells constituted the nondendritic tissue macrophage subset which was widely distributed, primarily outside of dendritic-cell microenvironments. These data indicate that although dendritic cells and macrophages share several common antigenic features, morphologically and microenvironmentally distinct subsets express distinct immunologic phenotypes. Such data may provide insight into the ontogeny and function of these subsets and constitute a basis for the comparison of normal dendritic cells and macrophages to various histiocytic proliferative disorders. Images Figure 1 Figure 2 p78-c Figure 3 Figure 4 Figure 5 PMID:3985124

  10. Silicon ribbon study program. [dendritic crystals for use in solar cells

    NASA Technical Reports Server (NTRS)

    Seidensticker, R. G.; Duncan, C. S.

    1975-01-01

    The feasibility is studied of growing wide, thin silicon dendritic web for solar cell fabrication and conceptual designs are developed for the apparatus required. An analysis of the mechanisms of dendritic web growth indicated that there were no apparent fundamental limitations to the process. The analysis yielded quantitative guidelines for the thermal conditions required for this mode of crystal growth. Crucible designs were then investigated: the usual quartz crucible configurations and configurations in which silicon itself is used for the crucible. The quartz crucible design is feasible and is incorporated into a conceptual design for a laboratory scale crystal growth facility capable of semi-automated quasi-continuous operation.

  11. The effect of refeeding after neonatal starvation on Purkinje cell dendritic growth in the rat.

    PubMed

    McConnell, P; Berry, M

    1978-04-15

    Male rats, undernourished from birth until 30 days by restricting access to the lactating dam, were given ad libitum food supplies unitl 80 days. Body weight, whole brain weight and cerebellar remained significantly lower in these animals than in normally fed controls. Significant deficits in the area of the molecular and granular layers persisted at 80 days, although there was some recovery during the refeeding period. At the same time granule and Purkinje cell density declined, suggesting that the areal recovery was due to the expansion of the interneuronal matrix. Granule cell numbers remained unchanged between 30 and 80 days. Network analysis of Golgi-Cox preparations indicated a 28% decrease in overall size of the Purkinje cell dendritic networks, due primarily to a deficit in segment frequency which remained unchanged throughout the rehabilitation period. Segment length did, however, show some recovery; distal segments from 80-day experimental networks were significantly longer than those of 30-day undernourished animals. The results of the topological analysis suggested that dendritic remodelling had taken place during the rehabilitation period. The failure to observe a complete recovery in the size and morphology of the dendritic network may be explained in terms of recent suggestions that dendritic development is influenced both by the metabolism of the neurons themselves, and by the number and density of adjacent afferent axons. It is suggested that refeeding from 30 days leads to the recovery of Purkinje cell metabolism, but is unable to restore the parallel fiber deficit. PMID:632380

  12. Dendrimer-like alpha-d-glucan nanoparticles activate dendritic cells and are effective vaccine adjuvants.

    PubMed

    Lu, Fangjia; Mencia, Alejandra; Bi, Lin; Taylor, Aaron; Yao, Yuan; HogenEsch, Harm

    2015-04-28

    The use of nanoparticles for delivery of vaccine antigens and as vaccine adjuvants is appealing because their size allows efficient uptake by dendritic cells and their biological properties can be tailored to the desired function. Here, we report the effect of chemically modified phytoglycogen, a dendrimer-like α-d-glucan nanoparticle, on dendritic cells in vitro, and the utility of this type of nanoparticle as a vaccine adjuvant in vivo. The modified phytoglycogen nanoparticle, termed Nano-11, has a positive surface charge which enabled electrostatic adsorption of negatively charged protein antigens. The Nano-11-antigen complexes were efficiently phagocytized by dendritic cells. Nano-11 induced increased expression of costimulatory molecules and the secretion of IL-1β and IL-12p40 by dendritic cells. Intramuscular injection of Nano-11-antigen formulations induced a significantly enhanced immune response to two different protein antigens. Examination of the injection site revealed numerous monocytes and relatively few neutrophils at one day after injection. The inflammation had nearly completely disappeared by 2 weeks after injection. These studies indicate that Nano-11 is an effective vaccine delivery vehicle that significantly enhances the immune response. This type of plant based nanoparticle is considered highly cost-effective compared with fully synthetic nanoparticles and appears to have an excellent safety profile making them an attractive adjuvant candidate for prophylactic vaccines. PMID:25747143

  13. Enhancing anti-melanoma immunity by electrochemotherapy and in vivo dendritic-cell activation

    PubMed Central

    Gerlini, Gianni; Di Gennaro, Paola; Borgognoni, Lorenzo

    2012-01-01

    Combining electrochemotherapy with dendritic cell-based immunotherapy is a promising strategy against human metastatic melanoma that deserves to be clinically assessed. While electrochemotherapy induces a rapid regression of metastases, immunotherapy generates systemic anticancer immunity, contributes to eradicate the tumor and maintains an immunological memory to control relapse. PMID:23264927

  14. Plasmacytoid dendritic cells, Janus-faced sentinels: progesterone, guilty or innocent?

    PubMed

    Konttinen, Yrjö T; Hänninen, Arno; Fuellen, Georg

    2009-11-01

    Evaluation of: Meier A, Chang JJ, Chan ES et al.: Sex differences in the Toll-like receptor-mediated responses of plasmacytoid dendritic cells to HIV-1. Nat. Med. 15, 955-959 (2009). Stimulation of Toll-like receptor (TLR)7 of plasmacytoid dendritic cells with ssRNA in internalized ribonucleic protein (RNP)-autoantibody complexes causes production of IFN-alpha and IFN signature in several female-dominant autoimmune diseases. This could relate to a gene-dose effect by the X chromosome or disturbances in the systemic endocrine and local intracrine sex steroid production. Meier et al. extend this paradigm to HIV-1-infected women. ssRNA, in oligoribonucleotides or aldrithiol-2-inactivated HIV-1, stimulated plasmacytoid dendritic cells via TLR7 to synthesize high concentrations of IFN-alpha. Women were disfavored and produced more IFN-alpha and subsequently CD38(high)CD8(+) lymphocytes upon similar viral loads in treatment-naive individuals. This predicts rapid progress to AIDS. There was a significant positive correlation between plasma progesterone concentrations and the percentage of responder plasmacytoid dendritic cells. TLR7-related pathways offer many potential targets for the treatment of viral and autoimmune diseases. PMID:20635911

  15. Dendritic Morphology of Caudal Periaqueductal Gray Projecting Retinal Ganglion Cells in Mongolian Gerbil (Meriones unguiculatus)

    PubMed Central

    Ren, Chaoran; Pu, Mingliang; Cui, Qi; So, Kwok-Fai

    2014-01-01

    In this study we investigated the morphological features of the caudal periaqueductal gray (cPAG)-projecting retinal ganglion cells (RGCs) in Mongolian gerbils using retrograde labeling, in vitro intracellular injection, confocal microscopy and three-dimensional reconstruction approaches. cPAG-projecting RGCs exhibit small somata (10–17 µm) and irregular dendritic fields (201–298 µm). Sizes of somata and dendritic fields do not show obvious variation at different distance from the optic disk (eccentricity). Dendrites are moderately branched. Morphological analysis (n = 23) reveals that cPAG-projecting RGCs ramified in sublamina a and b in the inner plexiform layer. These cells exhibit different stratification patterns based on the thickness of dendritic bands in sublaminas a and b: majority of analyzed cells (16 out of 23) have two bands of arborizations share similar thickness. The rest of analyzed cells (7 out of 23) exhibit thinner band in sublamina a than in sublamina b. Together, the present study suggests that cPAG of Mongolian gerbil could receive direct retinal inputs from two types of bistratified RGCs. Furthermore, a small subset of melanopsin-expressing RGCs (total 41 in 6 animals) is shown to innervate the rostral PAG (rPAG). Functional characteristics of these non-visual center projecting RGCs remain to be determined. PMID:25054882

  16. Foundational dendritic processing that is independent of the cell type-specific structure in model primary neurons.

    PubMed

    Kim, Hojeong; Heckman, C J

    2015-11-16

    It has long been known that primary neurons in the brain and spinal cord exhibit very distinctive dendritic structures. However, it remains unclear whether dendritic processing for signal propagation and channel activation over dendrites is a function of the cell type-specific dendritic structure. By applying an extended analysis of signal attenuation for the physiological distributions of synaptic inputs and active channels on dendritic branches, we first demonstrate that regardless of their specific structure, all anatomically reconstructed models of primary neurons display a similar pattern of directional signal attenuation and locational channel activation over their dendrites. Then, using a novel modeling approach that allows direct comparison of the anatomically reconstructed primary neurons with their reduced models that exclusively retain anatomical dendritic signaling without being associated with structural specificity, we show that the reduced model can accurately predict dendritic excitability of the anatomical model in both passive and active mode. These results indicate that the directional signaling, locational excitability and their relationship are foundational features of dendritic processing that are independent of the cell type-specific structure across primary neurons. PMID:26463670

  17. Comparative analysis of signature genes in PRRSV-infected porcine monocyte-derived dendritic cells at differential activation statuses

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Activation statuses of monocytic cells including monocytes, macrophages and dendritic cells (DCs) are critically important for antiviral immunity. In particular, some devastating viruses, including porcine reproductive and respiratory syndrome virus (PRRSV), are capable of directly infecting these c...

  18. Autophagy gene Atg16l1 prevents lethal T cell alloreactivity mediated by dendritic cells

    PubMed Central

    Hubbard-Lucey, Vanessa M.; Shono, Yusuke; Maurer, Katie; West, Mallory L.; Singer, Natalie V.; Ziegler, Carly G. K.; Lezcano, Cecilia; Motta, Ana Carolina Fragoso; Schmid, Karin; Levi, Samuel M.; Murphy, George F.; Liu, Chen; Winkler, Jeffrey D.; Amaravadi, Ravi K.; Rogler, Gerhard; Dickinson, Anne M.; Holler, Ernst; van den Brink, Marcel RM; Cadwell, Ken

    2014-01-01

    SUMMARY Atg16L1 mediates the cellular degradative process of autophagy and is considered a critical regulator of inflammation based on its genetic association with inflammatory bowel disease. Here we find that Atg16L1 deficiency leads to an exacerbated graft-versus-host disease (GVHD) in a mouse model of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Atg16L1-deficient allo-HSCT recipients with GVHD displayed increased T cell proliferation due to increased dendritic cell (DC) numbers and co-stimulatory molecule expression. Reduced autophagy within DCs was associated with lysosomal abnormalities and decreased amounts of A20, a negative regulator of DC activation. These results broaden the function of Atg16L1 and the autophagy pathway to include a role in limiting a DC-mediated response during inflammatory disease, such as GVHD. PMID:25308334

  19. Th1 or Th2 balance regulated by interaction between dendritic cells and NKT cells.

    PubMed

    Onoé, Kazunori; Yanagawa, Yoshiki; Minami, Keita; Iijima, Norifumi; Iwabuchi, Kazuya

    2007-01-01

    If Th1 or Th2 polarization could be artificially manipulated, effective immune responses would be generated depending on nature of the targets. In this study we attempted to regulate CD40 expressions on dendritic cells (DCs) in order to modify the T cell response. It was found that reducing agents selectively inhibited surface expression of CD40 on DCs. This finding may provide a new strategy of DC-mediated modulation of the Th1/Th2 balance. It was also shown that NKT-produced Th1/Th2 cytokine balance was under control of negative feedback loop through DCs. Th1 cytokine-pretreated DCs mainly induced Th2 cytokine production, whereas Th2 cytokine-pretreated DCs induced Th1 cytokine production by alpha-galactosylceramide-stimulated NKT cells. The negative feedback regulation system could be applicable to therapeutics of various diseases based on immunological disorders. PMID:17917039

  20. Whole-cell cancer vaccination: from autologous to allogeneic tumor- and dendritic cell-based vaccines

    PubMed Central

    de Gruijl, Tanja D.; van den Eertwegh, Alfons J. M.; Pinedo, Herbert M.

    2008-01-01

    The field of tumor vaccination is currently undergoing a shift in focus, from individualized tailor-made vaccines to more generally applicable vaccine formulations. Although primarily predicated by financial and logistic considerations, stemming from a growing awareness that clinical development for wide-scale application can only be achieved through backing from major pharmaceutical companies, these new approaches are also supported by a growing knowledge of the intricacies and minutiae of antigen presentation and effector T-cell activation. Here, the development of whole-cell tumor and dendritic cell (DC)-based vaccines from an individualized autologous set-up to a more widely applicable allogeneic approach will be discussed as reflected by translational studies carried out over the past two decades at our laboratories and clinics in the vrije universiteit medical center (VUmc) in Amsterdam, The Netherlands. PMID:18523771

  1. Autophagy gene Atg16L1 prevents lethal T cell alloreactivity mediated by dendritic cells.

    PubMed

    Hubbard-Lucey, Vanessa M; Shono, Yusuke; Maurer, Katie; West, Mallory L; Singer, Natalie V; Ziegler, Carly G K; Lezcano, Cecilia; Motta, Ana Carolina Fragoso; Schmid, Karin; Levi, Samuel M; Murphy, George F; Liu, Chen; Winkler, Jeffrey D; Amaravadi, Ravi K; Rogler, Gerhard; Dickinson, Anne M; Holler, Ernst; van den Brink, Marcel R M; Cadwell, Ken

    2014-10-16

    Atg16L1 mediates the cellular degradative process of autophagy and is considered a critical regulator of inflammation based on its genetic association with inflammatory bowel disease. Here we find that Atg16L1 deficiency leads to an exacerbated graft-versus-host disease (GVHD) in a mouse model of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Atg16L1-deficient allo-HSCT recipients with GVHD displayed increased T cell proliferation due to increased dendritic cell (DC) numbers and costimulatory molecule expression. Reduced autophagy within DCs was associated with lysosomal abnormalities and decreased amounts of A20, a negative regulator of DC activation. These results broaden the function of Atg16L1 and the autophagy pathway to include a role in limiting a DC-mediated response during inflammatory disease, such as GVHD. PMID:25308334

  2. Isolation of Splenic Dendritic Cells Using Fluorescence-activated Cell Sorting

    PubMed Central

    Tavernier, Simon J; Osorio, Fabiola; Janssens, Sophie; Lambrecht, Bart N

    2016-01-01

    The spleen is a vastly vasculated organ and consists of a complex organized network of innate and adaptive immune cells. This permits the specialized functions of the spleen such as antibacterial and antifungal immunity and iron metabolism among others (Mebius and Kraal, 2005). Different dendritic cell (DC) subsets reside in the spleen and can be defined by the expression of unique surface markers. These DC subsets are recognized to perform non-redundant functions in the immune system (Merad et al., 2013). In our recent study, we found that Inositol Requiring Enzyme (IRE)-1 is specifically activated in splenic CD8a+ DCs. Furthermore, loss of X-box binding protein (XBP)-1 – the transcription factor regulated by IRE-1 – resulted in defective cross-presentation of dead cell associated antigens by splenic CD8a+ DCs (Osorio et al., 2014). This protocol allows the isolation of specific DC subsets for experimental use ex-vivo. PMID:27376108

  3. Langerhans cells and more: langerin-expressing dendritic cell subsets in the skin

    PubMed Central

    Romani, Nikolaus; Clausen, Björn E.; Stoitzner, Patrizia

    2010-01-01

    Summary Langerhans cells (LCs) are antigen-presenting dendritic cells (DCs) that reside in epithelia. The best studied example is the LC of the epidermis. By electron microscopy, their identifying feature is the unique rod- or tennis racket-shaped Birbeck granule. The phenotypic hallmark is their expression of the C-type lectin receptor langerin/CD207. Langerin, however, is also expressed on a recently discovered population of DC in the dermis and other tissues of the body. These ‘dermal langerin+ dendritic cells’ are unrelated to LCs. The complex field of langerin-negative dermal DCs is not dealt with here. In this article, we briefly review the history, ontogeny, and homeostasis of LCs. More emphasis is laid on the discussion of functional properties in vivo. Novel models using genetically engineered mice are contributing tremendously to our understanding of the role of LCs in eliciting adaptive immune responses against pathogens or tumors and in inducing and maintaining tolerance against self antigens and innocuous substances in vivo. Also, innate effector functions are increasingly being recognized. Current activities in this area are reviewed, and possibilities for future exploitation of LC in medicine, e.g. for the improvement of vaccines, are contemplated. PMID:20193016

  4. Effects of heat shock protein gp96 on human dendritic cell maturation and CTL expansion.

    PubMed

    Zhang, Yuxia; Zan, Yanlu; Shan, Ming; Liu, Changmei; Shi, Ming; Li, Wei; Zhang, Zhixin; Liu, Na; Wang, Fusheng; Zhong, Weidong; Liao, Fulian; Gao, George F; Tien, Po

    2006-06-01

    We reported previously that heat shock protein gp96 and its N-terminal fragment were able to stimulate CTL expansion specific for a HBV peptide (SYVNTNMGL) in BALB/c mice. Here we characterized the adjuvant effects of gp96 on human HLA-A2 restricted T cells. Full-length gp96 isolated from healthy human liver and recombinant fragments both from prokaryotic cells and eukaryotic cells were analyzed for their ability to stimulate maturation of human dendritic cells. It was found that in vitro these proteins were capable of maturating human monocyte-derived dendritic cells (MDDC) isolated from healthy donors as well as from HBV-positive, hepatocellular carcinoma (HCC) patients. In HLA-A2.1/Kb transgenic mice, gp96 and the recombinant fragments were found to augment CTL response specific for the HBcAg(18-27) FLPSDFFPSV peptide of hepatitis B virus. PMID:16630554

  5. Physiological Role of Plasmacytoid Dendritic Cells and Their Potential Use in Cancer Immunity

    PubMed Central

    Schettini, Jorge; Mukherjee, Pinku

    2008-01-01

    Dendritic cells (DCs) play a pivotal role in the control of innate and adaptive immune responses. They are a heterogeneous cell population, where plasmacytoid dendritic cells (pDCs) are a unique subset capable of secreting high levels of type I IFNs. It has been demonstrated that pDCs can coordinate events during the course of viral infection, atopy, autoimmune diseases, and cancer. Therefore, pDC, as a main source of type I IFN, is an attractive target for therapeutic manipulations of the immune system to elicit a powerful immune response against tumor antigens in combination with other therapies. The therapeutic vaccination with antigen-pulsed DCs has shown a limited efficacy to generate an effective long-lasting immune response against tumor cells. A rational manipulation and design of vaccines which could include DC subsets outside “Langerhans cell paradigm” might allow us to improve the therapeutic approaches for cancer patients. PMID:19190769

  6. Antigen availability determines CD8+ T cell-dendritic cell interaction kinetics and memory fate decisions

    PubMed Central

    Henrickson, Sarah E.; Stutte, Susanne; Quigley, Michael; Alexe, Gabriela; Iannacone, Matteo; Flynn, Michael P.; Omid, Shaida; Jesneck, Jonathan L.; Imam, Sabrina; Mempel, Thorsten R.; Mazo, Irina B.; Haining, William N.; von Andrian, Ulrich H.

    2014-01-01

    Summary T cells are activated by antigen (Ag) bearing dendritic cells (DCs) in lymph nodes in 3 phases. The duration of the initial phase of transient, serial DC-T cell interactions is inversely correlated with Ag dose. The second phase, characterized by stable DC-T cell contacts, is believed to be necessary for full-fledged T cell activation. Here we have shown that this is not the case. CD8+ T cells interacting with DCs presenting low-dose, short-lived Ag did not transition to phase 2, while higher Ag dose yielded phase 2 transition. Both antigenic constellations promoted T cell proliferation and effector differentiation, but yielded different transcriptome signatures at 12h and 24h. T cells that experienced phase 2 developed long-lived memory, whereas conditions without stable contacts yielded immunological amnesia. Thus, T cells make fate decisions within hours after Ag exposure resulting in long-term memory or abortive effector responses, correlating with T cell-DCs interaction kinetics. PMID:24054328

  7. Oxidation of cell surface thiol groups by contact sensitizers triggers the maturation of dendritic cells.

    PubMed

    Kagatani, Saori; Sasaki, Yoshinori; Hirota, Morihiko; Mizuashi, Masato; Suzuki, Mie; Ohtani, Tomoyuki; Itagaki, Hiroshi; Aiba, Setsuya

    2010-01-01

    p38 mitogen-activated protein kinase (MAPK) has a crucial role in the maturation of dendritic cells (DCs) by sensitizers. Recently, it has been reported that the oxidation of cell surface thiols by an exogenous impermeant thiol oxidizer can phosphorylate p38 MAPK. In this study, we examined whether sensitizers oxidize cell surface thiols of monocyte-derived DCs (MoDCs). When cell surface thiols were quantified by flow cytometry using Alexa fluor maleimide, all the sensitizers that we examined decreased cell surface thiols on MoDCs. To examine the effects of decreased cell surface thiols by sensitizers on DC maturation, we analyzed the effects of an impermeant thiol oxidizer, o-phenanthroline copper complex (CuPhen). The treatment of MoDCs with CuPhen decreased cell surface thiols, phosphorylated p38 MAPK, and induced MoDC maturation, that is, the augmentation of CD83, CD86, HLA-DR, and IL-8 mRNA, as well as the downregulation of aquaporin-3 mRNA. The augmentation of CD86 was significantly suppressed when MoDCs were pretreated with N-acetyl-L-cystein or treated with SB203580. Finally, we showed that epicutaneous application of 2,4-dinitrochlorobenzene on mouse skin significantly decreased cell surface thiols of Langerhans cells in vivo. These data suggest that the oxidation of cell surface thiols has some role in triggering DC maturation by sensitizers. PMID:19641517

  8. Leukemia-associated activating mutation of Flt3 expands dendritic cells and alters T cell responses.

    PubMed

    Lau, Colleen M; Nish, Simone A; Yogev, Nir; Waisman, Ari; Reiner, Steven L; Reizis, Boris

    2016-03-01

    A common genetic alteration in acute myeloid leukemia is the internal tandem duplication (ITD) in FLT3, the receptor for cytokine FLT3 ligand (FLT3L). Constitutively active FLT3-ITD promotes the expansion of transformed progenitors, but also has pleiotropic effects on hematopoiesis. We analyzed the effect of FLT3-ITD on dendritic cells (DCs), which express FLT3 and can be expanded by FLT3L administration. Pre-leukemic mice with the Flt3(ITD) knock-in allele manifested an expansion of classical DCs (cDCs) and plasmacytoid DCs. The expansion originated in DC progenitors, was cell intrinsic, and was further enhanced in Flt3(ITD/ITD) mice. The mutation caused the down-regulation of Flt3 on the surface of DCs and reduced their responsiveness to Flt3L. Both canonical Batf3-dependent CD8(+) cDCs and noncanonical CD8(+) cDCs were expanded and showed specific alterations in their expression profiles. Flt3(ITD) mice showed enhanced capacity to support T cell proliferation, including a cell-extrinsic expansion of regulatory T (T reg) cells. Accordingly, these mice restricted alloreactive T cell responses during graft-versus-host reaction, but failed to control autoimmunity without T reg cells. Thus, the FLT3-ITD mutation directly affects DC development, indirectly modulating T cell homeostasis and supporting T reg cell expansion. We hypothesize that this effect of FLT3-ITD might subvert immunosurveillance and promote leukemogenesis in a cell-extrinsic manner. PMID:26903243

  9. Restricted dendritic cell and monocyte progenitors in human cord blood and bone marrow

    PubMed Central

    Lee, Jaeyop; Breton, Gaëlle; Oliveira, Thiago Yukio Kikuchi; Zhou, Yu Jerry; Aljoufi, Arafat; Puhr, Sarah; Cameron, Mark J.; Sékaly, Rafick-Pierre

    2015-01-01

    In mice, two restricted dendritic cell (DC) progenitors, macrophage/dendritic progenitors (MDPs) and common dendritic progenitors (CDPs), demonstrate increasing commitment to the DC lineage, as they sequentially lose granulocyte and monocyte potential, respectively. Identifying these progenitors has enabled us to understand the role of DCs and monocytes in immunity and tolerance in mice. In humans, however, restricted monocyte and DC progenitors remain unknown. Progress in studying human DC development has been hampered by lack of an in vitro culture system that recapitulates in vivo DC hematopoiesis. Here we report a culture system that supports development of CD34+ hematopoietic stem cell progenitors into the three major human DC subsets, monocytes, granulocytes, and NK and B cells. Using this culture system, we defined the pathway for human DC development and revealed the sequential origin of human DCs from increasingly restricted progenitors: a human granulocyte-monocyte-DC progenitor (hGMDP) that develops into a human monocyte-dendritic progenitor (hMDP), which in turn develops into monocytes, and a human CDP (hCDP) that is restricted to produce the three major DC subsets. The phenotype of the DC progenitors partially overlaps with granulocyte-macrophage progenitors (GMPs). These progenitors reside in human cord blood and bone marrow but not in the blood or lymphoid tissues. PMID:25687283

  10. Flagellin Modulates the Function of Invariant NKT Cells From Patients With Asthma via Dendritic Cells

    PubMed Central

    Shim, Jae-Uoong; Rhee, Joon-Haeng; Jeong, Ji-Ung

    2016-01-01

    Purpose Invariant natural killer T (iNKT) cells play a critical role in the pathogenesis of asthma. We previously reported the association between circulating Th2-like iNKT cells and lung function in asthma patients and the suppressive effect of Toll-like receptor 5 ligand flagellin B (FlaB) on asthmatic in a mouse model. Thus, we investigated whether FlaB modulates the function of circulating iNKT cells in asthmatic patients. Methods Peripheral blood mononuclear cells (PBMCs) were treated with FlaB, and the secreted and intracellular cytokines of iNKT cells were evaluated by using ELISA and flow cytometry, respectively, following stimulation with α-galactosylceramide. Foxp3+ iNKT cells were also measured. To determine the effect of FlaB-treated dendritic cells (DCs) on iNKT cells, we co-cultured CD14+ monocyte-derived DCs and T cells from patients with house dust mite-sensitive asthma and analyzed intracellular cytokines in iNKT cells. Results A reduction of IL-4 and IL-17 production by iNKT cells in PBMCs after FlaB treatment was alleviated following blocking of IL-10 signaling. A decrease in the frequencies of IL-4+ and IL-17+ iNKT cells by FlaB-treated DCs was reversed after blocking of IL-10 signaling. Simultaneously, an increase in Foxp3+ iNKT cells induced by FlaB treatment disappeared after blocking of IL-10. Conclusions FlaB may inhibit Th2- and Th17-like iNKT cells and induce Foxp3+ iNKT cells by DCs via an IL-10-dependent mechanism in asthmatic patients. In patients with a specific asthma phenotype associated with iNKT cells, FlaB may be an effective immunomodulator for iNKT cell-targeted immunotherapy. PMID:26922930

  11. DSCAM Promotes Refinement in the Mouse Retina through Cell Death and Restriction of Exploring Dendrites

    PubMed Central

    Li, Shuai; Sukeena, Joshua M.; Simmons, Aaron B.; Hansen, Ethan J.; Nuhn, Renee E.; Samuels, Ivy S.

    2015-01-01

    In this study we develop and use a gain-of-function mouse allele of the Down syndrome cell adhesion molecule (Dscam) to complement loss-of-function models. We assay the role of Dscam in promoting cell death, spacing, and laminar targeting of neurons in the developing mouse retina. We find that ectopic or overexpression of Dscam is sufficient to drive cell death. Gain-of-function studies indicate that Dscam is not sufficient to increase spatial organization, prevent cell-to-cell pairing, or promote active avoidance in the mouse retina, despite the similarity of the Dscam loss-of-function phenotype in the mouse retina to phenotypes observed in Drosophila Dscam1 mutants. Both gain- and loss-of-function studies support a role for Dscam in targeting neurites; DSCAM is necessary for precise dendrite lamination, and is sufficient to retarget neurites of outer retinal cells after ectopic expression. We further demonstrate that DSCAM guides dendrite targeting in type 2 dopaminergic amacrine cells, by restricting the stratum in which exploring retinal dendrites stabilize, in a Dscam dosage-dependent manner. Based on these results we propose a single model to account for the numerous Dscam gain- and loss-of-function phenotypes reported in the mouse retina whereby DSCAM eliminates inappropriately placed cells and connections. PMID:25855178

  12. Interaction between dendritic cells and nerve fibres in lymphoid organs after oral scrapie exposure.

    PubMed

    Dorban, Gauthier; Defaweux, Valérie; Demonceau, Caroline; Flandroy, Sylvain; Van Lerberghe, Pierre-Bernard; Falisse-Poirrier, Nandini; Piret, Joëlle; Heinen, Ernst; Antoine, Nadine

    2007-12-01

    In transmissible spongiform encephalopathies (TSEs), the infectious agent, called PrPsc, an abnormal isoform of the cellular prion protein, accumulates and replicates in lymphoid organs before affecting the nervous system. To clarify the cellular requirements for the neuroinvasion of the scrapie agent from the lymphoid organs to the central nervous system, we have studied, by confocal microscopy, the innervations within Peyer's patches, mesenteric lymph nodes and the spleen of mice in physiological conditions and after oral exposure to prion. Contacts between nerve fibres and PrPsc-associated cells, dendritic cells (DCs) and follicular dendritic cells (FDCs), were evaluated in preclinical prion-infected mice. Using a double immunolabelling strategy, we demonstrated the lack of innervation of PrPsc-accumulating cells (FDCs). Contacts between nerve fibers and PrPsc-propagating cells (DCs) were detected in T-cell zones and cell-trafficking areas. This supports, for the first time, the possible implication of dendritic cells in the prion neuroinvasion process. PMID:17823814

  13. Expression of Programmed Cell Death 1 Ligands (PD-L1 and PD-L2) in Histiocytic and Dendritic Cell Disorders.

    PubMed

    Xu, Jie; Sun, Heather H; Fletcher, Christopher D M; Hornick, Jason L; Morgan, Elizabeth A; Freeman, Gordon J; Hodi, F Stephen; Pinkus, Geraldine S; Rodig, Scott J

    2016-04-01

    Programmed cell death 1 ligands 1 and 2 (PD-L1 and PD-L2) are cell surface proteins expressed by activated antigen-presenting cells and by select malignancies that bind PD-1 on T cells to inhibit immune responses. Antibodies targeting PD-1 or PD-L1 elicit antitumor immunity in a subset of patients, and clinical response correlates with PD-1 ligand expression by malignant or immune cells within the tumor microenvironment. We examined the expression of PD-1 ligands on subsets of antigen-presenting cells and 87 histiocytic and dendritic cell disorders including those that are benign, borderline, and malignant. Within reactive lymphoid tissue, strong PD-L1 is detected on most macrophages, subsets of interdigitating dendritic cells, and plasmacytoid dendritic cells, but not on follicular dendritic cells or Langerhans cells. Macrophage/dendritic cell subsets do not express discernible PD-L2. Seven of 7 cases of sarcoidosis (100%), 6 of 6 cases of histiocytic necrotizing lymphadenitis (Kikuchi-Fujimoto disease) (100%), 2 of 11 cases of Rosai-Dorfman disease (18%), and 3 of 15 cases of Langerhans cell histiocytosis (20%) exhibited positivity for PD-L1. All cases of sarcoidosis were also positive for PD-L2. Seven of 14 histiocytic sarcomas (50%), 2 of 5 interdigitating dendritic cell sarcomas (40%), 10 of 20 follicular dendritic cell sarcomas (50%), and none of 9 blastic plasmacytoid dendritic cell neoplasms were positive for PD-L1. Eleven of 20 (55%) follicular dendritic cell sarcomas were also positive for PD-L2. PD-L1 and PD-L2 are useful new markers for identifying select histiocyte and dendritic cell disorders and reveal novel patient populations as rational candidates for immunotherapy. PMID:26752545

  14. Generation and characterization of regulatory dendritic cells derived from murine induced pluripotent stem cells

    PubMed Central

    Zhang, Qi; Fujino, Masayuki; Iwasaki, Shizue; Hirano, Hiroshi; Cai, Songjie; Kitajima, Yuya; Xu, Jinhua; Li, Xiao-Kang

    2014-01-01

    Regulatory dendritic cells (DCregs) represent a potential therapeutic tool for assessing a variety of immune overreaction conditions; however, current approaches for generating DCregs for therapeutic purposes are limited. We attempted to generate and characterize DCregs from murine induced pluripotent stem (iPS) cells. The iPS cells co-cultured with OP9 cells displayed mesodermally differentiated flat colonies. GM-CSF drove most of the colonies exhibiting a differentiated morphology. Thereafter, cells became morphologically heterologous under the effects of TGF-β and IL-10. Most of the floating cells developed an irregular shape with areas of protrusion. The generated iPS-DCregs demonstrated high CD11b/c and low CD40, CD80, CD86 and MHC-II expressions with a high antigen uptake ability and poor T-cell stimulatory function. Importantly, iPS-DCregs showed immune responsiveness regulation effects both in vitro and in vivo and the ability to generate regulatory T-cells in vitro. Our result illustrates a feasible approach for generating functional DCregs from murine iPS cells. PMID:24496181

  15. IRF8 Transcription-Factor-Dependent Classical Dendritic Cells Are Essential for Intestinal T Cell Homeostasis.

    PubMed

    Luda, Katarzyna M; Joeris, Thorsten; Persson, Emma K; Rivollier, Aymeric; Demiri, Mimoza; Sitnik, Katarzyna M; Pool, Lieneke; Holm, Jacob B; Melo-Gonzalez, Felipe; Richter, Lisa; Lambrecht, Bart N; Kristiansen, Karsten; Travis, Mark A; Svensson-Frej, Marcus; Kotarsky, Knut; Agace, William W

    2016-04-19

    The role of dendritic cells (DCs) in intestinal immune homeostasis remains incompletely defined. Here we show that mice lacking IRF8 transcription-factor-dependent DCs had reduced numbers of T cells in the small intestine (SI), but not large intestine (LI), including an almost complete absence of SI CD8αβ(+) and CD4(+)CD8αα(+) T cells; the latter requiring β8 integrin expression by migratory IRF8 dependent CD103(+)CD11b(-) DCs. SI homing receptor induction was impaired during T cell priming in mesenteric lymph nodes (MLN), which correlated with a reduction in aldehyde dehydrogenase activity by SI-derived MLN DCs, and inefficient T cell localization to the SI. These mice also lacked intestinal T helper 1 (Th1) cells, and failed to support Th1 cell differentiation in MLN and mount Th1 cell responses to Trichuris muris infection. Collectively these results highlight multiple non-redundant roles for IRF8 dependent DCs in the maintenance of intestinal T cell homeostasis. PMID:27067057

  16. Neural Cell Adhesion Molecule NrCAM Regulates Semaphorin 3F-Induced Dendritic Spine Remodeling

    PubMed Central

    Demyanenko, Galina P.; Mohan, Vishwa; Zhang, Xuying; Brennaman, Leann H.; Dharbal, Katherine E.S.; Tran, Tracy S.; Manis, Paul B.

    2014-01-01

    Neuron-glial related cell adhesion molecule (NrCAM) is a regulator of axon growth and repellent guidance, and has been implicated in autism spectrum disorders. Here a novel postsynaptic role for NrCAM in Semaphorin3F (Sema3F)-induced dendritic spine remodeling was identified in pyramidal neurons of the primary visual cortex (V1). NrCAM localized to dendritic spines of star pyramidal cells in postnatal V1, where it was coexpressed with Sema3F. NrCAM deletion in mice resulted in elevated spine densities on apical dendrites of star pyramidal cells at both postnatal and adult stages, and electron microscopy revealed increased numbers of asymmetric synapses in layer 4 of V1. Whole-cell recordings in cortical slices from NrCAM-null mice revealed increased frequency of mEPSCs in star pyramidal neurons. Recombinant Sema3F-Fc protein induced spine retraction on apical dendrites of wild-type, but not NrCAM-null cortical neurons in culture, while re-expression of NrCAM rescued the spine retraction response. NrCAM formed a complex in brain with Sema3F receptor subunits Neuropilin-2 (Npn-2) and PlexinA3 (PlexA3) through an Npn-2-binding sequence (TARNER) in the extracellular Ig1 domain. A trans heterozygous genetic interaction test demonstrated that Sema3F and NrCAM pathways interacted in vivo to regulate spine density in star pyramidal neurons. These findings reveal NrCAM as a novel postnatal regulator of dendritic spine density in cortical pyramidal neurons, and an integral component of the Sema3F receptor complex. The results implicate NrCAM as a contributor to excitatory/inhibitory balance in neocortical circuits. PMID:25143608

  17. Vaccine activation of the nutrient sensor GCN2 in dendritic cells enhances antigen presentation.

    PubMed

    Ravindran, Rajesh; Khan, Nooruddin; Nakaya, Helder I; Li, Shuzhao; Loebbermann, Jens; Maddur, Mohan S; Park, Youngja; Jones, Dean P; Chappert, Pascal; Davoust, Jean; Weiss, David S; Virgin, Herbert W; Ron, David; Pulendran, Bali

    2014-01-17

    The yellow fever vaccine YF-17D is one of the most successful vaccines ever developed in humans. Despite its efficacy and widespread use in more than 600 million people, the mechanisms by which it stimulates protective immunity remain poorly understood. Recent studies using systems biology approaches in humans have revealed that YF-17D-induced early expression of general control nonderepressible 2 kinase (GCN2) in the blood strongly correlates with the magnitude of the later CD8(+) T cell response. We demonstrate a key role for virus-induced GCN2 activation in programming dendritic cells to initiate autophagy and enhanced antigen presentation to both CD4(+) and CD8(+) T cells. These results reveal an unappreciated link between virus-induced integrated stress response in dendritic cells and the adaptive immune response. PMID:24310610

  18. Dendritic cells and skin sensitization: Biological roles and uses in hazard identification

    SciTech Connect

    Ryan, Cindy A.; Kimber, Ian; Basketter, David A.; Pallardy, Marc; Gildea, Lucy A.; Gerberick, G. Frank . E-mail: gerberick.gf@pg.com

    2007-06-15

    Recent advances have been made in our understanding of the roles played by cutaneous dendritic cells (DCs) in the induction of contact allergy. A number of associated changes in epidermal Langerhans cell phenotype and function required for effective skin sensitization are providing the foundations for the development of cellular assays (using DC and DC-like cells) for skin sensitization hazard identification. These alternative approaches to the identification and characterization of skin sensitizing chemicals were the focus of a Workshop entitled 'Dendritic Cells and Skin Sensitization: Biological Roles and Uses in Hazard Identification' that was given at the annual Society of Toxicology meeting held March 6-9, 2006 in San Diego, California. This paper reports information that was presented during the Workshop.

  19. FDC-B1: a new monoclonal antibody directed against bovine follicular dendritic cells.

    PubMed

    Mélot, F; Defaweux, V; Jolois, O; Collard, A; Robert, B; Heinen, E; Antoine, N

    2004-01-01

    Follicular dendritic cells (FDCs) are a unique population of accessory cells located in the light zone of the germinal centres of lymphoid follicles. Their involvement in the generation of humoral immune responses implies a potential role for these cells in many disorders. Indeed, in prion diseases, FDCs seem to be the major sites of extraneuronal cellular prion protein expression and the principal sites of the infectious agent accumulation in lymphoid organs. The identification of FDC is useful for the analysis of their distribution in reactive lymphoid tissue as well as in pathological conditions. The production and characterisation of a new mouse monoclonal antibody directed against bovine follicular dendritic cells (FDC-B1) is reported. The antigen detected by FDC-B1 is expressed exclusively on the surface of FDCs in ruminant lymphoid organs. The antigen has an approximate molecular weight of 28 kDa. PMID:14700533

  20. Blastic plasmacytoid dendritic cell neoplasm: A case report and literature review

    PubMed Central

    ZHANG, YI-WEI; ZHONG, JI-HUA; CHEN, XIAO-LONG; XIAO, FEI; CHEN, FANG-YUAN

    2016-01-01

    Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a clinically aggressive tumor, which frequently presents as cutaneous lesions and subsequently progresses to bone marrow (BM) involvement and leukemic dissemination. BPDCN is a rare entity that belongs in the same class as acute myeloid leukemia-associated precursor neoplasms, according to the 2008 World Health Organization classification. The present study reported the case of a 26-year-old female who presented with evident thrombocytopenia, leukocytosis and anemia, but without skin lesions. The results of peripheral blood, BM smear and BM biopsy examinations detected numerous blastic or abnormal cells. In addition, flow cytometric analysis of BM demonstrated the presence of plasmacytoid dendritic cell-neoplastic precursor cells (CD4+, CD56+, CD123+, CD304+ and human leukocyte antigen-DR+ phenotype). PMID:27347056

  1. Local postsynaptic voltage-gated sodium channel activation in dendritic spines of olfactory bulb granule cells.

    PubMed

    Bywalez, Wolfgang G; Patirniche, Dinu; Rupprecht, Vanessa; Stemmler, Martin; Herz, Andreas V M; Pálfi, Dénes; Rózsa, Balázs; Egger, Veronica

    2015-02-01

    Neuronal dendritic spines have been speculated to function as independent computational units, yet evidence for active electrical computation in spines is scarce. Here we show that strictly local voltage-gated sodium channel (Nav) activation can occur during excitatory postsynaptic potentials in the spines of olfactory bulb granule cells, which we mimic and detect via combined two-photon uncaging of glutamate and calcium imaging in conjunction with whole-cell recordings. We find that local Nav activation boosts calcium entry into spines through high-voltage-activated calcium channels and accelerates postsynaptic somatic depolarization, without affecting NMDA receptor-mediated signaling. Hence, Nav-mediated boosting promotes rapid output from the reciprocal granule cell spine onto the lateral mitral cell dendrite and thus can speed up recurrent inhibition. This striking example of electrical compartmentalization both adds to the understanding of olfactory network processing and broadens the general view of spine function. PMID:25619656

  2. Licensed human natural killer cells aid dendritic cell maturation via TNFSF14/LIGHT

    PubMed Central

    Holmes, Tim D.; Wilson, Erica B.; Black, Emma V. I.; Benest, Andrew V.; Vaz, Candida; Tan, Betty; Tanavde, Vivek M.; Cook, Graham P.

    2014-01-01

    Interactions between natural killer (NK) cells and dendritic cells (DCs) aid DC maturation and promote T-cell responses. Here, we have analyzed the response of human NK cells to tumor cells, and we identify a pathway by which NK–DC interactions occur. Gene expression profiling of tumor-responsive NK cells identified the very rapid induction of TNF superfamily member 14 [TNFSF14; also known as homologous to lymphotoxins, exhibits inducible expression, and competes with HSV glycoprotein D for HVEM, a receptor expressed by T lymphocytes (LIGHT)], a cytokine implicated in the enhancement of antitumor responses. TNFSF14 protein expression was induced by three primary mechanisms of NK cell activation, namely, via the engagement of CD16, by the synergistic activity of multiple target cell-sensing NK-cell activation receptors, and by the cytokines IL-2 and IL-15. For antitumor responses, TNFSF14 was preferentially produced by the licensed NK-cell population, defined by the expression of inhibitory receptors specific for self-MHC class I molecules. In contrast, IL-2 and IL-15 treatment induced TNFSF14 production by both licensed and unlicensed NK cells, reflecting the ability of proinflammatory conditions to override the licensing mechanism. Importantly, both tumor- and cytokine-activated NK cells induced DC maturation in a TNFSF14-dependent manner. The coupling of TNFSF14 production to tumor-sensing NK-cell activation receptors links the tumor immune surveillance function of NK cells to DC maturation and adaptive immunity. Furthermore, regulation by NK cell licensing helps to safeguard against TNFSF14 production in response to healthy tissues. PMID:25512551

  3. Dendritic Cell-Induced Th1 and Th17 Cell Differentiation for Cancer Therapy.

    PubMed

    Terhune, Julia; Berk, Erik; Czerniecki, Brian J

    2013-01-01

    The success of cellular immunotherapies against cancer requires the generation of activated CD4⁺ and CD8⁺ T-cells. The type of T-cell response generated (e.g., Th1 or Th2) will determine the efficacy of the therapy, and it is generally assumed that a type-1 response is needed for optimal cancer treatment. IL-17 producing T-cells (Th17/Tc17) play an important role in autoimmune diseases, but their function in cancer is more controversial. While some studies have shown a pro-cancerous role for IL-17, other studies have shown an anti-tumor function. The induction of polarized T-cell responses can be regulated by dendritic cells (DCs). DCs are key regulators of the immune system with the ability to affect both innate and adaptive immune responses. These properties have led many researchers to study the use of ex vivo manipulated DCs for the treatment of various diseases, such as cancer and autoimmune diseases. While Th1/Tc1 cells are traditionally used for their potent anti-tumor responses, mounting evidence suggests Th17/Tc17 cells should be utilized by themselves or for the induction of optimal Th1 responses. It is therefore important to understand the factors involved in the induction of both type-1 and type-17 T-cell responses by DCs. PMID:26344346

  4. Necroptosis of Dendritic Cells Promotes Activation of γδ T Cells.

    PubMed

    Collins, Cheryl C; Bashant, Kathleen; Erikson, Cuixia; Thwe, Phyu Myat; Fortner, Karen A; Wang, Hong; Morita, Craig T; Budd, Ralph C

    2016-01-01

    γδ T cells function at the interface between innate and adaptive immunity and have well-demonstrated roles in response to infection, autoimmunity and tumors. A common characteristic of these seemingly disparate conditions may be cellular stress or death. However, the conditions under which ligands for γδ T cells are induced or exposed remain largely undefined. We observed that induction of necroptosis of murine or human dendritic cells (DC) by inhibition of caspase activity paradoxically augments their ability to activate γδ T cells. Furthermore, upregulation of the stabilizer of caspase-8 activity, c-FLIP, by IL-4, not only greatly reduced the susceptibility of DC to necroptosis, but also considerably decreased their ability to activate γδ T cells. Collectively, these findings suggest that the induction of necroptosis in DC upregulates or exposes the expression of γδ T cell ligands, and they support the view that γδ T cells function in the immune surveillance of cell stress. PMID:27431410

  5. Mycobacterium tuberculosis infection induces non-apoptotic cell death of human dendritic cells

    PubMed Central

    2011-01-01

    Background Dendritic cells (DCs) connect innate and adaptive immunity, and are necessary for an efficient CD4+ and CD8+ T cell response after infection with Mycobacterium tuberculosis (Mtb). We previously described the macrophage cell death response to Mtb infection. To investigate the effect of Mtb infection on human DC viability, we infected these phagocytes with different strains of Mtb and assessed viability, as well as DNA fragmentation and caspase activity. In parallel studies, we assessed the impact of infection on DC maturation, cytokine production and bacillary survival. Results Infection of DCs with live Mtb (H37Ra or H37Rv) led to cell death. This cell death proceeded in a caspase-independent manner, and without nuclear fragmentation. In fact, substrate assays demonstrated that Mtb H37Ra-induced cell death progressed without the activation of the executioner caspases, 3/7. Although the death pathway was triggered after infection, the DCs successfully underwent maturation and produced a host-protective cytokine profile. Finally, dying infected DCs were permissive for Mtb H37Ra growth. Conclusions Human DCs undergo cell death after infection with live Mtb, in a manner that does not involve executioner caspases, and results in no mycobactericidal effect. Nonetheless, the DC maturation and cytokine profile observed suggests that the infected cells can still contribute to TB immunity. PMID:22024399

  6. Allergen recognition by innate immune cells: critical role of dendritic and epithelial cells.

    PubMed

    Salazar, Fabián; Ghaemmaghami, Amir M

    2013-01-01

    Allergy is an exacerbated response of the immune system against non-self-proteins called allergens and is typically characterized by biased type-2 T helper cell and deleterious IgE mediated immune responses. The allergic cascade starts with the recognition of allergens by antigen presenting cells, mainly dendritic cells (DCs), leading to Th2 polarization, switching to IgE production by B cells, culminating in mast cell sensitization and triggering. DCs have been demonstrated to play a crucial role in orchestrating allergic diseases. Using different C-type lectin receptors DCs are able to recognize and internalize a number of allergens from diverse sources leading to sensitization. Furthermore, there is increasing evidence highlighting the role of epithelial cells in triggering and modulating immune responses to allergens. As well as providing a physical barrier, epithelial cells can interact with allergens and influence DCs behavior through the release of a number of Th2 promoting cytokines. In this review we will summarize current understanding of how allergens are recognized by DCs and epithelial cells and what are the consequences of such interaction in the context of allergic sensitization and downstream events leading to allergic inflammation. Better understanding of the molecular mechanisms of allergen recognition and associated signaling pathways could enable developing more effective therapeutic strategies that target the initial steps of allergic sensitization hence hindering development or progression of allergic diseases. PMID:24204367

  7. NK cells enhance dendritic cell response against parasite antigens via NKG2D pathway.

    PubMed

    Guan, Hongbing; Moretto, Magali; Bzik, David J; Gigley, Jason; Khan, Imtiaz A

    2007-07-01

    Recent studies have shown that NK-dendritic cell (DC) interaction plays an important role in the induction of immune response against tumors and certain viruses. Although the effect of this interaction is bidirectional, the mechanism or molecules involved in this cross-talk have not been identified. In this study, we report that coculture with NK cells causes several fold increase in IL-12 production by Toxoplasma gondii lysate Ag-pulsed DC. This interaction also leads to stronger priming of Ag-specific CD8+ T cell response by these cells. In vitro blockade of NKG2D, a molecule present on human and murine NK cells, neutralizes the NK cell-induced up-regulation of DC response. Moreover, treatment of infected animals with Ab to NKG2D receptor compromises the development of Ag-specific CD8+ T cell immunity and reduces their ability to clear parasites. These studies emphasize the critical role played by NKG2D in the NK-DC interaction, which apparently is important for the generation of robust CD8+ T cell immunity against intracellular pathogens. To the best of our knowledge, this is the first work that describes in vivo importance of NKG2D during natural infection. PMID:17579080

  8. The Dendritic Cell Synapse: A Life Dedicated to T Cell Activation.

    PubMed

    Benvenuti, Federica

    2016-01-01

    T-cell activation within immunological synapses is a complex process whereby different types of signals are transmitted from antigen-presenting cells to T cells. The molecular strategies developed by T cells to interpret and integrate these signals have been systematically dissected in recent years and are now in large part understood. On the other side of the immune synapse, dendritic cells (DCs) participate actively in synapse formation and maintenance by remodeling of membrane receptors and intracellular content. However, the details of such changes have been only partially characterized. The DCs actin cytoskeleton has been one of the first systems to be identified as playing an important role in T-cell priming and some of the underlying mechanisms have been elucidated. Similarly, the DCs microtubule cytoskeleton undergoes major spatial changes during synapse formation that favor polarization of the DCs subcellular space toward the interacting T cell. Recently, we have begun to investigate the trafficking machinery that controls polarized delivery of endosomal vesicles at the DC-T immune synapse with the aim of understanding the functional relevance of polarized secretion of soluble factors during T-cell priming. Here, we will review the current knowledge of events occurring in DCs during synapse formation and discuss the open questions that still remain unanswered. PMID:27014259

  9. The Dendritic Cell Synapse: A Life Dedicated to T Cell Activation

    PubMed Central

    Benvenuti, Federica

    2016-01-01

    T-cell activation within immunological synapses is a complex process whereby different types of signals are transmitted from antigen-presenting cells to T cells. The molecular strategies developed by T cells to interpret and integrate these signals have been systematically dissected in recent years and are now in large part understood. On the other side of the immune synapse, dendritic cells (DCs) participate actively in synapse formation and maintenance by remodeling of membrane receptors and intracellular content. However, the details of such changes have been only partially characterized. The DCs actin cytoskeleton has been one of the first systems to be identified as playing an important role in T-cell priming and some of the underlying mechanisms have been elucidated. Similarly, the DCs microtubule cytoskeleton undergoes major spatial changes during synapse formation that favor polarization of the DCs subcellular space toward the interacting T cell. Recently, we have begun to investigate the trafficking machinery that controls polarized delivery of endosomal vesicles at the DC–T immune synapse with the aim of understanding the functional relevance of polarized secretion of soluble factors during T-cell priming. Here, we will review the current knowledge of events occurring in DCs during synapse formation and discuss the open questions that still remain unanswered. PMID:27014259

  10. Apoptotic cell-based therapies against transplant rejection: role of recipient’s dendritic cells

    PubMed Central

    Larregina, Adriana T.

    2010-01-01

    One of the ultimate goals in transplantation is to develop novel therapeutic methods for induction of donor-specific tolerance to reduce the side effects caused by the generalized immunosuppression associated to the currently used pharmacologic regimens. Interaction or phagocytosis of cells in early apoptosis exerts potent anti-inflammatory and immunosuppressive effects on antigen (Ag)-presenting cells (APC) like dendritic cells (DC) and macrophages. This observation led to the idea that apoptotic cell-based therapies could be employed to deliver donor-Ag in combination with regulatory signals to recipient’s APC as therapeutic approach to restrain the anti-donor response. This review describes the multiple mechanisms by which apoptotic cells down-modulate the immuno-stimulatory and pro-inflammatory functions of DC and macrophages, and the role of the interaction between apoptotic cells and APC in self-tolerance and in apoptotic cell-based therapies to prevent/treat allograft rejection and graft-versus-host disease in murine experimental systems and in humans. It also explores the role that in vivo-generated apoptotic cells could have in the beneficial effects of extracorporeal photopheresis, donor-specific transfusion, and tolerogenic DC-based therapies in transplantation. PMID:20140521

  11. REMOD: A Tool for Analyzing and Remodeling the Dendritic Architecture of Neural Cells

    PubMed Central

    Bozelos, Panagiotis; Stefanou, Stefanos S.; Bouloukakis, Georgios; Melachrinos, Constantinos; Poirazi, Panayiota

    2016-01-01

    Dendritic morphology is a key determinant of how individual neurons acquire a unique signal processing profile. The highly branched dendritic structure that originates from the cell body, explores the surrounding 3D space in a fractal-like manner, until it reaches a certain amount of complexity. Its shape undergoes significant alterations under various physiological or neuropathological conditions. Yet, despite the profound effect that these alterations can have on neuronal function, the causal relationship between the two remains largely elusive. The lack of a systematic approach for remodeling neural cells and their dendritic trees is a key limitation that contributes to this problem. Such causal relationships can be inferred via the use of large-scale neuronal models whereby the anatomical plasticity of neurons is accounted for, in order to enhance their biological relevance and hence their predictive performance. To facilitate this effort, we developed a computational tool named REMOD that allows the structural remodeling of any type of virtual neuron. REMOD is written in Python and can be accessed through a dedicated web interface that guides the user through various options to manipulate selected neuronal morphologies. REMOD can also be used to extract meaningful morphology statistics for one or multiple reconstructions, including features such as sholl analysis, total dendritic length and area, path length to the soma, centrifugal branch order, diameter tapering and more. As such, the tool can be used both for the analysis and/or the remodeling of neuronal morphologies of any type. PMID:26778971

  12. REMOD: A Tool for Analyzing and Remodeling the Dendritic Architecture of Neural Cells.

    PubMed

    Bozelos, Panagiotis; Stefanou, Stefanos S; Bouloukakis, Georgios; Melachrinos, Constantinos; Poirazi, Panayiota

    2015-01-01

    Dendritic morphology is a key determinant of how individual neurons acquire a unique signal processing profile. The highly branched dendritic structure that originates from the cell body, explores the surrounding 3D space in a fractal-like manner, until it reaches a certain amount of complexity. Its shape undergoes significant alterations under various physiological or neuropathological conditions. Yet, despite the profound effect that these alterations can have on neuronal function, the causal relationship between the two remains largely elusive. The lack of a systematic approach for remodeling neural cells and their dendritic trees is a key limitation that contributes to this problem. Such causal relationships can be inferred via the use of large-scale neuronal models whereby the anatomical plasticity of neurons is accounted for, in order to enhance their biological relevance and hence their predictive performance. To facilitate this effort, we developed a computational tool named REMOD that allows the structural remodeling of any type of virtual neuron. REMOD is written in Python and can be accessed through a dedicated web interface that guides the user through various options to manipulate selected neuronal morphologies. REMOD can also be used to extract meaningful morphology statistics for one or multiple reconstructions, including features such as sholl analysis, total dendritic length and area, path length to the soma, centrifugal branch order, diameter tapering and more. As such, the tool can be used both for the analysis and/or the remodeling of neuronal morphologies of any type. PMID:26778971

  13. GMP-Grade mRNA Electroporation of Dendritic Cells for Clinical Use.

    PubMed

    Derdelinckx, Judith; Berneman, Zwi N; Cools, Nathalie

    2016-01-01

    mRNA-electroporated dendritic cells (DC) are demonstrating clinical benefit in patients in many therapeutic areas, including cancer and infectious diseases. According to current good manufacturing guidelines, cell-based medicinal products have to be defined for identity, purity, potency, stability, and viability. In order to comply with the directives and guidelines defined by the regulatory authorities, we report here a standardized and reproducible method for the manufacturing of clinical-grade mRNA-transfected DC. PMID:27236797

  14. Antitumor effect of murine dendritic and tumor cells transduced with IL-2 gene.

    PubMed

    Wojas-Turek, Justyna; Pajtasz-Piasecka, Elżbieta; Rossowska, Joanna; Piasecki, Egbert; Duś, Danuta

    2012-01-01

    Interleukin (IL-) 2 acts on a number of types of immune cells promoting their effector functions. To replace systemic administration of recombinant form of this cytokine, various genetically modified cells have been used indifferent preclinical models for tumor growth inhibition. In this study, dendritic or tumor cells transduced with retroviral vector carrying IL-2 gene (JAWS II/IL-2, X63/IL-2, MC38/IL-2 cells) alone or combined with tumor antigen-stimulated dendritic cells (JAWS II/TAg) were exploited to treat colon carcinoma MC38-bearing mice. After the peritumoral injection of vaccine cells, the tumor growth delay and the increase in the number of tumor infiltrating CD4⁺ and CD8⁺ T lymphocytes were noted. A considerable increase in CD4⁺ cell influx into tumor tissue was observed when JAWS II/IL-2 cells or JAWS II/TAg with syngeneic MC38/IL-2 cells were applied. The increase in intensity of CD8⁺ cell infiltration was associated with immune reaction triggered by the same combination of applied cells or JAWS II/TAg with allogeneic X63/IL-2 cells. The effect observed in vivo was accompanied by MC38/0 cell specific cytotoxic activity of spleen cells in vitro. Thus, the application of vaccines, including IL-2-secreting cells of various origins, was able to induce different antitumor responses polarized by exogenous IL-2 and the encountered tumor antigen. PMID:23042272

  15. Plasmacytoid dendritic cells and dermatological disorders: focus on their role in autoimmunity and cancer

    PubMed Central

    Charles, Julie; Chaperot, Laurence; Salameire, Dimitri; Di Domizio, Jérémy; Aspord, Caroline; Gressin, Rémy; Jacob, Marie-Christine; Richard, Marie-Jeanne; Beani, Jean-Claude; Plumas, Joel; Leccia, Marie-Thérèse

    2010-01-01

    Dendritic cells (DC), considered as immunological sentinels of the organism since they are antigen presenting cells, create the link between innate and adaptive immunity. DC include myeloid dendritic cells (MDC) and plasmacytoid dendritic cells (PDC). The presence of PDC, cells capable of producing large quantities of interferon alpha (IFN-α) in response to pathogenic agents or danger signals, seem to be tightly related to pathological conditions. Thereby, PDC have been observed in inflammatory immunoallergic dermatological disorders, in malignant cutaneous tumours and in cutaneous lesions of infectious origin. They seem to play a crucial role in the initiation of the pathological process of autoimmune diseases such as lupus or psoriasis. Their function within a tumour context is not as well known and is controversial. They could have a tolerogenic role towards tumour cells in the absence of activator but they also have the capacity to become activated in response to Toll-like receptor (TLR) ligands and could therefore be usefull for therapeutic purposes. PMID:19850548

  16. β-glucan restores tumor-educated dendritic cell maturation to enhance antitumor immune responses.

    PubMed

    Ning, Yongling; Xu, Dongqin; Zhang, Xiaohang; Bai, Yu; Ding, Jun; Feng, Tongbao; Wang, Shizhong; Xu, Ning; Qian, Keqing; Wang, Yong; Qi, Chunjian

    2016-06-01

    Tumors can induce the generation and accumulation of immunosuppressive cells such as myeloid-derived suppressor cells (MDSCs) in a tumor microenvironment, contributing to tumor escape from immunological attack. Although dendritic cell-based cancer vaccines can initiate antitumor immune responses, tumor-educated dendritic cells (TEDCs) involved in the tolerance induction have attracted much attention recently. In this study, we investigated the effect of β-glucan on TEDCs and found that β-glucan treatment could promote the maturation and migration of TEDCs and that the suppressive function of TEDCs was significantly decreased. Treatment with β-glucan drastically decreased the levels of regulatory T (Treg) cells but increased the infiltration of macrophages, granulocytes and DCs in tumor masses, thus elicited Th1 differentiation and cytotoxic T-lymphocyte responses and led to a delay in tumor progression. These findings reveal that β-glucan can inhibit the regulatory function of TEDCs, therefore revealing a novel function for β-glucan in immunotherapy and suggesting its potential clinical benefit. β-Glucan directly abrogated tumor-educated dendritic cells-associated immune suppression, promoted Th1 differentiation and cytotoxic T-lymphocyte priming and improved antitumor responses. PMID:26773960

  17. Understanding Dendritic Cells and Their Role in Cutaneous Carcinoma and Cancer Immunotherapy

    PubMed Central

    Yanofsky, Valerie R.; Mitsui, Hiroshi; Felsen, Diane; Carucci, John A.

    2013-01-01

    Dendritic cells (DC) represent a diverse group of professional antigen-presenting cells that serve to link the innate and adaptive immune systems. Their capacity to initiate a robust and antigen-specific immune response has made them the ideal candidates for cancer immunotherapies. To date, the clinical impact of DC immunotherapy has been limited, which may, in part, be explained by the complex nature of DC biology. Multiple distinct subsets of DCs have been identified in the skin, where they can be broadly subcategorized into epidermal Langerhans cells (LC), myeloid-derived dermal dendritic cells (mDC) and plasmacytoid dendritic cells (pDC). Each subset is functionally unique and may activate alternate branches of the immune system. This may be relevant for the treatment of squamous cell carcinoma, where we have shown that the tumor microenvironment may preferentially suppress the activity of mDCs, while LCs remain potent stimulators of immunity. Here, we provide an in depth analysis of DC biology, with a particular focus on skin DCs and their role in cutaneous carcinoma. We further explore the current approaches to DC immunotherapy and provide evidence for the targeting of LCs as a promising new strategy in the treatment of skin cancer. PMID:23606870

  18. Aminopeptidase N (CD13) Is Involved in Phagocytic Processes in Human Dendritic Cells and Macrophages

    PubMed Central

    Villaseñor-Cardoso, Mónica I.; Frausto-Del-Río, Dulce A.

    2013-01-01

    Aminopeptidase N (APN or CD13) is a membrane ectopeptidase expressed by many cell types, including myelomonocytic lineage cells: monocytes, macrophages, and dendritic cells. CD13 is known to regulate the biological activity of various peptides by proteolysis, and it has been proposed that CD13 also participates in several functions such as angiogenesis, cell adhesion, metastasis, and tumor invasion. We had previously reported that, in human monocytes and macrophages, CD13 modulates the phagocytosis mediated by receptors for the Fc portion of IgG antibodies (FcγRs). In this work, we analyzed the possible interaction of CD13 with other phagocytic receptors. We found out that the cross-linking of CD13 positively modulates the phagocytosis mediated by receptors of the innate immune system, since a significant increase in the phagocytosis of zymosan particles or heat-killed E. coli was observed when CD13 was cross-linked using anti-CD13 antibodies, in both macrophages and dendritic cells. Also, we observed that, during the phagocytosis of zymosan, CD13 redistributes and is internalized into the phagosome. These findings suggest that, besides its known functions, CD13 participates in phagocytic processes in dendritic cells and macrophages. PMID:24063007

  19. In silico investigation into dendritic cell regulation of CD8Treg mediated killing of Th1 cells in murine experimental autoimmune encephalomyelitis

    PubMed Central

    2013-01-01

    Background Experimental autoimmune encephalomyelitis has been used extensively as an animal model of T cell mediated autoimmunity. A down-regulatory pathway through which encephalitogenic CD4Th1 cells are killed by CD8 regulatory T cells (Treg) has recently been proposed. With the CD8Treg cells being primed by dendritic cells, regulation of recovery may be occuring around these antigen presenting cells. CD4Treg cells provide critical help within this process, by licensing dendritic cells to prime CD8Treg cells, however the spatial and temporal aspects of this help in the CTL response is currently unclear. Results We have previously developed a simulator of experimental autoimmune encephalomyelitis (ARTIMMUS). We use ARTIMMUS to perform novel in silico experimentation regarding the priming of CD8Treg cells by dendritic cells, and the resulting CD8Treg mediated killing of encephalitogenic CD4Th1 cells. Simulations using dendritic cells that present antigenic peptides in a mutually exclusive manner (either MBP or TCR-derived, but not both) suggest that there is no significant reliance on dendritic cells that can prime both encephalitogenic CD4Th1 and Treg cells. Further, in silico experimentation suggests that dynamics of CD8Treg priming are significantly influenced through their spatial competition with CD4Treg cells and through the timing of Qa-1 expression by dendritic cells. Conclusion There is no requirement for the encephalitogenic CD4Th1 cells and cytotoxic CD8Treg cells to be primed by the same dendritic cells. We conjecture that no significant portion of CD4Th1 regulation by Qa-1 restricted CD8Treg cells occurs around individual dendritic cells, and as such, that CD8Treg mediated killing of CD4Th1 cells occurring around dendritic cells is not critical for recovery from the murine autoimmune disease. Furthermore, the timing of the CD4Treg licensing of dendritic cells and the spatial competition between CD4Treg and CD8Treg cells around the dendritic cell is

  20. Bridging channel dendritic cells induce immunity to transfused red blood cells.

    PubMed

    Calabro, Samuele; Gallman, Antonia; Gowthaman, Uthaman; Liu, Dong; Chen, Pei; Liu, Jingchun; Krishnaswamy, Jayendra Kumar; Nascimento, Manuela Sales L; Xu, Lan; Patel, Seema R; Williams, Adam; Tormey, Christopher A; Hod, Eldad A; Spitalnik, Steven L; Zimring, James C; Hendrickson, Jeanne E; Stowell, Sean R; Eisenbarth, Stephanie C

    2016-05-30

    Red blood cell (RBC) transfusion is a life-saving therapeutic tool. However, a major complication in transfusion recipients is the generation of antibodies against non-ABO alloantigens on donor RBCs, potentially resulting in hemolysis and renal failure. Long-lived antibody responses typically require CD4(+) T cell help and, in murine transfusion models, alloimmunization requires a spleen. Yet, it is not known how RBC-derived antigens are presented to naive T cells in the spleen. We sought to answer whether splenic dendritic cells (DCs) were essential for T cell priming to RBC alloantigens. Transient deletion of conventional DCs at the time of transfusion or splenic DC preactivation before RBC transfusion abrogated T and B cell responses to allogeneic RBCs, even though transfused RBCs persisted in the circulation for weeks. Although all splenic DCs phagocytosed RBCs and activated RBC-specific CD4(+) T cells in vitro, only bridging channel 33D1(+) DCs were required for alloimmunization in vivo. In contrast, deletion of XCR1(+)CD8(+) DCs did not alter the immune response to RBCs. Our work suggests that blocking the function of one DC subset during a narrow window of time during RBC transfusion could potentially prevent the detrimental immune response that occurs in patients who require lifelong RBC transfusion support. PMID:27185856

  1. Linking CD11b+ Dendritic Cells and Natural Killer T Cells to Plaque Inflammation in Atherosclerosis

    PubMed Central

    Rombouts, Miche; Ammi, Rachid; Van Brussel, Ilse; Roth, Lynn; De Winter, Benedicte Y.; Vercauteren, Sven R.; Hendriks, Jeroen M. H.; Lauwers, Patrick; Van Schil, Paul E.; De Meyer, Guido R. Y.; Fransen, Erik; Cools, Nathalie; Schrijvers, Dorien M.

    2016-01-01

    Atherosclerosis remains the leading cause of death and disability in our Western society. To investigate whether the dynamics of leukocyte (sub)populations could be predictive for plaque inflammation during atherosclerosis, we analyzed innate and adaptive immune cell distributions in blood, plaques, and lymphoid tissue reservoirs in apolipoprotein E-deficient (ApoE−/−) mice and in blood and plaques from patients undergoing endarterectomy. Firstly, there was predominance of the CD11b+ conventional dendritic cell (cDC) subset in the plaque. Secondly, a strong inverse correlation was observed between CD11b+ cDC or natural killer T (NKT) cells in blood and markers of inflammation in the plaque (including CD3, T-bet, CCR5, and CCR7). This indicates that circulating CD11b+ cDC and NKT cells show great potential to reflect the inflammatory status in the atherosclerotic plaque. Our results suggest that distinct changes in inflammatory cell dynamics may carry biomarker potential reflecting atherosclerotic lesion progression. This not only is crucial for a better understanding of the immunopathogenesis but also bares therapeutic potential, since immune cell-based therapies are emerging as a promising novel strategy in the battle against atherosclerosis and its associated comorbidities. The cDC-NKT cell interaction in atherosclerosis serves as a good candidate for future investigations. PMID:27051078

  2. PD-1 expression on dendritic cells suppresses CD8+ T cell function and antitumor immunity

    PubMed Central

    Lim, Tong Seng; Chew, Valerie; Sieow, Je Lin; Goh, Siting; Yeong, Joe Poh-Sheng; Soon, Ai Ling; Ricciardi-Castagnoli, Paola

    2016-01-01

    ABSTRACT Programmed death one (PD-1) is a well-established co-inhibitory regulator that suppresses proliferation and cytokine production of T cells. Despite remarkable progress in delineating the functional roles of PD-1 on T lymphocytes, little is known about the regulatory role of PD-1 expressed on myeloid cells such as dendritic cells (DCs). Here, we show that CD8+ T cells can be more potently activated to secrete IL-2 and IFNγ by PD-1-deficient DCs compared to wild-type DCs. Adoptive transfer of PD-1-deficient DCs demonstrated their superior capabilities in inducing antigen-specific CD8+ T cell proliferation in vivo. In addition, we provide first evidence demonstrating the existence of peripheral blood DCs and CD11c+ tumor-infiltrating myeloid cells that co-express PD-1 in patients with hepatocellular carcinoma (HCC). The existence of PD-1-expressing HCC-infiltrating DCs (HIDCs) was further supported in a mouse model of HCC. Intratumoral transfer of PD-1-deficient DCs rendered recipient mice resistant to the growth of HCC by promoting tumor-infiltrating CD8+ effector T cells to secrete perforin and granzyme B. This novel finding provides a deeper understanding of the role of PD-1 in immune regulation and has significant implications for cancer immunotherapies targeting PD-1. PMID:27141339

  3. Human Dendritic Cells Activated by TSLP and CD40L Induce Proallergic Cytotoxic T Cells

    PubMed Central

    Gilliet, Michel; Soumelis, Vassili; Watanabe, Norihiko; Hanabuchi, Shino; Antonenko, Svetlana; de Waal-Malefyt, Rene; Liu, Yong-Jun

    2003-01-01

    Human thymic stromal lymphopoietin (TSLP) is a novel epithelial cell–derived cytokine, which induces dendritic cell (DC)-mediated CD4+ T cell responses with a proallergic phenotype. Although the participation of CD8+ T cells in allergic inflammation is well documented, their functional properties as well as the pathways leading to their generation remain poorly understood. Here, we show that TSLP-activated CD11c+ DCs potently activate and expand naive CD8+ T cells, and induce their differentiation into interleukin (IL)-5 and IL-13–producing effectors exhibiting poor cytolytic activity. Additional CD40L triggering of TSLP-activated DCs induced CD8+ T cells with potent cytolytic activity, producing large amounts of interferon (IFN)-γ, while retaining their capacity to produce IL-5 and IL-13. These data further support the role of TSLP as initial trigger of allergic T cell responses and suggest that CD40L-expressing cells may act in combination with TSLP to amplify and sustain pro-allergic responses and cause tissue damage by promoting the generation of IFN-γ–producing cytotoxic effectors. PMID:12707303

  4. Cell-free tumor microparticle vaccines stimulate dendritic cells via cGAS/STING signaling.

    PubMed

    Zhang, Huafeng; Tang, Ke; Zhang, Yi; Ma, Ruihua; Ma, Jingwei; Li, Yong; Luo, Shunqun; Liang, Xiaoyu; Ji, Tiantian; Gu, Zhichao; Lu, Jinzhi; He, Wei; Cao, Xuetao; Wan, Yonghong; Huang, Bo

    2015-02-01

    Tumor antigens and innate signals are vital considerations in developing new therapeutic or prophylactic antitumor vaccines. The role or requirement of intact tumor cells in the development of an effective tumor vaccine remains incompletely understood. This study reveals the mechanism by which tumor cell-derived microparticles (T-MP) can act as a cell-free tumor vaccine. Vaccinations with T-MPs give rise to prophylactic effects against the challenge of various tumor cell types, while T-MP-loaded dendritic cells (DC) also exhibit therapeutic effects in various tumor models. Such antitumor effects of T-MPs are perhaps attributable to their ability to generate immune signaling and to represent tumor antigens. Mechanically, T-MPs effectively transfer DNA fragments to DCs, leading to type I IFN production through the cGAS/STING-mediated DNA-sensing pathway. In turn, type I IFN promotes DC maturation and presentation of tumor antigens to T cells for antitumor immunity. These findings highlight a novel tumor cell-free vaccine strategy with potential clinical applications. PMID:25477253

  5. The role of dendritic cells and regulatory T cells in the pathogenesis of morphea

    PubMed Central

    Teresiak-Mikołajczak, Ewa; Dańczak-Pazdrowska, Aleksandra; Kowalczyk, Michał; Żaba, Ryszard; Adamski, Zygmunt

    2015-01-01

    Morphea is one of diseases characterised by fibrosis of the skin and subcutaneous tissue. It is a chronic disease that does not shorten the life of the patient, yet significantly affects its quality. The group of factors responsible for its pathogenesis is thought to include disturbed functioning of endothelial cells as well as immune disturbances leading to chronic inflammatory conditions, accompanied by increased production of collagen and of other extracellular matrix components. Dendritic cells (DC) are a type of professional antigen-presenting cells and can be found in almost all body tissues. Individual investigations have demonstrated high numbers of plasmacytoid DC (pDC) in morphoeic skin lesions, within deeper dermal layers, around blood vessels, and around collagen fibres in subcutaneous tissue. It appears that DC has a more pronounced role in the development of inflammation and T cell activation in morphea, as compared to systemic sclerosis (SSc). Regulatory T (Treg) cells represent a subpopulation of T cells with immunosuppressive properties. Recent studies have drawn attention to the important role played by Treg in the process of autoimmunisation. Just a few studies have demonstrated a decrease in the number and activity of Treg in patients with SSc, and only such studies involve morphea. This article reviews recent studies on the role of DC and regulatory T cells in the pathogenesis of morphea. Moreover, mechanisms of phototherapy and potential therapeutic targets in the treatment of morphea are discussed in this context. PMID:26155191

  6. Dendritic cells respond to nasopharygeal carcinoma cells through annexin A2-recognizing DC-SIGN

    PubMed Central

    Cheng, Chao-Wen; Hsu, Tin-Jui; Lin, Yun-Tien; Lai, Chang-Hao; Liao, Chen-Chung; Chen, Wei-Yu; Leung, Ting-Kai; Lee, Fei-Peng; Lin, Yung-Feng; Chen, Chien-Ho

    2015-01-01

    Dendritic cells (DCs) play an essential role in immunity and are used in cancer immunotherapy. However, these cells can be tuned by tumors with immunosuppressive responses. DC-specific intercellular adhesion molecule 3-Grabbing Nonintegrin (DC-SIGN), a C-type lectin expressed on DCs, recognizes certain carbohydrate structures which can be found on cancer cells. Nasopharyngeal carcinoma (NPC) is an epithelial cell-derived malignant tumor, in which immune response remains unclear. This research is to reveal the molecular link on NPC cells that induces the immunosuppressive responses in DCs. In this article, we report identification of annexin A2 (ANXA2) on NPC cells as a ligand for DC-SIGN on DCs. N-linked mannose-rich glycan on ANXA2 may mediate the interaction. ANXA2 was abundantly expressed in NPC, and knockdown of ANXA2 suppressed NPC xenograft in mice, suggesting a crucial role of ANXA2 in NPC growth. Interaction with NPC cells caused DC-SIGN activation in DCs. Consequently DC maturation and the proinflammatory interleukin (IL)-12 production were inhibited, and the immunosuppressive IL-10 production was promoted. Blockage of either DC-SIGN or ANXA2 eliminated the production of IL-10 from DCs. This report suggests that suppression of ANXA2 at its expression or glycosylation on NPC may improve DC-mediated immunotherapy for the tumor. PMID:25402728

  7. Dectin-1-activated dendritic cells trigger potent antitumour immunity through the induction of Th9 cells.

    PubMed

    Zhao, Yinghua; Chu, Xiao; Chen, Jintong; Wang, Ying; Gao, Sujun; Jiang, Yuxue; Zhu, Xiaoqing; Tan, Guangyun; Zhao, Wenjie; Yi, Huanfa; Xu, Honglin; Ma, Xingzhe; Lu, Yong; Yi, Qing; Wang, Siqing

    2016-01-01

    Dectin-1 signalling in dendritic cells (DCs) has an important role in triggering protective antifungal Th17 responses. However, whether dectin-1 directs DCs to prime antitumour Th9 cells remains unclear. Here, we show that DCs activated by dectin-1 agonists potently promote naive CD4(+) T cells to differentiate into Th9 cells. Abrogation of dectin-1 in DCs completely abolishes their Th9-polarizing capability in response to dectin-1 agonist curdlan. Notably, dectin-1 stimulation of DCs upregulates TNFSF15 and OX40L, which are essential for dectin-1-activated DC-induced Th9 cell priming. Mechanistically, dectin-1 activates Syk, Raf1 and NF-κB signalling pathways, resulting in increased p50 and RelB nuclear translocation and TNFSF15 and OX40L expression. Furthermore, immunization of tumour-bearing mice with dectin-1-activated DCs induces potent antitumour response that depends on Th9 cells and IL-9 induced by dectin-1-activated DCs in vivo. Our results identify dectin-1-activated DCs as a powerful inducer of Th9 cells and antitumour immunity and may have important clinical implications. PMID:27492902

  8. Dectin-1-activated dendritic cells trigger potent antitumour immunity through the induction of Th9 cells

    PubMed Central

    Zhao, Yinghua; Chu, Xiao; Chen, Jintong; Wang, Ying; Gao, Sujun; Jiang, Yuxue; Zhu, Xiaoqing; Tan, Guangyun; Zhao, Wenjie; Yi, Huanfa; Xu, Honglin; Ma, Xingzhe; Lu, Yong; Yi, Qing; Wang, Siqing

    2016-01-01

    Dectin-1 signalling in dendritic cells (DCs) has an important role in triggering protective antifungal Th17 responses. However, whether dectin-1 directs DCs to prime antitumour Th9 cells remains unclear. Here, we show that DCs activated by dectin-1 agonists potently promote naive CD4+ T cells to differentiate into Th9 cells. Abrogation of dectin-1 in DCs completely abolishes their Th9-polarizing capability in response to dectin-1 agonist curdlan. Notably, dectin-1 stimulation of DCs upregulates TNFSF15 and OX40L, which are essential for dectin-1-activated DC-induced Th9 cell priming. Mechanistically, dectin-1 activates Syk, Raf1 and NF-κB signalling pathways, resulting in increased p50 and RelB nuclear translocation and TNFSF15 and OX40L expression. Furthermore, immunization of tumour-bearing mice with dectin-1-activated DCs induces potent antitumour response that depends on Th9 cells and IL-9 induced by dectin-1-activated DCs in vivo. Our results identify dectin-1-activated DCs as a powerful inducer of Th9 cells and antitumour immunity and may have important clinical implications. PMID:27492902

  9. A generic RNA-pulsed dendritic cell vaccine strategy for renal cell carcinoma

    PubMed Central

    Geiger, Christiane; Regn, Sybille; Weinzierl, Andreas; Noessner, Elfriede; Schendel, Dolores J

    2005-01-01

    We present a generic dendritic cell (DC) vaccine strategy for patients with renal cell carcinoma (RCC) based on the use of RNA as a source of multiplex tumor-associated antigens (TAAs). Instead of preparing RNA from tumor tissue of each individual RCC patient, we propose to substitute RNA prepared from a well characterized highly immunogenic RCC cell line (RCC-26 tumor cells) as a generic source of TAAs for loading of DCs. We demonstrate here that efficient RNA transfer can be achieved using lipofection of immature DCs, which are subsequently matured with a cytokine cocktail to express high levels of MHC and costimulatory molecules as well as the chemokine receptor CCR7. Neither RNA itself nor the lipid component impacted on the phenotype or the cytokine secretion of mature DCs. Following RNA loading, DCs derived from HLA-A2-positive donors were able to activate effector-memory cytotoxic T lymphocytes (CTLs) specific for a TAA ligand expressed by the RCC-26 cell line. CTL responses to RNA-loaded DCs reached levels comparable to those stimulated directly by the RCC-26 tumor cells. Furthermore, DCs expressing tumor cell RNA primed naïve T cells, yielding T cell lines with cytotoxicity and cytokine secretion after contact with RCC tumor cells. RCC-26 cell lines are available as good manufacturing practice (GMP)-certified reagents enabling this source of RNA to be easily standardized and adapted for clinical testing. In addition, well defined immune monitoring tools, including the use of RNA expressing B cell lines, are available. Thus, this DC vaccine strategy can be directly compared with an ongoing gene therapy trial using genetically-engineered variants of the RCC-26 cell line as vaccines for RCC patients with metastatic disease. PMID:16045799

  10. SAMHD1 Restricts HIV-1 Cell-to-Cell Transmission and Limits Immune Detection in Monocyte-Derived Dendritic Cells

    PubMed Central

    Puigdomènech, Isabel; Casartelli, Nicoletta; Porrot, Françoise

    2013-01-01

    SAMHD1 is a viral restriction factor expressed in dendritic cells and other cells, inhibiting infection by cell-free human immunodeficiency virus type 1 (HIV-1) particles. SAMHD1 depletes the intracellular pool of deoxynucleoside triphosphates, thus impairing HIV-1 reverse transcription and productive infection in noncycling cells. The Vpx protein from HIV-2 or simian immunodeficiency virus (SIVsm/SIVmac) antagonizes the effect of SAMHD1 by triggering its degradation. A large part of HIV-1 spread occurs through direct contacts between infected cells and bystander target cells. Here, we asked whether SAMHD1 impairs direct HIV-1 transmission from infected T lymphocytes to monocyte-derived dendritic cells (MDDCs). HIV-1-infected lymphocytes were cocultivated with MDDCs that have been pretreated or not with Vpx or with small interfering RNA against SAMHD1. We show that in the cocultures, SAMHD1 significantly inhibits productive cell-to-cell transmission to target MDDCs and prevents the type I interferon response and expression of the interferon-stimulated gene MxA. Therefore, SAMHD1, by controlling the sensitivity of MDDCs to HIV-1 infection during intercellular contacts, impacts their ability to sense the virus and to trigger an innate immune response. PMID:23269793

  11. The skin-resident and migratory immune system in steady state and memory: innate lymphocytes, dendritic cells and T cells.

    PubMed

    Heath, William R; Carbone, Francis R

    2013-10-01

    The skin is a highly complex organ interspersed with a variety of smaller organ-like structures and a plethora of cell types that together perform essential functions such as physical sensing, temperature control, barrier maintenance and immunity. In this Review, we outline many of the innate and adaptive immune cell types associated with the skin, focusing on the steady state in mice and men, and include a broad update of dendritic cell function and T cell surveillance. PMID:24048119

  12. Follicular Dendritic Cell Sarcoma of Lymph Node: A report of a Patient with Chronic Myeloid Leukemia Treated with Imatinib

    PubMed Central

    Sharma, Nisha; Singh, Ragini; Marwah, Nisha; Gupta, Sumiti; Sen, Rajeev

    2015-01-01

    Follicular dendritic cells or dendritic reticulum cells are important components of the immune system essential for antigen presentation. Malignancies arising from these cells are uncommon and the first case was reported in 1986. The most common sites of follicular dendritic cell sarcomas are lymph nodes, especially cervical, axillary and mediastinal regions, but extranodal sites including head and neck and gastrointestinal tract may be affected in one-third of patients. Immunohistochemistry plays an important role in its diagnosis to differentiate it from morphologically similar malignancies The present report describes a case of follicular dendritic cell sarcoma in a patient with chronic myeloid leukemia (CML) treated with imatininb mesylate for 6 years. This case deserves reporting due to rarity of the disease and hitherto unreported association with CML. Furthermore, the pathological diagnosis is challenging and requires a close-knit effort between the pathologist and haematologist. PMID:26261702

  13. Apoptotic cells induce dendritic cell-mediated suppression via interferon-γ-induced IDO

    PubMed Central

    Williams, Charlotte A; Harry, Rachel A; McLeod, Julie D

    2008-01-01

    Dendritic cells (DC) are sensitive to their local environment and are affected by proximal cell death. This study investigated the modulatory effect of cell death on DC function. Monocyte-derived DC exposed to apoptotic Jurkat or primary T cells failed to induce phenotypic maturation of the DC and were unable to support CD4+ allogeneic T-cell proliferation compared with DC exposed to lipopolysaccharide (LPS) or necrotic cells. Apoptotic cells coincubated with LPS- or necrotic cell-induced mature DC significantly suppressed CD80, CD86 and CD83 and attenuated LPS-induced CD4+ T-cell proliferation. Reduced levels of interleukin-12 (IL-12), IL-10, IL-6, tumour necrosis factor-α and interferon-γ (IFN-γ) were found to be concomitant with the suppressive activity of apoptotic cells upon DC. Furthermore, intracellular staining confirmed IFN-γ expression by DC in association with apoptotic environments. The specific generation of IFN-γ by DC within apoptotic environments is suggestive of an anti-inflammatory role by the induction of indoleamine 2,3-dioxygenase (IDO). Both neutralization of IFN-γ and IDO blockade demonstrated a role for IFN-γ and IDO in the suppression of CD4+ T cells. Moreover, we demonstrate that IDO expression within the DC was found to be IFN-γ-dependent. Blocking transforming growth factor-β (TGF-β) also produced a partial release in T-cell proliferation. Our study strongly suggests that apoptosis-induced DC suppression is not an immunological null event and two prime mediators underpinning these functional effects are IFN-γ-induced IDO and TGF-β. PMID:18067553

  14. TLR5 mediates CD172α+ intestinal lamina propria dendritic cell induction of Th17 cells

    PubMed Central

    Liu, Han; Chen, Feidi; Wu, Wei; Cao, Anthony T; Xue, Xiaochang; Yao, Suxia; Evans-Marin, Heather L; Li, Yan-Qing; Cong, Yingzi

    2016-01-01

    Multiple mechanisms exist in regulation of host responses to massive challenges from microbiota to maintain immune homeostasis in the intestines. Among these is the enriched Th17 cells in the intestines, which regulates intestinal homeostasis through induction of antimicrobial peptides and secretory IgA among others. However, the means by which Th17 cells develop in response to microbiota is still not completely understood. Although both TLR5 and CD172α+ lamina propria dendritic cells (LPDC) have been shown to promote Th17 cell development, it is still unclear whether TLR5 mediates the CD172α+LPDC induction of Th17 cells. By using a microbiota antigen-specific T cell reporter mouse system, we demonstrated that microbiota antigen-specific T cells developed into Th17 cells in the intestinal LP, but not in the spleen when transferred into TCRβxδ−/− mice. LPDCs expressed high levels of TLR5, and most CD172α+LPDCs also co-expressed TLR5. LPDCs produced high levels of IL-23, IL-6 and TGFβ when stimulated with commensal flagellin and promoted Th17 cell development when cultured with full-length CBir1 flagellin but not CBir1 peptide. Wild-type CD172α+, but not CD172α−, LPDCs induced Th17 cells, whereas TLR5-deficient LPDC did not induce Th17 cells. Our data thereby demonstrated that TLR5 mediates CD172α+LPDC induction of Th17 cells in the intestines. PMID:26907705

  15. Immune responses of macrophages and dendritic cells regulated by mTOR signalling.

    PubMed

    Katholnig, Karl; Linke, Monika; Pham, Ha; Hengstschläger, Markus; Weichhart, Thomas

    2013-08-01

    The innate myeloid immune system is a complex network of cells that protect against disease by identifying and killing pathogens and tumour cells, but it is also implicated in homoeostatic mechanisms such as tissue remodelling and wound healing. Myeloid phagocytes such as monocytes, macrophages or dendritic cells are at the basis of controlling these immune responses in all tissues of the body. In the present review, we summarize recent studies demonstrating that mTOR [mammalian (or mechanistic) target of rapamycin] regulates innate immune reactions in macrophages and dendritic cells. The mTOR pathway serves as a decision maker to control the cellular response to pathogens and tumours by regulating the expression of inflammatory mediators such as cytokines, chemokines or interferons. In addition to various in vivo mouse models, kidney transplant patients under mTOR inhibitor therapy allowed the elucidation of important innate immune functions regulated by mTOR in humans. The role of the mTOR pathway in macrophages and dendritic cells enhances our understanding of the immune system and suggests new therapeutic avenues for the regulation of pro- versus anti-inflammatory mediators with potential relevance to cancer therapy, the design of novel adjuvants and the control of distinct infectious and autoimmune diseases. PMID:23863158

  16. Evaluation of in vivo labelled dendritic cell migration in cancer patients

    PubMed Central

    Ridolfi, Ruggero; Riccobon, Angela; Galassi, Riccardo; Giorgetti, Gianluigi; Petrini, Massimiliano; Fiammenghi, Laura; Stefanelli, Monica; Ridolfi, Laura; Moretti, Andrea; Migliori, Giuseppe; Fiorentini, Giuseppe

    2004-01-01

    Background Dendritic Cell (DC) vaccination is a very promising therapeutic strategy in cancer patients. The immunizing ability of DC is critically influenced by their migration activity to lymphatic tissues, where they have the task of priming naïve T-cells. In the present study in vivo DC migration was investigated within the context of a clinical trial of antitumor vaccination. In particular, we compared the migration activity of mature Dendritic Cells (mDC) with that of immature Dendritic Cells (iDC) and also assessed intradermal versus subcutaneous administration. Methods DC were labelled with 99mTc-HMPAO or 111In-Oxine, and the presence of labelled DC in regional lymph nodes was evaluated at pre-set times up to a maximum of 72 h after inoculation. Determinations were carried out in 8 patients (7 melanoma and 1 renal cell carcinoma). Results It was verified that intradermal administration resulted in about a threefold higher migration to lymph nodes than subcutaneous administration, while mDC showed, on average, a six-to eightfold higher migration than iDC. The first DC were detected in lymph nodes 20–60 min after inoculation and the maximum concentration was reached after 48–72 h. Conclusions These data obtained in vivo provide preliminary basic information on DC with respect to their antitumor immunization activity. Further research is needed to optimize the therapeutic potential of vaccination with DC. PMID:15285807

  17. Dendritic cell and macrophage staining by monoclonal antibodies in tissue sections and epidermal sheets.

    PubMed Central

    Flotte, T. J.; Springer, T. A.; Thorbecke, G. J.

    1983-01-01

    Mouse tissue sections were stained by monoclonal antibodies to macrophage antigens (Mac-1 (M1/70), Mac-2 (M3/38), Mac-3 (M3/84) with the use of immunoperoxidase. Mac-1 was located diffusely in the cytoplasm of round cells in a high percentage of alveolar macrophages, resident peritoneal and bone marrow cells, in splenic red pulp, and in rare perivascular cells in the thymus. Mac-1 was absent in epithelial cells and Langerhans cells. Mac-2 was strongly positive in many dendritic cells in the thymic medulla, more than the cortex, in paracortex and medulla of lymph nodes, sparing the follicles, and in the marginal zone of spleen. There were a few positive cells in germinal centers. Mac-2 was located in a low percentage of bone marrow and a high percentage of resident peritoneal cells. When positive in sections Mac-3 always showed granular cytoplasmic staining. Bone marrow showed a high percentage of cytoplasmic staining (greater than 50%), as compared with low surface staining (less than 1%). It was found in hematopoietic cells, and in all endothelium, including postcapillary venules and lining of sinuses. It was probable that the resulting dendritic staining pattern for Mac-3 in paracortex of lymph node, white and red pulp, thymic cortex, and medulla included dendritic cells other than endothelial cells. Alveolar macrophages and Kupffer cells were positive for Mac-2 and Mac-3. Mac-3 also stained bile canaliculi. Clearly different staining patterns were found in epithelial cells for Mac-2 and Mac-3 in kidney tubules, intestinal mucosal lining, bronchi, choroid plexus, and epidermis. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 PMID:6340516

  18. Plasmacytoid dendritic cells sequester high prion titres at early stages of prion infection.

    PubMed

    Castro-Seoane, Rocio; Hummerich, Holger; Sweeting, Trevor; Tattum, M Howard; Linehan, Jacqueline M; Fernandez de Marco, Mar; Brandner, Sebastian; Collinge, John; Klöhn, Peter-Christian

    2012-02-01

    In most transmissible spongiform encephalopathies prions accumulate in the lymphoreticular system (LRS) long before they are detectable in the central nervous system. While a considerable body of evidence showed that B lymphocytes and follicular dendritic cells play a major role in prion colonization of lymphoid organs, the contribution of various other cell types, including antigen-presenting cells, to the accumulation and the spread of prions in the LRS are not well understood. A comprehensive study to compare prion titers of candidate cell types has not been performed to date, mainly due to limitations in the scope of animal bioassays where prohibitively large numbers of mice would be required to obtain sufficiently accurate data. By taking advantage of quantitative in vitro prion determination and magnetic-activated cell sorting, we studied the kinetics of prion accumulation in various splenic cell types at early stages of prion infection. Robust estimates for infectious titers were obtained by statistical modelling using a generalized linear model. Whilst prions were detectable in B and T lymphocytes and in antigen-presenting cells like dendritic cells and macrophages, highest infectious titers were determined in two cell types that have previously not been associated with prion pathogenesis, plasmacytoid dendritic (pDC) and natural killer (NK) cells. At 30 days after infection, NK cells were more than twice, and pDCs about seven-fold, as infectious as lymphocytes respectively. This result was unexpected since, in accordance to previous reports prion protein, an obligate requirement for prion replication, was undetectable in pDCs. This underscores the importance of prion sequestration and dissemination by antigen-presenting cells which are among the first cells of the immune system to encounter pathogens. We furthermore report the first evidence for a release of prions from lymphocytes and DCs of scrapie-infected mice ex vivo, a process that is associated with

  19. Flt3 permits survival during infection by rendering dendritic cells competent to activate NK cells.

    PubMed

    Eidenschenk, Céline; Crozat, Karine; Krebs, Philippe; Arens, Ramon; Popkin, Daniel; Arnold, Carrie N; Blasius, Amanda L; Benedict, Chris A; Moresco, Eva Marie Y; Xia, Yu; Beutler, Bruce

    2010-05-25

    A previously unappreciated signal necessary for dendritic cell (DC)-mediated activation of natural killer (NK) cells during viral infection was revealed by a recessive N-ethyl-N-nitrosourea-induced mutation called warmflash (wmfl). Wmfl homozygotes displayed increased susceptibility to mouse cytomegalovirus (MCMV) infection. In response to MCMV infection in vivo, delayed NK cell activation was observed, but no intrinsic defects in NK cell activation or function were identified. Rather, coculture experiments demonstrated that NK cells are suboptimally activated by wmfl DCs, which showed impaired cytokine production in response to MCMV or synthetic TLR7 and TLR9 ligands. The wmfl mutation was identified in the gene encoding the Fms-like tyrosine kinase 3 (Flt3). Flt3 ligand (Flt3L) is transiently induced in the serum upon infection or TLR activation. However, antibody blockade reveals no acute requirement for Flt3L, suggesting that the Flt3L --> Flt3 axis programs the development of DCs, making them competent to support NK effector function. In the absence of Flt3 signaling, NK cell activation is delayed and survival during MCMV infection is markedly compromised. PMID:20457904

  20. Flt3 permits survival during infection by rendering dendritic cells competent to activate NK cells

    PubMed Central

    Eidenschenk, Céline; Crozat, Karine; Krebs, Philippe; Arens, Ramon; Popkin, Daniel; Arnold, Carrie N.; Blasius, Amanda L.; Benedict, Chris A.; Moresco, Eva Marie Y.; Xia, Yu; Beutler, Bruce

    2010-01-01

    A previously unappreciated signal necessary for dendritic cell (DC)-mediated activation of natural killer (NK) cells during viral infection was revealed by a recessive N-ethyl-N-nitrosourea-induced mutation called warmflash (wmfl). Wmfl homozygotes displayed increased susceptibility to mouse cytomegalovirus (MCMV) infection. In response to MCMV infection in vivo, delayed NK cell activation was observed, but no intrinsic defects in NK cell activation or function were identified. Rather, coculture experiments demonstrated that NK cells are suboptimally activated by wmfl DCs, which showed impaired cytokine production in response to MCMV or synthetic TLR7 and TLR9 ligands. The wmfl mutation was identified in the gene encoding the Fms-like tyrosine kinase 3 (Flt3). Flt3 ligand (Flt3L) is transiently induced in the serum upon infection or TLR activation. However, antibody blockade reveals no acute requirement for Flt3L, suggesting that the Flt3L → Flt3 axis programs the development of DCs, making them competent to support NK effector function. In the absence of Flt3 signaling, NK cell activation is delayed and survival during MCMV infection is markedly compromised. PMID:20457904

  1. Klf4 expression in conventional dendritic cells is required for T helper 2 cell responses

    PubMed Central

    Tussiwand, Roxane; Everts, Bart; Grajales-Reyes, Gary E.; Kretzer, Nicole M.; Iwata, Arifumi; Bagaitkar, Juhi; Wu, Xiaodi; Wong, Rachel; Anderson, David A.; Murphy, Theresa L.; Pearce, Edward J.; Murphy, Kenneth M.

    2015-01-01

    Summary The two major lineages of classical dendritic cells (cDCs) express and require either IRF8 or IRF4 transcription factors for their development and function. IRF8-dependent cDCs promote anti-viral and T-helper 1 (Th1) cell responses, whereas IRF4-expressing cDCs have been implicated in controlling both Th2 and Th17 cell responses. Here, we have provided evidence that Kruppel-like factor 4 (Klf4) is required in IRF4-expressing cDCs to promote Th2 but not Th17 cell responses in vivo. Conditional Klf4 deletion within cDCs impaired Th2 cell responses during Schistosoma mansoni infection, Schistosoma egg antigen (SEA) immunization, and house dust mite challenge (HDM), without affecting cytotoxic T lymphocyte (CTL), Th1 and Th17 cell responses to herpes simplex virus, Toxoplasma gondii and Citrobacter rodentium infections. Further, Klf4 deletion reduced IRF4 expression in pre-cDCs and resulted in selective loss of IRF4-expressing cDCs subsets in several tissues. These results indicate that Klf4 guides a transcriptional program promoting IRF4-expressing cDCs heterogeneity. PMID:25992862

  2. Characterization of Dendritic Cell and Regulatory T Cell Functions against Mycobacterium tuberculosis Infection

    PubMed Central

    Morris, Devin; Gonzalez, Brenda; Khurasany, Melissa; Kassissa, Christine; Luong, Jennifer; Kasko, Sarah; Pandya, Shalin; Chu, Michael; Chi, Po-Ting; Bui, Steven; Guerra, Carlos; Chan, John; Venketaraman, Vishwanath

    2013-01-01

    Glutathione (GSH) is a tripeptide that regulates intracellular redox and other vital aspects of cellular functions. GSH plays a major role in enhancing the immune system. Dendritic cells (DCs) are potent antigen presenting cells that participate in both innate and acquired immune responses against microbial infections. Regulatory T cells (Tregs) play a significant role in immune homeostasis. In this study, we investigated the effects of GSH in enhancing the innate and adaptive immune functions of DCs against Mycobacterium tuberculosis (M. tb) infection. We also characterized the functions of the sub-populations of CD4+T cells such as Tregs and non-Tregs in modulating the ability of monocytes to control the intracellular M. tb infection. Our results indicate that GSH by its direct antimycobacterial activity inhibits the growth of intracellular M. tb inside DCs. GSH also increases the expressions of costimulatory molecules such as HLA-DR, CD80 and CD86 on the cell surface of DCs. Furthermore, GSH-enhanced DCs induced a higher level of T-cell proliferation. We also observed that enhancing the levels of GSH in Tregs resulted in downregulation in the levels of IL-10 and TGF-β and reduction in the fold growth of M. tb inside monocytes. Our studies demonstrate novel regulatory mechanisms that favor both innate and adaptive control of M. tb infection. PMID:23762843

  3. Granzyme B produced by human plasmacytoid dendritic cells suppresses T-cell expansion

    PubMed Central

    Vollmer, Angelika; Blackwell, Sue E.; Maier, Julia; Sontheimer, Kai; Beyer, Thamara; Mandel, Birgit; Lunov, Oleg; Tron, Kyrylo; Nienhaus, G. Ulrich; Simmet, Thomas; Debatin, Klaus-Michael; Weiner, George J.

    2010-01-01

    Human plasmacytoid dendritic cells (pDCs) are crucially involved in the modulation of adaptive T-cell responses in the course of neoplastic, viral, and autoimmune disorders. In several of these diseases elevated extracellular levels of the serine protease granzyme B (GrB) are observed. Here we demonstrate that human pDCs can be an abundant source of GrB and that such GrB+ pDCs potently suppress T-cell proliferation in a GrB-dependent, perforin-independent manner, a process reminiscent of regulatory T cells. Moreover, we show that GrB expression is strictly regulated on a transcriptional level involving Janus kinase 1 (JAK1), signal transducer and activator of transcription 3 (STAT3), and STAT5 and that interleukin-3 (IL-3), a cytokine secreted by activated T cells, plays a central role for GrB induction. Moreover, we find that the immunosuppressive cytokine IL-10 enhances, while Toll-like receptor agonists and CD40 ligand strongly inhibit, GrB secretion by pDCs. GrB-secreting pDCs may play a regulatory role for immune evasion of tumors, antiviral immune responses, and autoimmune processes. Our results provide novel information about the complex network of pDC–T-cell interactions and may contribute to an improvement of prophylactic and therapeutic vaccinations. PMID:19965634

  4. Tolerogenic IDO+ Dendritic Cells Are Induced by PD-1-Expressing Mast Cells

    PubMed Central

    Rodrigues, Cecilia Pessoa; Ferreira, Ana Carolina Franco; Pinho, Mariana Pereira; de Moraes, Cristiano Jacob; Bergami-Santos, Patrícia Cruz; Barbuto, José Alexandre Marzagão

    2016-01-01

    Mast cells (MCs) are tissue resident cells, rich in inflammatory mediators, involved in allergic reactions, and with an increasingly recognized role in immunomodulation. Dendritic cells (DCs), on the other hand, are central to the determination of immune response patterns, being highly efficient antigen-presenting cells that respond promptly to changes in their microenvironment. Here, we show that direct cell contact between immature monocyte-derived DCs (iDCs) and MC bends DCs toward tolerance induction. DCs that had direct contact with MC (MC-iDC) decreased HLA-DR but increased PD-L1 expression and stimulated regulatory T lymphocytes, which expresses FoxP3+, secrete TGF-β and IL-10, and suppress the proliferation of mitogen-stimulated naïve T lymphocytes. Furthermore, MC-iDC expressed higher levels of indoleamine-2,3-deoxigenase (IDO), a phenomenon that was blocked by treatment of MC with anti-PD-1 or by the treatment of DCs with anti-PD-L1 or anti-PD-L2, but not by blocking of H1 and H2 histamine receptors on DCs. Contact with MC also increased phosphorylated STAT-3 levels in iDCs. When a STAT-3 inhibitor, JSI-124, was added to the DCs before contact with MC, the MC-iDC recovered their ability to induce allogeneic T cell proliferation and did not increase their IDO expression. PMID:26834749

  5. Dendritic cells: an important link between antiphospholipid antibodies, endothelial dysfunction, and atherosclerosis in autoimmune and non-autoimmune diseases.

    PubMed

    Broder, Anna; Chan, Jimmy J; Putterman, Chaim

    2013-03-01

    The presence of dendritic cells, antigen-presenting cells that link innate and adaptive immunity, is necessary to generate and maintain the production of antiphospholipid antibodies in response to exposed intracellular phospholipids on the outer surface of apoptotic cells. In turn, antiphospholipid antibodies enhance dendritic cell-induced inflammatory and proatherogenic responses in a number of conditions that are associated with accelerated atherosclerosis, including diabetes, chronic kidney disease, periodontal infections, and aging. While altering dendritic cells by modifying the ubiquitin-proteasome system enhances antiphospholipid antibody production and leads to development of accelerated atherosclerosis and autoimmune features, inducing tolerance by dendritic cell manipulation leads to decreased atherosclerosis and thrombosis. Therefore, further translational studies are needed to understand the interplay between dendritic cells and antiphospholipid antibodies, and to develop potential new therapies for antiphospholipid syndrome and atherosclerosis. Here we review current experimental and translational studies that have examined the role of dendritic cells in antiphospholipid antibody formation and in antiphospholipid-associated atherosclerosis and thrombosis. PMID:23376063

  6. Induction of CD4+ Regulatory and Polarized Effector/helper T Cells by Dendritic Cells

    PubMed Central

    2016-01-01

    Dendritic cells (DCs) are considered to play major roles during the induction of T cell immune responses as well as the maintenance of T cell tolerance. Naive CD4+ T cells have been shown to respond with high plasticity to signals inducing their polarization into effector/helper or regulatory T cells. Data obtained from in vitro generated bone-marrow (BM)-derived DCs as well as genetic mouse models revealed an important but not exclusive role of DCs in shaping CD4+ T cell responses. Besides the specialization of some conventional DC subsets for the induction of polarized immunity, also the maturation stage, activation of specialized transcription factors and the cytokine production of DCs have major impact on CD4+ T cells. Since in vitro generated BM-DCs show a high diversity to shape CD4+ T cells and their high similarity to monocyte-derived DCs in vivo, this review reports data mainly on BM-DCs in this process and only touches the roles of transcription factors or of DC subsets, which have been discussed elsewhere. Here, recent findings on 1) the conversion of naive into anergic and further into Foxp3− regulatory T cells (Treg) by immature DCs, 2) the role of RelB in steady state migratory DCs (ssmDCs) for conversion of naive T cells into Foxp3+ Treg, 3) the DC maturation signature for polarized Th2 cell induction and 4) the DC source of IL-12 for Th1 induction are discussed. PMID:26937228

  7. Impaired NK Cell Activation and Chemotaxis toward Dendritic Cells Exposed to Complement-Opsonized HIV-1

    PubMed Central

    Ellegård, Rada; Crisci, Elisa; Andersson, Jonas; Shankar, Esaki M.; Nyström, Sofia; Hinkula, Jorma

    2015-01-01

    Mucosa resident dendritic cells (DCs) may represent one of the first immune cells that HIV-1 encounters during sexual transmission. The virions in body fluids can be opsonized with complement factors because of HIV-mediated triggering of the complement cascade, and this appears to influence numerous aspects of the immune defense targeting the virus. One key attribute of host defense is the ability to attract immune cells to the site of infection. In this study, we investigated whether the opsonization of HIV with complement (C-HIV) or a mixture of complement and Abs (CI-HIV) affected the cytokine and chemokine responses generated by DCs, as well as their ability to attract other immune cells. We found that the expression levels of CXCL8, CXCL10, CCL3, and CCL17 were lowered after exposure to either C-HIV or CI-HIV relative to free HIV (F-HIV). DCs exposed to F-HIV induced higher cell migration, consisting mainly of NK cells, compared with opsonized virus, and the chemotaxis of NK cells was dependent on CCL3 and CXCL10. NK cell exposure to supernatants derived from HIV-exposed DCs showed that F-HIV induced phenotypic activation (e.g., increased levels of TIM3, CD69, and CD25) and effector function (e.g., production of IFNγ and killing of target cells) in NK cells, whereas C-HIV and CI-HIV did not. The impairment of NK cell recruitment by DCs exposed to complement-opsonized HIV and the lack of NK activation may contribute to the failure of innate immune responses to control HIV at the site of initial mucosa infection. PMID:26157174

  8. Communication between Human Dendritic Cell Subsets in Tuberculosis: Requirements for Naive CD4+ T Cell Stimulation

    PubMed Central

    Lozza, Laura; Farinacci, Maura; Bechtle, Marina; Stäber, Manuela; Zedler, Ulrike; Baiocchini, Andrea; del Nonno, Franca; Kaufmann, Stefan H. E.

    2014-01-01

    Human primary dendritic cells (DCs) are heterogeneous by phenotype, function, and tissue localization and distinct from inflammatory monocyte-derived DCs. Current information regarding the susceptibility and functional role of primary human DC subsets to Mycobacterium tuberculosis (Mtb) infection is limited. Here, we dissect the response of different primary DC subsets to Mtb infection. Myeloid CD11c+ cells and pDCs (C-type lectin 4C+ cells) were located in human lymph nodes (LNs) of tuberculosis (TB) patients by histochemistry. Rare CD141hi DCs (C-type lectin 9A+ cells) were also identified. Infection with live Mtb revealed a higher responsiveness of myeloid CD1c+ DCs compared to CD141hi DCs and pDCs. CD1c+ DCs produced interleukin (IL)-6, tumor necrosis factor α, and IL-1β but not IL-12p70, a cytokine important for Th1 activation and host defenses against Mtb. Yet, CD1c+ DCs were able to activate autologous naïve CD4+ T cells. By combining cell purification with fluorescence-activated cell sorting and gene expression profiling on rare cell populations, we detected in responding CD4+ T cells, genes related to effector-cytolytic functions and transcription factors associated with Th1, Th17, and Treg polarization, suggesting multifunctional properties in our experimental conditions. Finally, immunohistologic analyses revealed contact between CD11c+ cells and pDCs in LNs of TB patients and in vitro data suggest that cooperation between Mtb-infected CD1c+ DCs and pDCs favors stimulation of CD4+ T cells. PMID:25071784

  9. Impaired NK Cell Activation and Chemotaxis toward Dendritic Cells Exposed to Complement-Opsonized HIV-1.

    PubMed

    Ellegård, Rada; Crisci, Elisa; Andersson, Jonas; Shankar, Esaki M; Nyström, Sofia; Hinkula, Jorma; Larsson, Marie

    2015-08-15

    Mucosa resident dendritic cells (DCs) may represent one of the first immune cells that HIV-1 encounters during sexual transmission. The virions in body fluids can be opsonized with complement factors because of HIV-mediated triggering of the complement cascade, and this appears to influence numerous aspects of the immune defense targeting the virus. One key attribute of host defense is the ability to attract immune cells to the site of infection. In this study, we investigated whether the opsonization of HIV with complement (C-HIV) or a mixture of complement and Abs (CI-HIV) affected the cytokine and chemokine responses generated by DCs, as well as their ability to attract other immune cells. We found that the expression levels of CXCL8, CXCL10, CCL3, and CCL17 were lowered after exposure to either C-HIV or CI-HIV relative to free HIV (F-HIV). DCs exposed to F-HIV induced higher cell migration, consisting mainly of NK cells, compared with opsonized virus, and the chemotaxis of NK cells was dependent on CCL3 and CXCL10. NK cell exposure to supernatants derived from HIV-exposed DCs showed that F-HIV induced phenotypic activation (e.g., increased levels of TIM3, CD69, and CD25) and effector function (e.g., production of IFNγ and killing of target cells) in NK cells, whereas C-HIV and CI-HIV did not. The impairment of NK cell recruitment by DCs exposed to complement-opsonized HIV and the lack of NK activation may contribute to the failure of innate immune responses to control HIV at the site of initial mucosa infection. PMID:26157174

  10. Thy-1+ dendritic cells in murine epidermis are bone marrow-derived

    SciTech Connect

    Breathnach, S.M.; Katz, S.I.

    1984-07-01

    Thy-1+, Ly-5+ dendritic cells have recently been described as a resident cell population in murine epidermis, but their ontogeny and function are unknown. The origin and turnover of epidermal Thy-1+ cells utilizing chimeric mice were investigated. Lethally x-irradiated AKR/J (Thy-1.1+) and AKR/Cum (Thy-1.2+) mice were reconstituted with allogeneic bone marrow cells with or without thymocytes from congenic AKR/Cum or AKR/J mice, respectively. The density of residual indigenous Thy-1.1+ cells in AKR/J chimeras and Thy-1.2+ cells in AKR/Cum chimeras was substantially reduced following x-irradiation, as determined by immunofluorescence staining of epidermal sheets. Epidermal repopulation by allogeneic Thy-1+ dendritic epidermal cells was first observed at 5 weeks in AKR/J chimeras and at 7 weeks in AKR/Cum chimeras and progressed slowly. Repopulation was not enhanced by increasing the number of allogeneic bone marrow cells injected from 2 X 10(7) to 10(8) cells or by the addition of 8 X 10(7) allogeneic thymocytes to the donor inoculate. Epidermal repopulation by allogeneic Thy-1.2+ cells was not seen in AKR/J mice reconstituted with syngeneic bone marrow cells and allogeneic Thy-1.2+ AKR/Cum thymocytes. Taken together, these results indicate that Thy-1+ dendritic epidermal cells are derived from the bone marrow and suggest that they are not related to conventional peripheral T-lymphocytes.

  11. Gene Expression Profiling of Dendritic Cells Reveals Important Mechanisms Associated with Predisposition to Staphylococcus Infections

    PubMed Central

    Toufeer, Mehdi; Bonnefont, Cécile M. D.; Foulon, Eliane; Caubet, Cécile; Tasca, Christian; Aurel, Marie-Rose; Robert-Granié, Christèle; Rupp, Rachel; Foucras, Gilles

    2011-01-01

    Background Staphylococcus aureus is a major pathogen of humans and animals and emerging antibiotic-resistant strains have further increased the concern of this health issue. Host genetics influence susceptibility to S. aureus infections, and the genes determining the outcome of infections should be identified to find alternative therapies to treatment with antibiotics. Here, we used outbred animals from a divergent selection based on susceptibility towards Staphylococcus infection to explore host immunogenetics. Methodology/Principal Findings We investigated how dendritic cells respond to heat-inactivated S. aureus and whether dendritic cells from animals showing different degrees of susceptibility had distinct gene expression profiles. We measured gene expression levels of in vitro S. aureus-stimulated bone marrow-derived dendritic cells at three different time points (0, 3 and 8 hrs) by using 15 k ovine Agilent microarrays. Furthermore, differential expression of a selected number of genes was confirmed by RT-qPCR. Gene signatures of stimulated DCs were obtained and showed that genes involved in the inflammatory process and T helper cell polarization were highly up-regulated upon stimulation. Moreover, a set of 204 genes were statistically differentially expressed between susceptible and resistant animals, and grouped them according to their predisposition to staphylococcal infection. Interestingly, over-expression of the C1q and Ido1 genes was observed in the resistant line and suggested a role of classical pathway of complement and early regulation of inflammation pathways, respectively. On the contrary, over expression of genes involved in the IL1R pathway was observed in susceptible animals. Furthermore, the leucocyte extravasation pathway was also found to be dominant in the susceptible line. Conclusion/Significance We successfully obtained Staphylococcus aureus associated gene expression of ovine BM-DC in an 8-hour kinetics experiment. The distinct

  12. Braf mutation in interdigitating dendritic cell sarcoma: a case report and review of the literature

    PubMed Central

    Di Liso, Elisabetta; Pennelli, Natale; Lodovichetti, Gigliola; Ghiotto, Cristina; Dei Tos, Angelo Paolo; Conte, PierFranco; Bonanno, Laura

    2015-01-01

    Interdigitating dendritic cell sarcoma is an extremely rare tumor. The diagnosis is difficult and is based on clinical, pathological and immunohistochemical evaluation. Differential diagnosis includes melanoma, mesenchymal and hematological malignancies. The mainstay of treatment is surgery for limited disease and different chemotherapy combinations have been tested for advanced disease. No evidence from prospective trials is currently available. We report the case of a 59 year-old male patient who experienced axillary lymphadenopathy with initial diagnosis of large-cell lung cancer on tumor biopsy. He underwent surgical resection with radical intent. Pathological diagnosis of interdigitating dendritic cell sarcoma was obtained on surgical samples. Nine months after radical surgery, he experienced systemic recurrence of disease and underwent chemotherapy with epirubicin and ifosfamide for 4 courses. During chemotherapy, he developed brain disease progression and underwent whole-brain radiotherapy. Systemic progression was then observed and molecular characterization was performed. B-RAF evaluation resulted positive for V600E mutation and the patient was treated with Vemurafenib according to molecular findings. He thus obtained initial clinical benefit but eventually died of brain hemorrhage. In conclusion, we report a case of B-RAF mutation detected in an interdigitating dendritic cell sarcoma patient treated with targeted therapy. B-RAF pathway could have a role in pathogenesis and evolution of this rare disease and could open new perspectives of treatment. PMID:26047060

  13. Update on the role of plasmacytoid dendritic cells in inflammatory/autoimmune skin diseases.

    PubMed

    Saadeh, Dana; Kurban, Mazen; Abbas, Ossama

    2016-06-01

    Plasmacytoid dendritic cells (pDCs) represent a specialized dendritic cell population that exhibit plasma cell morphology, express CD4, CD123, blood-derived dendritic cell antigen-2 (BDCA-2) and Toll-like receptor (TLR)7 and TLR9 within endosomal compartments. When activated, pDCs are capable of producing large quantities of type I IFNs (mainly IFN-α/β), which provide antiviral resistance and link the innate and adaptive immunity. While generally lacking from normal skin, pDCs infiltrate the skin and appear to be involved in the pathogenesis of several inflammatory, infectious (especially viral) and neoplastic entities. In recent years, pDC role in inflammatory/autoimmune skin conditions has been extensively studied. Unlike type I IFN-mediated protective immunity that pDCs provide at the level of the skin by regulated sensing of microbial or self-nucleic acids upon skin damage, excessive sensing may elicit IFN-driven inflammatory/autoimmune diseases. In this review, focus will be on the role of pDCs in cutaneous inflammatory/autoimmune dermatoses. PMID:26837058

  14. Glycan modification of antigen alters its intracellular routing in dendritic cells, promoting priming of T cells

    PubMed Central

    Streng-Ouwehand, Ingeborg; Ho, Nataschja I; Litjens, Manja; Kalay, Hakan; Boks, Martine Annemarie; Cornelissen, Lenneke AM; Kaur Singh, Satwinder; Saeland, Eirikur; Garcia-Vallejo, Juan J; Ossendorp, Ferry A; Unger, Wendy WJ; van Kooyk, Yvette

    2016-01-01

    Antigen uptake by dendritic cells and intracellular routing of antigens to specific compartments is regulated by C-type lectin receptors that recognize glycan structures. We show that the modification of Ovalbumin (OVA) with the glycan-structure LewisX (LeX) re-directs OVA to the C-type lectin receptor MGL1. LeX-modification of OVA favored Th1 skewing of CD4+ T cells and enhanced cross-priming of CD8+ T cells. While cross-presentation of native OVA requires high antigen dose and TLR stimuli, LeX modification reduces the required amount 100-fold and obviates its dependence on TLR signaling. The OVA-LeX-induced enhancement of T cell cross-priming is MGL1-dependent as shown by reduced CD8+ effector T cell frequencies in MGL1-deficient mice. Moreover, MGL1-mediated cross-presentation of OVA-LeX neither required TAP-transporters nor Cathepsin-S and was still observed after prolonged intracellular storage of antigen in Rab11+LAMP1+ compartments. We conclude that controlled neo-glycosylation of antigens can crucially influence intracellular routing of antigens, the nature and strength of immune responses and should be considered for optimizing current vaccination strategies. DOI: http://dx.doi.org/10.7554/eLife.11765.001 PMID:26999763

  15. Antigenically Modified Human Pluripotent Stem Cells Generate Antigen-Presenting Dendritic Cells

    PubMed Central

    Zeng, Jieming; Wu, Chunxiao; Wang, Shu

    2015-01-01

    Human pluripotent stem cells (hPSCs) provide a promising platform to produce dendritic cell (DC) vaccine. To streamline the production process, we investigated a unique antigen-loading strategy that suits this novel platform. Specifically, we stably modified hPSCs using tumour antigen genes in the form of a full-length tumour antigen gene or an artificial tumour antigen epitope-coding minigene. Such antigenically modified hPSCs were able to differentiate into tumour antigen-presenting DCs. Without conventional antigen-loading, DCs derived from the minigene-modified hPSCs were ready to prime a tumour antigen-specific T cell response and further expand these specific T cells in restimulation processes. These expanded tumour antigen-specific T cells were potent effectors with central memory or effector memory phenotype. Thus, we demonstrated that immunocompetent tumour antigen-loaded DCs can be directly generated from antigenically modified hPSCs. Using such strategy, we can completely eliminate the conventional antigen-loading step and significantly simplify the production of DC vaccine from hPSCs. PMID:26471005

  16. Functional Specialization of Skin Dendritic Cell Subsets in Regulating T Cell Responses

    PubMed Central

    Clausen, Björn E.; Stoitzner, Patrizia

    2015-01-01

    Dendritic cells (DC) are a heterogeneous family of professional antigen-presenting cells classically recognized as most potent inducers of adaptive immune responses. In this respect, Langerhans cells have long been considered to be prototypic immunogenic DC in the skin. More recently this view has considerably changed. The generation of in vivo cell ablation and lineage tracing models revealed the complexity of the skin DC network and, in particular, established the existence of a number of phenotypically distinct Langerin+ and negative DC populations in the dermis. Moreover, by now we appreciate that DC also exert important regulatory functions and are required for the maintenance of tolerance toward harmless foreign and self-antigens. This review summarizes our current understanding of the skin-resident DC system in the mouse and discusses emerging concepts on the functional specialization of the different skin DC subsets in regulating T cell responses. Special consideration is given to antigen cross-presentation as well as immune reactions toward contact sensitizers, cutaneous pathogens, and tumors. These studies form the basis for the manipulation of the human counterparts of the murine DC subsets to promote immunity or tolerance for the treatment of human disease. PMID:26557117

  17. ITAM signaling in dendritic cells controls T helper cell priming by regulating MHC class II recycling

    PubMed Central

    Graham, Daniel B.; Akilesh, Holly M.; Gmyrek, Grzegorz B.; Piccio, Laura; Gilfillan, Susan; Sim, Julia; Belizaire, Roger; Carrero, Javier A.; Wang, Yinan; Blaufuss, Gregory S.; Sandoval, Gabriel; Fujikawa, Keiko; Cross, Anne H.; Russell, John H.; Cella, Marina

    2010-01-01

    Immature dendritic cells (DCs) specialize in antigen capture and maintain a highly dynamic pool of intracellular major histocompatibility complex class II (MHCII) that continuously recycles from peptide loading compartments to the plasma membrane and back again. This process facilitates sampling of environmental antigens for presentation to T helper cells. Here, we show that a signaling pathway mediated by the DC immunoreceptor tyrosine-based activation motif (ITAM)–containing adaptors (DAP12 and FcRγ) and Vav family guanine nucleotide exchange factors controls the half-life of surface peptide-MHCII (pMHCII) complexes and is critical for CD4 T-cell triggering in vitro. Strikingly, mice with disrupted DC ITAMs show defective T helper cell priming in vivo and are protected from experimental autoimmune encephalitis. Mechanistically, we show that deficiency in ITAM signaling results in increased pMHCII internalization, impaired recycling, and an accumulation of ubiquitinated MHCII species that are prematurely degraded in lysosomes. We propose a novel mechanism for control of T helper cell priming. PMID:20634378

  18. What are the molecules involved in regulatory T-cells induction by dendritic cells in cancer?

    PubMed

    Ramos, Rodrigo Nalio; de Moraes, Cristiano Jacob; Zelante, Bruna; Barbuto, José Alexandre M

    2013-01-01

    Dendritic cells (DCs) are essential for the maintenance of homeostasis in the organism, and they do that by modulating lymphocyte priming, expansion, and response patterns according to signals they receive from the environment. The induction of suppressive lymphocytes by DCs is essential to hinder the development of autoimmune diseases but can be reverted against homeostasis when in the context of neoplasia. In this setting, the induction of suppressive or regulatory T cells contributes to the establishment of a state of tolerance towards the tumor, allowing it to grow unchecked by an otherwise functional immune system. Besides affecting its local environment, tumor also has been described as potent sources of anti-inflammatory/suppressive factors, which may act systemically, generating defects in the differentiation and maturation of immune cells, far beyond the immediate vicinity of the tumor mass. Cytokines, as IL-10 and TGF-beta, as well as cell surface molecules like PD-L1 and ICOS seem to be significantly involved in the redirection of DCs towards tolerance induction, and recent data suggest that tumor cells may, indeed, modulate distinct DCs subpopulations through the involvement of these molecules. It is to be expected that the identification of such molecules should provide molecular targets for more effective immunotherapeutic approaches to cancer. PMID:23762097

  19. slan/M-DC8+ cells constitute a distinct subset of dendritic cells in human tonsils

    PubMed Central

    Micheletti, Alessandra; Finotti, Giulia; Calzetti, Federica; Lonardi, Silvia; Zoratti, Elisa; Bugatti, Mattia; Stefini, Stefania; Vermi, William; Cassatella, Marco A.

    2016-01-01

    Human blood dendritic cells (DCs) include three main distinct subsets, namely the CD1c+ and CD141+ myeloid DCs (mDCs) and the CD303+ plasmacytoid DCs (pDCs). More recently, a population of slan/M-DC8+ cells, also known as “slanDCs”, has been described in blood and detected even in inflamed secondary lymphoid organs and non-lymphoid tissues. Nevertheless, hallmarks of slan/M-DC8+ cells in tissues are poorly defined. Herein, we report a detailed characterization of the phenotype and function of slan/M-DC8+ cells present in human tonsils. We found that tonsil slan/M-DC8+ cells represent a unique DC cell population, distinct from their circulating counterpart and also from all other tonsil DC and monocyte/macrophage subsets. Phenotypically, slan/M-DC8+ cells in tonsils display a CD11c+HLA-DR+CD14+CD11bdim/negCD16dim/negCX3CR1dim/neg marker repertoire, while functionally they exhibit an efficient antigen presentation capacity and a constitutive secretion of TNFα. Notably, such DC phenotype and functions are substantially reproduced by culturing blood slan/M-DC8+ cells in tonsil-derived conditioned medium (TDCM), further supporting the hypothesis of a full DC-like differentiation program occurring within the tonsil microenvironment. Taken together, our data suggest that blood slan/M-DC8+ cells are immediate precursors of a previously unrecognizedcompetent DC subset in tonsils, and pave the way for further characterization of slan/M-DC8+ cells in other tissues. PMID:26695549

  20. Mechanism of NK cell activation induced by coculture with dendritic cells derived from peripheral blood monocytes

    PubMed Central

    Amakata, Y; Fujiyama, Y; Andoh, A; Hodohara, K; Bamba, T

    2001-01-01

    Dendritic cells (DCs) have been regarded as one of the effective antigen-presenting cells, but the relationship between DCs and lymphocytes, in particular natural killer (NK) cells, remains unclear. In this study, we evaluated how DCs interact with both lymphocytes and NK cells using a coculture system. The number of lymphocytes increased significantly when cocultured with DCs (1·8-fold increase). In particular, the proliferation of NK cells was prominent. Furthermore, the coculture of DCs with lymphocytes induced a marked increase in IL-12 and IFN-γ secretion. When contact between the DCs and lymphocytes was prevented, the secretion of both IL-12 and IFN-γ was markedly reduced. IFN-γ production was completely blocked by an anti-IL-12 antibody, indicating that IFN-γ secretion was dependent on IL-12 secretion. The stimulating effect of the DCs on the proliferation of the lymphocytes was partially suppressed by anti-IL-12 antibodies, and was completely attenuated when cellular contact was prevented. Furthermore, the NK cell proliferation induced by coculture with DCs was significantly blocked by the inhibition of the interaction of either CD40–CD40L or CD28–B7 molecule. The coculture with DCs enhanced NK activity by 40%, and this was partially suppressed by anti-IL-12 antibodies and was completely blocked by the inhibition of cell-to-cell contact. These results indicate that the activation of NK cells by DCs is partially mediated by IL-12 secretion, and that direct contact between DCs and NK cells play a major role in this response. PMID:11422197

  1. Dendritic Cell-Mediated T Cell Proliferation -A Functional Bioindicator of Inflammatory Source-Specific Particulate Matter

    EPA Science Inventory

    Previously we found that dendritic cells (DC) were sensitive functional bioindicators of ambient PM (APM) exposure mediating Th2-allergic inflammation in the draining lymph nodes. Here, the ability of bone-marrow-derived DC (DC) and putative BM-derived basophils (Ba) to present a...

  2. CD45 is required for type I IFN production by dendritic cells.

    PubMed

    Montoya, Maria; Dawes, Ritu; Reid, Delyth; Lee, Lian Ni; Piercy, Jenny; Borrow, Persephone; Tchilian, Elma Z; Beverley, Peter C L

    2006-08-01

    CD45 is a leukocyte tyrosine phosphatase, essential for normal immune responses. We have studied the function of splenic dendritic cells of CD45(+/+), CD45(-/-), CD45RABC and CD45RO transgenic mice. We show that there are increased numbers of plasmacytoid dendritic cells in CD45(-/-) mice. DC of all mice are capable of responding to lymphocytic choriomeningitis virus (LCMV) infection by up-regulation of MHC and costimulatory molecules. DC of CD45(-/-) mice have an impaired capacity to produce type I interferons in response to LCMV infection in vivo. These data indicate that lack of CD45 expression in DC has a profound effect on their function. This is largely restored by CD45RABC or CD45RO transgenes. PMID:16856204

  3. Low dose daily rhGM-CSF application activates monocytes and dendritic cells in vivo.

    PubMed

    Demir, Gokhan; Klein, Hans Otto; Tuzuner, Nukhet

    2003-12-01

    Granulocyte macrophage colony stimulating factor (GM-CSF) is a powerful cytokine with multiple actions. We investigated the effects of low dose daily rhGM-CSF application on monocytes and peripheral circulating dendritic cells (DC) in malignant melanoma patients in vivo. Twenty patients were included; rhGM-CSF was given as daily subcutaneous injections for 14 days. A significant increase was noted in monocytes and granulocytes, starting on the 5th day. Expression of CD95 (Apo-1/Fas) and CD45RO on monocytes increased significantly on the 5th day, and CD4 expression on monocytes increased significantly on the 14th day. Peripheral circulating dendritic cells which were 0.94% in the beginning, increased to 1.35% (P<0.04) and to 1.96% (P<0.001) on days 5 and 14, respectively. PMID:12921948

  4. Computer Tomography Imaging Findings of Abdominal Follicular Dendritic Cell Sarcoma: A Report of 5 Cases.

    PubMed

    Li, Jing; Geng, Zhi-Jun; Xie, Chuan-Miao; Zhang, Xin-Ke; Chen, Rui-Ying; Cai, Pei-Qiang; Lv, Xiao-Fei

    2016-01-01

    Follicular dendritic cell sarcoma (FDCS) is a neoplasm that arises from follicular dendritic cells. FDCSs originating in the abdomen are extremely rare. Clinically, they often mimic a wide variety of other abdominal tumors, and correct preoperative diagnosis is often a challenging task. To date, only scattered cases of abdominal FDCS have been reported and few data are available on their radiological features. Here we present the computer tomography imaging findings of 5 patients with surgically and pathologically demonstrated abdominal FDCS. An abdominal FDCS should be included in the differential diagnosis when single or multiple masses with relatively large size, well- or ill-defined borders, complex internal architecture with marked internal necrosis and/or focal calcification, and heterogeneous enhancement with "rapid wash-in and slow wash-out" or "progressive enhancement" enhancement patterns in the solid component are seen. PMID:26735543

  5. Dendrite inhibitor

    DOEpatents

    Miller, William E.

    1989-01-01

    An apparatus for removing dendrites or other crystalline matter from the surface of a liquid in a matter transport process, and an electrolytic cell including such an apparatus. A notch may be provided to allow continuous exposure of the liquid surface, and a bore may be further provided to permit access to the liquid.

  6. Dendrite inhibitor

    DOEpatents

    Miller, W.E.

    1988-06-07

    An apparatus for removing dendrites or other crystalline matter from the surface of a liquid in a matter transport process, and an electrolytic cell including such an apparatus. A notch may be provided to allow continuous exposure of the liquid surface, and a bore may be further provided to permit access to the liquid. 2 figs.

  7. Deletion of Wiskott-Aldrich syndrome protein triggers Rac2 activity and increased cross-presentation by dendritic cells.

    PubMed

    Baptista, Marisa A P; Keszei, Marton; Oliveira, Mariana; Sunahara, Karen K S; Andersson, John; Dahlberg, Carin I M; Worth, Austen J; Liedén, Agne; Kuo, I-Chun; Wallin, Robert P A; Snapper, Scott B; Eidsmo, Liv; Scheynius, Annika; Karlsson, Mikael C I; Bouma, Gerben; Burns, Siobhan O; Forsell, Mattias N E; Thrasher, Adrian J; Nylén, Susanne; Westerberg, Lisa S

    2016-01-01

    Wiskott-Aldrich syndrome (WAS) is caused by loss-of-function mutations in the WASp gene. Decreased cellular responses in WASp-deficient cells have been interpreted to mean that WASp directly regulates these responses in WASp-sufficient cells. Here, we identify an exception to this concept and show that WASp-deficient dendritic cells have increased activation of Rac2 that support cross-presentation to CD8(+) T cells. Using two different skin pathology models, WASp-deficient mice show an accumulation of dendritic cells in the skin and increased expansion of IFNγ-producing CD8(+) T cells in the draining lymph node and spleen. Specific deletion of WASp in dendritic cells leads to marked expansion of CD8(+) T cells at the expense of CD4(+) T cells. WASp-deficient dendritic cells induce increased cross-presentation to CD8(+) T cells by activating Rac2 that maintains a near neutral pH of phagosomes. Our data reveals an intricate balance between activation of WASp and Rac2 signalling pathways in dendritic cells. PMID:27425374

  8. Deletion of Wiskott–Aldrich syndrome protein triggers Rac2 activity and increased cross-presentation by dendritic cells

    PubMed Central

    Baptista, Marisa A. P.; Keszei, Marton; Oliveira, Mariana; Sunahara, Karen K. S.; Andersson, John; Dahlberg, Carin I. M.; Worth, Austen J.; Liedén, Agne; Kuo, I-Chun; Wallin, Robert P. A.; Snapper, Scott B.; Eidsmo, Liv; Scheynius, Annika; Karlsson, Mikael C. I.; Bouma, Gerben; Burns, Siobhan O.; Forsell, Mattias N. E.; Thrasher, Adrian J.; Nylén, Susanne; Westerberg, Lisa S.

    2016-01-01

    Wiskott–Aldrich syndrome (WAS) is caused by loss-of-function mutations in the WASp gene. Decreased cellular responses in WASp-deficient cells have been interpreted to mean that WASp directly regulates these responses in WASp-sufficient cells. Here, we identify an exception to this concept and show that WASp-deficient dendritic cells have increased activation of Rac2 that support cross-presentation to CD8+ T cells. Using two different skin pathology models, WASp-deficient mice show an accumulation of dendritic cells in the skin and increased expansion of IFNγ-producing CD8+ T cells in the draining lymph node and spleen. Specific deletion of WASp in dendritic cells leads to marked expansion of CD8+ T cells at the expense of CD4+ T cells. WASp-deficient dendritic cells induce increased cross-presentation to CD8+ T cells by activating Rac2 that maintains a near neutral pH of phagosomes. Our data reveals an intricate balance between activation of WASp and Rac2 signalling pathways in dendritic cells. PMID:27425374

  9. Stimulation of dendritic cells by DAMPs in ALA-PDT treated SCC tumor cells

    PubMed Central

    Zhang, Haiyan; Fan, Zhixia; Zhang, Linglin; Shi, Lei; Zhou, Feifan; Chen, Wei R.; Wang, Hongwei; Wang, Xiuli

    2015-01-01

    Photodynamic therapy (PDT) not only kills tumor cells directly but also rapidly recruits and activates immune cells favoring the development of antitumor adaptive immunity. It is believed that Topical 5-aminolevulinic acid mediated photodynamic therapy (ALA-PDT) can induce anti-tumor immune responses through dangerous signals damage-associated molecular patterns (DAMPs). In this study, we investigated the effect of ALA-PDT induced DAMPs on immune cells. We focused on the stimulation of dendritic cells by major DAMPs, enhanced the expression of calreticulin (CRT), heat shock proteins 70 (HSP70), and high mobility group box 1 (HMGB1), either individually or in combination. We evaluated in vitro and in vivo expressions of DAMPs induced by ALA-PDT using immunohistochemistry, western blot, and ELISA in a squamous cell carcinoma (SCC) mouse model. The role of DAMPs in the maturation of DCs potentiated by ALA-PDT-treated tumor cells was detected by FACS and ELISA. Our results showed that ALA-PDT enhanced the expression of CRT, HSP70, and HMGB1. These induced DAMPs played an important part in activating DCs by PDT-treated tumor cells, including phenotypic maturation (increase of surface expression of MHC-II, CD80, and CD86) and functional maturation (enhanced capability to secrete IFN-γ and IL-12). Furthermore, injecting ALA-PDT-treated tumor cells into naïve mice resulted in complete protection against cancer cells of the same origin. Our findings indicate that ALA-PDT can increase DAMPs and enhance tumor immunogenicity, providing a promising strategy for inducing a systemic anticancer immune response. PMID:26625309

  10. CD5 monoclonal antibodies react with human peripheral blood dendritic cells.

    PubMed Central

    Wood, G. S.; Freudenthal, P. S.

    1992-01-01

    CD5 monoclonal antibodies (MAbs) define a 67,000 kd monomeric glycoprotein expressed predominantly by thymocytes, mature T cells and a subpopulation of B cells. CD5 is believed to be an alternative signaling molecules capable of increasing the supply of second messengers and thereby altering the cellular response threshold to other activation stimuli. Human peripheral blood dendritic cells (PBDC) are a circulating component of the immune dendritic cell family, which also includes Langerhans' cells in epithelia and interdigitating cells in the T-cell domains of lymphoid tissues. PBDC comprise less than 1% of the peripheral blood mononuclear cell fraction. They are morphologically, immunophenotypically, and functionally distinct from monocytes. In this study, we report that at least a subpopulation of PBDC react with the anti-CD5 MAbs Leu-1 and UCHT2, which define the two major non-crossblocking CD5 epitopes. In contrast, Langerhans' cells, interdigitating cells, monocytes, and macrophages were uniformly CD5-. These findings suggest that PBDC can express the CD5 molecule. Furthermore, they define an additional feature of many enriched PBDC that distinguishes them from monocytes and certain other mononuclear leukocytes, and may provide insights into their activation pathways. Images Figure 1 Figure 2 Figure 4 Figure 3 PMID:1384337

  11. Early Transcriptome Signatures from Immunized Mouse Dendritic Cells Predict Late Vaccine-Induced T-Cell Responses

    PubMed Central

    Dérian, Nicolas; Bellier, Bertrand; Pham, Hang Phuong; Tsitoura, Eliza; Kazazi, Dorothea; Huret, Christophe; Mavromara, Penelope; Klatzmann, David; Six, Adrien

    2016-01-01

    Systems biology offers promising approaches for identifying response-specific signatures to vaccination and assessing their predictive value. Here, we designed a modelling strategy aiming to predict the quality of late T-cell responses after vaccination from early transcriptome analysis of dendritic cells. Using standardized staining with tetramer, we first quantified antigen-specific T-cell expansion 5 to 10 days after vaccination with one of a set of 41 different vaccine vectors all expressing the same antigen. Hierarchical clustering of the responses defined sets of high and low T cell response inducers. We then compared these responses with the transcriptome of splenic dendritic cells obtained 6 hours after vaccination with the same vectors and produced a random forest model capable of predicting the quality of the later antigen-specific T-cell expansion. The model also successfully predicted vector classification as low or strong T-cell response inducers of a novel set of vaccine vectors, based on the early transcriptome results obtained from spleen dendritic cells, whole spleen and even peripheral blood mononuclear cells. Finally, our model developed with mouse datasets also accurately predicted vaccine efficacy from literature-mined human datasets. PMID:26998760

  12. A Single Subset of Dendritic Cells Controls the Cytokine Bias of Natural Killer T Cell Responses to Diverse Glycolipid Antigens

    PubMed Central

    Arora, Pooja; Baena, Andres; Yu, Karl O.A.; Saini, Neeraj K.; Kharkwal, Shalu S.; Goldberg, Michael F.; Kunnath-Velayudhan, Shajo; Carreño, Leandro J.; Venkataswamy, Manjunatha M.; Kim, John; Lazar-Molnar, Eszter; Lauvau, Gregoire; Chang, Young-tae; Liu, Zheng; Bittman, Robert; Al-Shamkhani, Aymen; Cox, Liam R.; Jervis, Peter J.; Veerapen, Natacha; Besra, Gurdyal S.; Porcelli, Steven A.

    2014-01-01

    Summary Many hematopoietic cell types express CD1d and are capable of presenting glycolipid antigens to invariant natural killer T cells (iNKT cells). However, the question of which cells are the principal presenters of glycolipid antigens in vivo remains controversial, and it has been suggested that this might vary depending on the structure of a particular glycolipid antigen. Here we have shown that a single type of cell, the CD8α+ DEC-205+ dendritic cell, was mainly responsible for capturing and presenting a variety of different glycolipid antigens, including multiple forms of α-galactosylceramide that stimulate widely divergent cytokine responses. After glycolipid presentation, these dendritic cells rapidly altered their expression of various costimulatory and coinhibitory molecules in a manner that was dependent on the structure of the antigen. These findings show flexibility in the outcome of two-way communication between CD8α+ dendritic cells and iNKT cells, providing a mechanism for biasing toward either proinflammatory or anti-inflammatory responses. PMID:24412610