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Sample records for d3-modified regulatory dendritic

  1. 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

  2. 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

  3. 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

  4. 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

  5. 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

  6. 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

  7. 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

  8. 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

  9. 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

  10. 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

  11. Origin and pharmacological modulation of tumor-associated regulatory dendritic cells

    PubMed Central

    Zhong, Hua; Gutkin, Dmitriy W.; Han, Baohui; Ma, Yang; Keskinov, Anton A.; Shurin, Michael R.; Shurin, Galina V.

    2014-01-01

    Protumorigenic activity of immune regulatory cells has been proven to play a major role in precluding immunosurveillance and limiting the efficacy of anticancer therapies. Although several approaches have been offered to deplete myeloid-derived suppressor cells (MDSC) and regulatory T cells, there are no data on how to control suppressive dendritic cell (DC) accumulation or function in the tumor environment. Although immunosuppressive function of DC in cancer was implicated to immature and plasmacytoid DC, details of how conventional DC (cDC) develop immunosuppressive properties remain less understood. Here, we show that the development of lung cancer in mice was associated with fast accumulation of regulatory DC (regDC) prior to the appearance of MDSC. Using the in vitro and in vivo approaches, we demonstrated that (i)both cDC and MDSC could be polarized into protumor regDC in the lung cancer environment; (ii) cDC → regDC polarization was mediated by the small Rho GTPase signaling, which could be controlled by noncytotoxic doses of paclitaxel; and (iii) prevention of regDC appearance increased the antitumor potential of DC vaccine in lung cancer. These findings not only bring new players to the family of myeloid regulatory cells and provide new targets for cancer therapy, but offer novel insights into the immunomodulatory capacity of chemotherapeutic agents used in low, noncytotoxic doses. PMID:24443321

  12. Drosophila Valosin-Containing Protein is required for dendrite pruning through a regulatory role in mRNA metabolism

    PubMed Central

    Rumpf, Sebastian; Bagley, Joshua A.; Thompson-Peer, Katherine L.; Zhu, Sijun; Gorczyca, David; Beckstead, Robert B.; Jan, Lily Yeh; Jan, Yuh Nung

    2014-01-01

    The dendritic arbors of the larval Drosophila peripheral class IV dendritic arborization neurons degenerate during metamorphosis in an ecdysone-dependent manner. This process—also known as dendrite pruning—depends on the ubiquitin–proteasome system (UPS), but the specific processes regulated by the UPS during pruning have been largely elusive. Here, we show that mutation or inhibition of Valosin-Containing Protein (VCP), a ubiquitin-dependent ATPase whose human homolog is linked to neurodegenerative disease, leads to specific defects in mRNA metabolism and that this role of VCP is linked to dendrite pruning. Specifically, we find that VCP inhibition causes an altered splicing pattern of the large pruning gene molecule interacting with CasL and mislocalization of the Drosophila homolog of the human RNA-binding protein TAR–DNA-binding protein of 43 kilo-Dalton (TDP-43). Our data suggest that VCP inactivation might lead to specific gain-of-function of TDP-43 and other RNA-binding proteins. A similar combination of defects is also seen in a mutant in the ubiquitin-conjugating enzyme ubcD1 and a mutant in the 19S regulatory particle of the proteasome, but not in a 20S proteasome mutant. Thus, our results highlight a proteolysis-independent function of the UPS during class IV dendritic arborization neuron dendrite pruning and link the UPS to the control of mRNA metabolism. PMID:24799714

  13. 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

  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. 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

  16. Human spleen contains different subsets of dendritic cells and regulatory T lymphocytes

    PubMed Central

    Velásquez-Lopera, M M; Correa, L A; García, L F

    2008-01-01

    Most knowledge about dendritic cells (DCs) and regulatory T cells in humans has been gathered from circulating cells but little is known about their frequency and distribution in lymphoid organs. This report shows the frequency, phenotype and location of DCs and regulatory T cells in deceased organ donors' spleens. As determined by flow cytometry, conventional/myeloid DCs (cDCs) CD11chighHLA-DR+CD123−/low were 2·3 ± 0·9% and LIN- HLA-DR+CD11chigh 2·1 ± 0·3% of total spleen cells. Mature CD11chighHLA-DR+CD83+ were 1·5 ± 0·8% and 1·0 ± 1·6% immature CD11chighHLA-DR+CD83- cDC. There were 0·3 ± 0·3% plasmacytoid DCs (pDC) CD11c−/lowHLA-DR+CD123high and 0·3 ± 0·1% LIN-HLA-DR+CD123high. Cells expressing cDCs markers, BDCA-1 and BDCA-3, and pDCs markers BDCA-2 and BDCA-4 were observed in higher frequencies than DCs with other phenotypes evaluated. CD11c+, CD123+ and CD83+ cells were located in subcapsular zone, T cells areas and B-cell follicles. CD4+CD25high Tregs were 0·2 ± 0·2% and CD8+CD28- comprised 11·5 ± 8·1% of spleen lymphocytes. FOXP3+ cells were found in T- and B-cell areas. The improvement in cell separation, manipulation and expansion techniques, will facilitate the manipulation of donor spleen cells as a part of protocols for induction and maintenance of allograft tolerance or treatment of autoimmune diseases. PMID:18727627

  17. 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

  18. Zinc Induces Dendritic Cell Tolerogenic Phenotype and Skews Regulatory T Cell-Th17 Balance.

    PubMed

    George, Mariam Mathew; Subramanian Vignesh, Kavitha; Landero Figueroa, Julio A; Caruso, Joseph A; Deepe, George S

    2016-09-01

    Zinc (Zn) is an essential metal for development and maintenance of both the innate and adaptive compartments of the immune system. Zn homeostasis impacts maturation of dendritic cells (DCs) that are important in shaping T cell responses. The mechanisms by which Zn regulates the tolerogenic phenotype of DCs remain largely unknown. In this study, we investigated the effect of Zn on DC phenotype and the generation of Foxp3(+) regulatory T cells (Tregs) using a model of Histoplasma capsulatum fungal infection. Exposure of bone marrow-derived DCs to Zn in vitro induced a tolerogenic phenotype by diminishing surface MHC class II (MHCII) and promoting the tolerogenic markers, programmed death-ligand (PD-L)1, PD-L2, and the tryptophan degrading enzyme, IDO. Zn triggered tryptophan degradation by IDO and kynurenine production by DCs and strongly suppressed the proinflammatory response to stimulation by TLR ligands. In vivo, Zn supplementation and subsequent H. capsulatum infection supressed MHCII on DCs, enhanced PD-L1 and PD-L2 expression on MHCII(lo) DCs, and skewed the Treg-Th17 balance in favor of Foxp3(+) Tregs while decreasing Th17 cells. Thus, Zn shapes the tolerogenic potential of DCs in vitro and in vivo and promotes Tregs during fungal infection. PMID:27465530

  19. 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

  20. Interleukin 10 and dendritic cells are the main suppression mediators of regulatory T cells in human neurocysticercosis.

    PubMed

    Arce-Sillas, A; Álvarez-Luquín, D D; Cárdenas, G; Casanova-Hernández, D; Fragoso, G; Hernández, M; Proaño Narváez, J V; García-Vázquez, F; Fleury, A; Sciutto, E; Adalid-Peralta, L

    2016-02-01

    Neurocysticercosis is caused by the establishment of Taenia solium cysticerci in the central nervous system. It is considered that, during co-evolution, the parasite developed strategies to modulate the host's immune response. The action mechanisms of regulatory T cells in controlling the immune response in neurocysticercosis are studied in this work. Higher blood levels of regulatory T cells with CD4(+) CD45RO(+) forkhead box protein 3 (FoxP3)(high) and CD4(+) CD25(high) FoxP3(+) CD95(high) phenotype and of non-regulatory CD4(+) CD45RO(+) FoxP3(med) T cells were found in neurocysticercosis patients with respect to controls. Interestingly, regulatory T cells express higher levels of cytotoxic T lymphocyte antigen 4 (CTLA-4), lymphocyte-activation gene 3 (LAG-3), programmed death 1 (PD-1) and glucocorticoid-induced tumour necrosis factor receptor (GITR), suggesting a cell-to-cell contact mechanism with dendritic cells. Furthermore, higher IL-10 and regulatory T cell type 1 (Tr1) levels were found in neurocysticercosis patients' peripheral blood, suggesting that the action mechanism of regulatory T cells involves the release of immunomodulatory cytokines. No evidence was found of the regulatory T cell role in inhibiting the proliferative response. Suppressive regulatory T cells from neurocysticercosis patients correlated negatively with late activated lymphocytes (CD4(+) CD38(+) ). Our results suggest that, during neurocysticercosis, regulatory T cells could control the immune response, probably by a cell-to-cell contact with dendritic cells and interleukin (IL)-10 release by Tr1, to create an immunomodulatory environment that may favour the development of T. solium cysticerci and their permanence in the central nervous system. PMID:26391104

  1. Natural IgM Switches the Function of Lipopolysaccharide-Activated Murine Bone Marrow-Derived Dendritic Cells to a Regulatory Dendritic Cell That Suppresses Innate Inflammation.

    PubMed

    Lobo, Peter I; Schlegel, Kailo H; Bajwa, Amandeep; Huang, Liping; Kurmaeva, Elvira; Wang, Binru; Ye, Hong; Tedder, Thomas F; Kinsey, Gilbert R; Okusa, Mark D

    2015-12-01

    We have previously shown that polyclonal natural IgM protects mice from renal ischemia/reperfusion injury (IRI) by inhibiting the reperfusion inflammatory response. We hypothesized that a potential mechanism involved IgM modulation of dendritic cells (DC), as we observed high IgM binding to splenic DC. To test this hypothesis, we pretreated bone marrow-derived DC (BMDC) with polyclonal murine or human IgM prior to LPS activation and demonstrated that 0.5 × 10(6) IgM/LPS-pretreated BMDC, when injected into wild-type C57BL/6 mice 24 h before renal ischemia, protect mice from developing renal IRI. We show that this switching of LPS-activated BMDC to a regulatory phenotype requires modulation of BMDC function that is mediated by IgM binding to nonapoptotic BMDC receptors. Regulatory BMDC require IL-10 and programmed death 1 as well as downregulation of CD40 and p65 NF-κB phosphorylation to protect in renal IRI. Blocking the programmed death ligand 1 binding site just before i.v. injection of IgM/LPS-pretreated BMDC or using IL-10 knockout BMDC fails to induce protection. Similarly, IgM/LPS-pretreated BMDC are rendered nonprotective by increasing CD40 expression and phosphorylation of p65 NF-κB. How IgM/LPS regulatory BMDC suppress in vivo ischemia-induced innate inflammation remains to be determined. However, we show that suppression is dependent on other in vivo regulatory mechanisms in the host, that is, CD25(+) T cells, B cells, IL-10, and circulating IgM. There was no increase in Foxp3(+) regulatory T cells in the spleen either before or after renal IRI. Collectively, these findings show that natural IgM anti-leukocyte Abs can switch BMDC to a regulatory phenotype despite the presence of LPS that ordinarily induces BMDC maturation. PMID:26519533

  2. Dendritic Cells in the Periphery Control Antigen-Specific Natural and Induced Regulatory T Cells

    PubMed Central

    Yamazaki, Sayuri; Morita, Akimichi

    2013-01-01

    Dendritic cells (DCs) are specialized antigen-presenting cells that regulate both immunity and tolerance. DCs in the periphery play a key role in expanding naturally occurring Foxp3+ CD25+ CD4+ regulatory T cells (Natural T-regs) and inducing Foxp3 expression (Induced T-regs) in Foxp3− CD4+ T cells. DCs are phenotypically and functionally heterogeneous, and further classified into several subsets depending on distinct marker expression and their location. Recent findings indicate the presence of specialized DC subsets that act to expand Natural T-regs or induce Foxp3+ T-regs from Foxp3− CD4+ T cells. For example, two major subsets of DCs in lymphoid organs act differentially in inducing Foxp3+ T-regs from Foxp3− cells or expanding Natural T-regs with model-antigen delivery by anti-DC subset monoclonal antibodies in vivo. Furthermore, DCs expressing CD103 in the intestine induce Foxp3+ T-regs from Foxp3− CD4+ T cells with endogenous TGF-β and retinoic acid. In addition, antigen-presenting DCs have a capacity to generate Foxp3+ T-regs in the oral cavity where many antigens and commensals exist, similar to intestine and skin. In skin and skin-draining lymph nodes, at least six DC subsets have been identified, suggesting a complex DC-T-reg network. Here, we will review the specific activity of DCs in expanding Natural T-regs and inducing Foxp3+ T-regs from Foxp3− precursors, and further discuss the critical function of DCs in maintaining tolerance at various locations including skin and oral cavity. PMID:23801989

  3. Characterization of regulatory dendritic cells differentiated from the bone marrow of UV-irradiated mice.

    PubMed

    Ng, Royce L X; Scott, Naomi M; Bisley, Jackie L; Lambert, Misty J; Gorman, Shelley; Norval, Mary; Hart, Prue H

    2013-12-01

    When antigen-loaded dendritic cells (DCs) differentiated from the bone marrow (BM) of UV-irradiated mice (UV-BMDCs) were adoptively transferred into naive mice or mice pre-sensitized with that antigen, the recipients exhibited a reduced immune response following antigen challenge. Hence, UV-BMDCs are poorly immunogenic and can suppress pre-existing immunity. The UV-induced effect on BM-derived DCs was rapid (observed 1 day after UV radiation), long-lasting (observed 10 days after UV radiation) and UV dose-dependent. The mechanism by which UV-BMDCs could regulate immunity was investigated. The CD11c(+) cells, differentiated using granulocyte-macrophage colony-stimulating factor + interleukin-4, were confirmed to be DCs because they did not express the myeloid-derived suppressor cell marker, Gr1. UV-BMDCs did not display altered antigen uptake, processing or ability to activate T cells in vitro. When gene expression in UV-BMDCs and DCs differentiated from the BM of non-irradiated mice (control-BMDCs) was examined, Ccl7, Ccl8 and CSF1R (CD115) mRNA transcripts were up-regulated in UV-BMDCs compared with control-BMDCs. However, neutralizing antibodies for Ccl7 and Ccl8 did not abrogate the reduced immunogenicity of UV-BMDCs in vivo. Moreover, the up-regulation of CSF1R transcript did not correspond with increased receptor expression on UV-BMDCs. The phenotypes of UV-BMDCs and control-BMDCs were similar, with no difference in the expression of CD4, CD8α, CD103, B220 or F4/80, or the regulatory molecules CCR7 (CD197), FasL (CD95L), B7H3 (CD276) and B7H4. However, PDL1 (CD274) expression was reduced in UV-BMDCs compared with control-BMDCs following lipopolysaccharide stimulation. In summary, UV-BMDCs do not express the classical phenotypic or gene expression properties of DCs reported by others as 'regulatory' or 'tolerogenic'. PMID:23826713

  4. Tumor-educated CD11bhighIalow regulatory dendritic cells suppress T cell response through arginase I.

    PubMed

    Liu, Qiuyan; Zhang, Chaoxiong; Sun, Anna; Zheng, Yuanyuan; Wang, Li; Cao, Xuetao

    2009-05-15

    Tumors can induce generation and accumulation of the immunosuppressive cells such as regulatory T cells in the tumor microenvironment, contributing to tumor escape from immunological attack. Although dendritic cell (DC)-based cancer vaccine can initiate antitumor immune response, regulatory DC subsets involved in the tolerance induction attracted much attention recently. Our previous studies demonstrate that the stromal microenvironment of the spleen, lung, and liver can program generation of CD11c(low)CD11b(high)Ia(low) DCs with regulatory function (CD11b(high)Ia(low) regulatory DCs). However, whether and how the tumor microenvironment can program generation of CD11b(high)Ia(low) regulatory DCs remain to be investigated. In this study, we used the freshly isolated tumor cells to mimic tumor microenvironment to coculture DCs and found that the freshly isolated tumor cells could drive DCs to differentiate into regulatory DCs with a CD11c(low)CD11b(high)Ia(low) phenotype and high expression of IL-10, NO, vascular endothelial growth factor, and arginase I. Tumor-educated CD11b(high)Ia(low) regulatory DCs inhibited CD4(+) T cell proliferation both in vitro and in vivo. 3LL lung cancer-derived TGF-beta and PGE(2) were responsible for the generation of regulatory DCs. PGE(2) was the main inducer of arginase I in regulatory DCs. Arginase I played a major role in the suppression of T cell response by regulatory DCs induced by 3LL lung cancer. A natural counterpart of CD11b(high)Ia(low) DCs was identified in tumor tissue, and CD11b(high)Ia(low) DCs sorted from 3LL lung cancer tissue expressed arginase I and inhibited T cell response. Therefore, tumors can educate DCs to differentiate into a regulatory DC subset, which contributes to constitution of the immunosuppressive tumor microenvironment and promotes tumor immune escape. PMID:19414774

  5. Complement-induced regulatory T cells suppress T-cell responses but allow for dendritic-cell maturation

    PubMed Central

    Barchet, Winfried; Price, Jeffrey D.; Cella, Marina; Colonna, Marco; MacMillan, Sandra K.; Cobb, J. Perren; Thompson, Paul A.; Murphy, Kenneth M.; Atkinson, John P.; Kemper, Claudia

    2006-01-01

    Concurrent activation of the T-cell receptor (TCR) and complement regulator CD46 on human CD4+ T lymphocytes induces Tr1-like regulatory T cells that suppress through IL-10 secretion bystander T-cell proliferation. Here we show that, despite their IL-10 production, CD46-induced T-regulatory T cells (Tregs) do not suppress the activation/maturation of dendritic cells (DCs). DC maturation by complement/CD46-induced Tregs is mediated through simultaneous secretion of GM-CSF and soluble CD40L, factors favoring DC differentiation and reversing inhibitory effects of IL-10. Thus, CD46-induced Tregs produce a distinct cytokine profile that inhibits T-cell responses but leaves DC activation unimpaired. Such “DC-sparing” Tregs could be desirable at host/environment interfaces such as the gastrointestinal tract where their specific cytokine profile provides a mechanism that ensures unresponsiveness to commensal bacteria while maintaining reactivity to invading pathogens. PMID:16239430

  6. Leptin deficiency impairs maturation of dendritic cells and enhances induction of regulatory T and Th17 cells

    PubMed Central

    Moraes-Vieira, Pedro M.M.; Larocca, Rafael A.; Bassi, Enio J.; Peron, Jean Pierre S.; Andrade-Oliveira, Vinícius; Wasinski, Frederick; Araujo, Ronaldo; Thornley, Thomas; Quintana, Francisco J.; Basso, Alexandre S.; Strom, Terry B.; Câmara, Niels O.S.

    2016-01-01

    Leptin is an adipose-secreted hormone that plays an important role in both metabolism and immunity. Leptin has been shown to induce Th1-cell polarization and inhibit Th2-cell responses. Additionally, leptin induces Th17-cell responses, inhibits regulatory T (Treg) cells and modulates autoimmune diseases. Here, we investigated whether leptin mediates its activity on T cells by influencing dendritic cells (DCs) to promote Th17 and Treg-cell immune responses in mice. We observed that leptin deficiency (i) reduced the expression of DC maturation markers, (ii) decreased DC production of IL-12, TNF-α, and IL-6, (iii) increased DC production of TGF-β, and (iv) limited the capacity of DCs to induce syngeneic CD4+ T-cell proliferation. As a consequence of this unique phenotype, DCs generated under leptin-free conditions induced Treg or TH17 cells more efficiently than DCs generated in the presence of leptin. These data indicate important roles for leptin in DC homeostasis and the initiation and maintenance of inflammatory and regulatory immune responses by DCs. PMID:24271843

  7. CD8α+ Dendritic cells prime TCR-peptide-reactive regulatory CD4+FOXP3− T cells

    PubMed Central

    Smith, Trevor R. F.; Maricic, Igor; Ria, Francesco; Schneider, Susan; Kumar, Vipin

    2011-01-01

    Summary CD4+ T cells with immune regulatory function can be either FOXP3+ or FOXP3−. We have previously shown that priming of naturally occurring TCR-peptide-reactive regulatory CD4+FOXP3− T cells (Treg) specifically controls Vβ8.2+CD4+ T cells mediating experimental autoimmune encephalomyelitis (EAE). However, the mechanism by which these Treg are primed to recognize their cognate antigenic determinant, which is derived from the TCRVβ8.2-chain, is not known. In this study we show that antigen presenting cells (APC) derived from splenocytes of naïve mice are able to stimulate cloned CD4+ Treg in the absence of exogenous antigen, and their stimulation capacity is augmented during EAE. Among the APC populations DC were the most efficient in stimulating the Treg. Stimulation of CD4+ Treg was dependent upon processing and presentation of TCR peptides from ingested Vβ8.2TCR+ CD4+ T cells. Additionally, dendritic cells pulsed with TCR peptide or apoptotic Vβ8.2+ T cells are able to prime Treg in vivo and mediate protection from disease in a CD8-dependent fashion. These data highlight a novel mechanism for the priming of CD4+ Treg by CD8α+ DC, and suggest a pathway that can be exploited to prime antigen-specific regulation of T cell-mediated inflammatory disease. PMID:20394075

  8. Role of Dendritic Cell Maturity/Costimulation for Generation, Homeostasis, and Suppressive Activity of Regulatory T Cells

    PubMed Central

    Pletinckx, Katrien; Döhler, Anja; Pavlovic, Vladimir; Lutz, Manfred B.

    2011-01-01

    Tolerogenicity of dendritic cells (DCs) has initially been attributed exclusively to immature/resting stages, while mature/activated DCs were considered strictly immunogenic. Later, all different subsets among the myeloid/conventional DCs and plasmacytoid DCs have been shown to bear tolerogenic potential, so that tolerogenicity could not be attributed to a specific subset. Immunosuppressive treatments of immature DC subsets could prevent re-programming into mature DCs or upregulated inhibitory surface markers or cytokines. Furthermore, the different T cell tolerance mechanisms anergy, deletion, immune deviation, and suppression require different quantities and qualities of costimulation by DCs. Since expansion of regulatory T cells (Tregs) has been shown to be promoted best by fully mature DCs the role of CD80/B7-1 and CD86/B7-2 as major costimulatory molecules for Treg biology is under debate. In this review, we discuss the role of these and other costimulatory molecules on myeloid DCs and their ligands CD28 and CD152/CTLA-4 on Tregs for peripheral conversion from naive CD4+ T cells into the major subsets of Foxp3+ Tregs and Foxp3− IL-10+ regulatory type-1 T cells (Tr1) or Tr1-like cells and their role for peripheral maintenance in the steady state and after activation. PMID:22566829

  9. The SOCS3-independent expression of IDO2 supports the homeostatic generation of T regulatory cells by human dendritic cells.

    PubMed

    Trabanelli, Sara; Očadlíková, Darina; Ciciarello, Marilena; Salvestrini, Valentina; Lecciso, Mariangela; Jandus, Camilla; Metz, Richard; Evangelisti, Cecilia; Laury-Kleintop, Lisa; Romero, Pedro; Prendergast, George C; Curti, Antonio; Lemoli, Roberto M

    2014-02-01

    Dendritic cells (DCs) are professional APCs that have a role in the initiation of adaptive immune responses and tolerance. Among the tolerogenic mechanisms, the expression of the enzyme IDO1 represents an effective tool to generate T regulatory cells. In humans, different DC subsets express IDO1, but less is known about the IDO1-related enzyme IDO2. In this study, we found a different pattern of expression and regulation between IDO1 and IDO2 in human circulating DCs. At the protein level, IDO1 is expressed only in circulating myeloid DCs (mDCs) and is modulated by PGE2, whereas IDO2 is expressed in both mDCs and plasmacytoid DCs and is not modulated by PGE2. In healthy subjects, IDO1 expression requires the presence of PGE2 and needs continuous transcription and translation, whereas IDO2 expression is constitutive, independent from suppressor of cytokine signaling 3 activity. Conversely, in patients suffering from inflammatory arthritis, circulating DCs express both IDO1 and IDO2. At the functional level, both mDCs and plasmacytoid DCs generate T regulatory cells through an IDO1/IDO2-dependent mechanism. We conclude that, in humans, whereas IDO1 provides an additional mechanism of tolerance induced by proinflammatory mediators, IDO2 is stably expressed in steady-state conditions and may contribute to the homeostatic tolerogenic capacity of DCs. PMID:24391212

  10. Induction of T helper 3 regulatory cells by dendritic cells infected with porcine reproductive and respiratory syndrome virus

    SciTech Connect

    Silva-Campa, Erika; Flores-Mendoza, Lilian; Resendiz, Monica; Pinelli-Saavedra, Araceli; Mata-Haro, Veronica; Mwangi, Waithaka; Hernandez, Jesus

    2009-05-10

    Delayed development of virus-specific immune response has been observed in pigs infected with the porcine reproductive and respiratory syndrome virus (PRRSV). Several studies support the hypothesis that the PRRSV is capable of modulating porcine immune system, but the mechanisms involved are yet to be defined. In this study, we evaluated the induction of T regulatory cells by PRRSV-infected dendritic cells (DCs). Our results showed that PRRSV-infected DCs significantly increased Foxp3{sup +}CD25{sup +} T cells, an effect that was reversible by IFN-alpha treatment, and this outcome was reproducible using two distinct PRRSV strains. Analysis of the expressed cytokines suggested that the induction of Foxp3{sup +}CD25{sup +} T cells is dependent on TGF-beta but not IL-10. In addition, a significant up-regulation of Foxp3 mRNA, but not TBX21 or GATA3, was detected. Importantly, our results showed that the induced Foxp3{sup +}CD25{sup +} T cells were able to suppress the proliferation of PHA-stimulated PBMCs. The T cells induced by the PRRSV-infected DCs fit the Foxp3{sup +}CD25{sup +} T helper 3 (Th3) regulatory cell phenotype described in the literature. The induction of this cell phenotype depended, at least in part, on PRRSV viability because IFN-alpha treatment or virus inactivation reversed these effects. In conclusion, this data supports the hypothesis that the PRRSV succeeds to establish and replicate in porcine cells early post-infection, in part, by inducing Th3 regulatory cells as a mechanism of modulating the porcine immune system.

  11. HLA-G Level on Monocytoid Dendritic Cells Correlates with Regulatory T Cell Foxp3 Expression in Liver Transplant Tolerance

    PubMed Central

    Castellaneta, Antonino; Mazariegos, George V; Nayyar, Navdeep; Zeevi, Adriana; Thomson, Angus W

    2011-01-01

    Background Human leukocyte antigen (HLA)-G is a non-classical HLA class I molecule expressed as membrane-bound and soluble isoforms. Interaction of HLA-G with its receptor, immunoglobulin (Ig)-like transcript (ILT) 4 on dendritic cells (DC) down-regulates their T cell stimulatory ability. Methods We examined expression of HLA-G, ILT4, other immune regulatory molecules (inducible costimulator ligand and glucocorticoid-induced tumor necrosis factor-related receptor ligand), and the activation marker CMRF44 on circulating monocytoid (m) and plasmacytoid (p)DC by monoclonal antibody staining and flow cytometry. Three groups of stable liver transplant recipients,-operationally tolerant (TOL), prospective immunosuppressive drug weaning (PW) and maintenance immunosuppression (MI) were studied, together with healthy controls (HC). Serum HLA-G levels were measured by enzyme-linked immunosorbent assay. Results In TOL patients, mDC but not pDC expressed higher HLA-G than in MI patients or HC. In TOL patients, the incidence of CD4+CD25hiCD127− regulatory T cells (Treg) and the intensity of Treg forkhead box p3 (Foxp3) expression were significantly higher than in the MI group. HLA-G expression on circulating mDC correlated significantly with that of Foxp3 in the TOL group. There was no correlation between immunosuppressive drug (tacrolimus) dose or trough level and HLA-G expression or Treg frequency or Foxp3 expression. The incidence of patients with circulating HLA-G levels >100ng/ml was highest in the TOL group, although statistical significance was not achieved. Conclusions Higher HLA-G expression on circulating mDC in TOL recipients compared with MI or HC, suggests a possible role of HLA-G in immune regulation possibly mediated by enhanced host Treg Foxp3 expression. PMID:21423069

  12. Levels of dendritic cell populations and regulatory T cells vary significantly between two commonly used mouse strains.

    PubMed

    Vogelsang, Petra; Hovden, Arnt-Ove; Jonsson, Roland; Appel, Silke

    2009-12-01

    Dendritic cells (DC) are a heterogeneous group of professional antigen-presenting cells (APC) involved in both initiating immune responses and maintaining tolerance. Roughly, DC can be divided into plasmacytoid DC (pDC) and conventional DC (cDC). By controlling regulatory T cells (Treg), DC can influence the outcome of both immunity and autoimmunity. Since the use of mice as in vivo models became a practical tool for researchers studying pathological events in all kind of human diseases, we decided to compare levels of cDC, pDC and Treg in both spleen and blood between two inbred mouse strains. Here we show that two commonly used mouse strains, BALB/c and C57BL/10J mice, have significantly different levels of distinct CD11c(+)/CD4(-)/CD8a(+), CD11c(+)/CD4(+)/CD8a(-) and CD11c(+)/CD4(-)/CD8a(-) cDC populations, pDC and Treg. Therefore, we emphasize the importance of considering the proper model when comparing data sets from different mouse strains. PMID:19906196

  13. Clec4A4 is a regulatory receptor for dendritic cells that impairs inflammation and T-cell immunity

    PubMed Central

    Uto, Tomofumi; Fukaya, Tomohiro; Takagi, Hideaki; Arimura, Keiichi; Nakamura, Takeshi; Kojima, Naoya; Malissen, Bernard; Sato, Katsuaki

    2016-01-01

    Dendritic cells (DCs) comprise several subsets that are critically involved in the initiation and regulation of immunity. Clec4A4/DC immunoreceptor 2 (DCIR2) is a C-type lectin receptor (CLR) exclusively expressed on CD8α− conventional DCs (cDCs). However, how Clec4A4 controls immune responses through regulation of the function of CD8α− cDCs remains unclear. Here we show that Clec4A4 is a regulatory receptor for the activation of CD8α− cDCs that impairs inflammation and T-cell immunity. Clec4a4−/−CD8α− cDCs show enhanced cytokine production and T-cell priming following Toll-like receptor (TLR)-mediated activation. Furthermore, Clec4a4−/− mice exhibit TLR-mediated hyperinflammation. On antigenic immunization, Clec4a4−/− mice show not only augmented T-cell responses but also progressive autoimmune pathogenesis. Conversely, Clec4a4−/− mice exhibit resistance to microbial infection, accompanied by enhanced T-cell responses against microbes. Thus, our findings highlight roles of Clec4A4 in regulation of the function of CD8α− cDCs for control of the magnitude and quality of immune response. PMID:27068492

  14. Microbiota/Host Crosstalk Biomarkers: Regulatory Response of Human Intestinal Dendritic Cells Exposed to Lactobacillus Extracellular Encrypted Peptide

    PubMed Central

    Al-Hassi, Hafid O.; Mann, Elizabeth R.; Urdaci, María C.; Knight, Stella C.; Margolles, Abelardo

    2012-01-01

    The human gastrointestinal tract is exposed to a huge variety of microorganisms, either commensal or pathogenic; at this site, a balance between immunity and immune tolerance is required. Intestinal dendritic cells (DCs) control the mechanisms of immune response/tolerance in the gut. In this paper we have identified a peptide (STp) secreted by Lactobacillus plantarum, characterized by the abundance of serine and threonine residues within its sequence. STp is encoded in one of the main extracellular proteins produced by such species, which includes some probiotic strains, and lacks cleavage sites for the major intestinal proteases. When studied in vitro, STp expanded the ongoing production of regulatory IL-10 in human intestinal DCs from healthy controls. STp-primed DC induced an immunoregulatory cytokine profile and skin-homing profile on stimulated T-cells. Our data suggest that some of the molecular dialogue between intestinal bacteria and DCs may be mediated by immunomodulatory peptides, encoded in larger extracellular proteins, secreted by commensal bacteria. These peptides may be used for the development of nutraceutical products for patients with IBD. In addition, this kind of peptides seem to be absent in the gut of inflammatory bowel disease patients, suggesting a potential role as biomarker of gut homeostasis. PMID:22606249

  15. Antigen targeting to dendritic cells combined with transient regulatory T cell inhibition results in long-term tumor regression

    PubMed Central

    Unger, Wendy WJ; Mayer, Christian T; Engels, Steef; Hesse, Christina; Perdicchio, Maurizio; Puttur, Franz; Streng-Ouwehand, Ingeborg; Litjens, Manja; Kalay, Hakan; Berod, Luciana; Sparwasser, Tim; van Kooyk, Yvette

    2014-01-01

    Therapeutic vaccinations against cancer are still largely ineffective. Major caveats are inefficient delivery of tumor antigens to dendritic cells (DCs) and excessive immune suppression by Foxp3+ regulatory T cells (Tregs), resulting in defective T cell priming and failure to induce tumor regression. To circumvent these problems we evaluated a novel combinatorial therapeutic strategy. We show that tumor antigen targeting to DC-SIGN in humanized hSIGN mice via glycans or specific antibodies induces superior T cell priming. Next, this targeted therapy was combined with transient Foxp3+ Treg depletion employing hSIGNxDEREG mice. While Treg depletion alone slightly delayed B16-OVA melanoma growth, only the combination therapy instigated long-term tumor regression in a substantial fraction of mice. This novel strategy resulted in optimal generation of antigen-specific activated CD8+ T cells which accumulated in regressing tumors. Notably, Treg depletion also allowed the local appearance of effector T cells specific for endogenous B16 antigens. This indicates that antitumor immune responses can be broadened by therapies aimed at controlling Tregs in tumor environments. Thus, transient inhibition of Treg-mediated immune suppression potentiates DC targeted antigen vaccination and tumor-specific immunity. PMID:26405564

  16. Embryonic Trophoblasts Induce Decidual Regulatory T Cell Differentiation and Maternal–Fetal Tolerance through Thymic Stromal Lymphopoietin Instructing Dendritic Cells

    PubMed Central

    Du, Mei-Rong; Guo, Pei-Fen; Piao, Hai-Lan; Wang, Song-Cun; Sun, Chan; Jin, Li-Ping; Tao, Yu; Li, Yan-Hong; Zhang, Di; Zhu, Rui; Fu, Qiang

    2014-01-01

    Physiological pregnancy requires the maternal immune system to recognize and tolerate embryonic Ags. Although multiple mechanisms have been proposed, it is not yet clear how the fetus evades the maternal immune system. In this article, we demonstrate that trophoblast-derived thymic stromal lymphopoietin (TSLP) instructs decidual CD11c+ dendritic cells (dDCs)with increased costimulatory molecules; MHC class II; and Th2/3-type, but not Th1-type, cytokines. TSLP-activated dDCs induce proliferation and differentiation of decidual CD4+CD25− T cells into CD4+CD25+FOXP3+ regulatory T cells (Tregs) through TGF-β1. TSLP-activated dDC–induced Tregs display immunosuppressive features and express Th2-type cytokines. In addition, decidual CD4+CD25+FOXP3+ Tregs promote invasiveness and HLA-G expression of trophoblasts, resulting in preferential production of Th2 cytokines and reduced cytotoxicity in decidual CD56brightCD16− NK cells. Of interest, decreased TSLP expression and reduced numbers of Tregs were observed at the maternal–fetal interface during miscarriage. Our study identifies a novel feedback loop between embryo-derived trophoblasts and maternal decidual leukocytes, which induces a tolerogenic immune response to ensure a successful pregnancy. PMID:24453244

  17. Corruption of dendritic cell antigen presentation during acute GVHD leads to regulatory T-cell failure and chronic GVHD.

    PubMed

    Leveque-El Mouttie, Lucie; Koyama, Motoko; Le Texier, Laetitia; Markey, Kate A; Cheong, Melody; Kuns, Rachel D; Lineburg, Katie E; Teal, Bianca E; Alexander, Kylie A; Clouston, Andrew D; Blazar, Bruce R; Hill, Geoffrey R; MacDonald, Kelli P A

    2016-08-11

    Chronic graft-versus-host disease (cGVHD) is a major cause of late mortality following allogeneic bone marrow transplantation (BMT) and is characterized by tissue fibrosis manifesting as scleroderma and bronchiolitis obliterans. The development of acute GVHD (aGVHD) is a powerful clinical predictor of subsequent cGVHD, suggesting that aGVHD may invoke the immunologic pathways responsible for cGVHD. In preclinical models in which sclerodermatous cGVHD develops after a preceding period of mild aGVHD, we show that antigen presentation within major histocompatibility complex (MHC) class II of donor dendritic cells (DCs) is markedly impaired early after BMT. This is associated with a failure of regulatory T-cell (Treg) homeostasis and cGVHD. Donor DC-restricted deletion of MHC class II phenocopied this Treg deficiency and cGVHD. Moreover, specific depletion of donor Tregs after BMT also induced cGVHD, whereas adoptive transfer of Tregs ameliorated it. These data demonstrate that the defect in Treg homeostasis seen in cGVHD is a causative lesion and is downstream of defective antigen presentation within MHC class II that is induced by aGVHD. PMID:27338097

  18. Allostimulatory Effects of Dendritic Cells with Characteristic Features of a Regulatory Phenotype

    PubMed Central

    Jacobs, C. W. M.; van der Vlag, J.; Hilbrands, L. B.

    2016-01-01

    Introduction Tolerogenic dendritic cells (DCs) have the potential to prolong graft survival after transplantation. Tolerogenic DCs are in general characterized by a low expression of co-stimulatory molecule and a high IL-10:IL-12 production ratio. Based on promising results with earlier used alternatively activated DCs, we aimed to generate in culture potentially tolerogenic DC by simultaneously blocking GSK3 by lithium chloride (LiCl) and stimulating TLR2 by PAM3CysSerLys4. Materials and Methods Bone marrow-derived LiClPAM3 DCs were generated by the addition of LiCl 24 hours before harvesting, and one hour later PAM3CysSerLys4. The phenotype of the DCs was assessed by determining the expression of co-stimulatory molecules in flow cytometry and cytokine production in ELISA, whereas their functional properties were tested in a mixed lymphocyte reaction. A fully MHC mismatched heterotopic heart transplant preceded by infusion of donor-derived LiClPAM3 DC was performed to assess the tolerogenic potential of LiClPAM3 DCs in vivo. Results LiClPAM3 DCs displayed a tolerogenic phenotype accompanied with a low expression of co-stimulatory molecules and a high IL-10:IL-12 production ratio. However, in mixed lymphocyte reaction, LiClPAM3 DCs appeared superior in T cell stimulation, and induced Th1 and Th17 differentiation. Moreover, mice pretreated with LiClPAM3 DC displayed a reduced graft survival. Analysis of LiClPAM3 DC culture supernatant revealed high levels of CXCL-1, which was also found in supernatants of co-cultures of LiClPAM3 DC and T cells. Nevertheless, we could not show a role for CXCL-1 in T cell proliferation or activation in vitro. Discussion LiClPAM3 DCs display in vitro a tolerogenic phenotype with a high IL-10:IL-12 ratio, but appeared to be highly immunogenic, since allograft rejection was accelerated. As yet unidentified LiClPAM3 DC-derived factors, may explain the immunogenic character of LiClPAM3 DCs in vivo. PMID:27525971

  19. Differentially modulated dendritic cells induce regulatory T cells with different characteristics.

    PubMed

    Roelen, Dave L; van den Boogaardt, Daniëlle E M; van Miert, Paula P M C; Koekkoek, Karin; Offringa, Rienk; Claas, Frans H J

    2008-07-01

    Dexamethason (DEX) treated DC display several features that establish them as candidates for specific allogeneic tolerance induction. We report the results of in vitro studies of polarization of the alloimmune T cell response with two types of differentially modulated human DC. Both DEX treated DC triggered by LPS for 6 h (DEX6-DC) and DEX treated DC triggered by LPS for 48 h (DEX48-DC) acquired low levels of costimulatory, adhesion, and MHC class II molecules compared with mature DC (mDC). In contrast to mDC, both DEX6-DC and DEX48-DC did not produce any IL-12. DEX6-DC were able to produce significant amounts of IL-10 whereas DEX48-DC did not actively produce IL-10. Conversely, the induction of IL-10 producing cells was significantly increased when PBL were stimulated with DEX48-DC compared with DEX6-DC. Both stimulation of PBL with DEX6-DC and DEX48-DC led to the induction of cell populations able to suppress the proliferative alloimmune response of primed T cells in a cell-cell contact independent and antigen-nonspecific manner. Tregs obtained after stimulation with DEX48-DC were also able to inhibit the IFN-gamma production of the effector cells and this effect could be blocked by anti-IL-10. Tregs induced by DEX6-DC produced similar amounts of IL-10, yet were not able to inhibit IFN-gamma production of the effector T cells, indicating a different mechanism. In summary, we show that differential modulation of DC results in the induction of different populations of regulatory T cells. PMID:18639635

  20. Thymic Stromal Lymphopoietin-Activated Plasmacytoid Dendritic Cells Induce the Generation of FOXP3+ Regulatory T Cells in Human Thymus

    PubMed Central

    Hanabuchi, Shino; Ito, Tomoki; Park, Woon-Ryon; Watanabe, Norihiko; Shaw, Joanne L.; Roman, Eulogia; Arima, Kazuhiko; Wang, Yui-Hsi; Voo, Kui Shin; Cao, Wei; Liu, Yong-Jun

    2012-01-01

    Human thymus contains major dendritic cell (DC) subsets, myeloid DCs (mDCs), and plasmacytoid DCs (pDCs). We previously showed that mDCs, educated by thymic stromal lymphopoietin (TSLP) produced by the epithelial cells of the Hassall’s corpuscles, induced differentiation of CD4+CD25− thymocytes into Forkhead Box P3+ (FOXP3+) regulatory T cells (TR) within the medulla of human thymus. In this study, we show that pDCs expressed the TSLP receptor and IL-7 receptor a complexes upon activation and became responsive to TSLP. TSLP-activated human pDCs secrete macrophage-derived chemokine CCL-22 and thymus- and activation-regulated chemokine CCL-17 but not Th1- or Th2-polarizing cytokines. TSLP-activated pDCs induced the generation of FOXP3+ TR from CD4+CD8−CD25− thymocytes, which could be strongly inhibited by Th1-polarizing cytokine IL-12 or Th2-polarizing cytokine IL-4. Interestingly, the FOXP3+ TR induced by the TSLP-pDCs expressed more IL-10 but less TGF-b than that induced by the TSLP-mDCs. These data suggest that TSLP expressed by thymic epithelial cells can activate mDCs and pDCs to positively select the FOXP3+ TR with different cytokine production potential in human thymus. The inability of TSLP to induce DC maturation without producing Th1- or Th2-polarizing cytokines may provide a thymic niche for TR development. PMID:20173030

  1. Decreased Numbers of Blood Dendritic Cells and Defective Function of Regulatory T Cells in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis

    PubMed Central

    Rimbert, Marie; Hamidou, Mohamed; Braudeau, Cécile; Puéchal, Xavier; Teixeira, Luis; Caillon, Hélène; Néel, Antoine; Audrain, Marie; Guillevin, Loic; Josien, Régis

    2011-01-01

    Background Dendritic cells (DC) and regulatory cells (Treg) play pivotal roles in controlling both normal and autoimmune adaptive immune responses. DC are the main antigen-presenting cells to T cells, and they also control Treg functions. In this study, we examined the frequency and phenotype of DC subsets, and the frequency and function of Treg from patients with ANCA-associated vasculitis (AAV). Methodology/Principal Findings Blood samples from 19 untreated patients with AAV during flares and before any immunosuppressive treatment were analyzed, along with 15 AAV patients in remission and 18 age-matched healthy controls. DC and Treg numbers, and phenotypes were assessed by flow cytometry, and in vitro suppressive function of Treg was determined by co-culture assay. When compared to healthy volunteers, absolute numbers of conventional and plasmacytoid DC were decreased in AAV patients. During the acute phase this decrease was significantly more pronounced and was associated with an increased DC expression of CD62L. Absolute numbers of Treg (CD4+CD25highCD127low/− Tcells) were moderately decreased in patients. FOXP3 and CD39 were expressed at similar levels on Treg from patients as compared to controls. The suppressive function of Treg from AAV patients was dramatically decreased as compared to controls, and this defect was more pronounced during flares than remission. This Treg functional deficiency occurred in the absence of obvious Th17 deviation. Conclusion In conclusion, these data show that AAV flares are associated with both a decrease number and altered phenotype of circulating DC and point to a role for Treg functional deficiency in the pathogenesis of AAV. PMID:21494636

  2. Ginsenoside Rp1 Exerts Anti-inflammatory Effects via Activation of Dendritic Cells and Regulatory T Cells.

    PubMed

    Bae, Jingyu; Koo, Jihye; Kim, Soochan; Park, Tae-Yoon; Kim, Mi-Yeon

    2012-10-01

    Ginsenoside Rp1 (G-Rp1) is a saponin derivate that provides anti-metastatic activities through inhibition of the NF-κB pathway. In this study, we examined the effects of G-Rp1 on regulatory T cell (Treg) activation. After treatment of splenocytes with G-Rp1, Tregs exhibited upregulation of IL-10 expression, and along with dendritic cells (DCs), these Tregs showed increased cell number compared to other cell populations. The effect of G-Rp1 on Treg number was augmented in the presence of lipopolysaccharide (LPS), which mimics pathological changes that occur during inflammation. However, depletion of DCs prevented the increase in Treg number in the presence of G-Rp1 and/or LPS. In addition, G-Rp1 promoted the differentiation of the memory types of CD4(+)Foxp3(+)CD62L(low) Tregs rather than the generation of new Tregs. In vivo experiments also demonstrated that Tregs and DCs from mice that were fed G-Rp1 for 7 d and then injected with LPS exhibited increased activation compared with those from mice that were injected with LPS alone. Expression of TGF-β and CTLA4 in Tregs was increased, and upregulation of IL-2 and CD80/ CD86 expression by DCs affected the suppressive function of Tregs through IL-2 receptors and CTLA4. These data demonstrate that G-Rp1 exerts anti-inflammatory effects by activating Tregs in vitro and in vivo. PMID:23717139

  3. Murine Melanoma-Infiltrating Dendritic Cells Are Defective in Antigen Presenting Function Regardless of the Presence of CD4+CD25+ Regulatory T Cells

    PubMed Central

    Ataera, Haley; Hyde, Evelyn; Price, Kylie M.; Stoitzner, Patrizia; Ronchese, Franca

    2011-01-01

    Tumor-infiltrating dendritic cells are often ineffective at presenting tumor-derived antigen in vivo, a defect usually ascribed to the suppressive tumor environment. We investigated the effects of depleting CD4+CD25+ “natural” regulatory T cells (Treg) on the frequency, phenotype and function of total dendritic cell populations in B16.OVA tumors and in tumor-draining lymph nodes. Intraperitoneal injection of the anti-CD25 monoclonal antibody PC61 reduced Treg frequency in blood and tumors, but did not affect the frequency of tumor-infiltrating dendritic cells, or their expression of CD40, CD86 and MHCII. Tumor-infiltrating dendritic cells from PC61-treated or untreated mice induced the proliferation of allogeneic T cells in vitro, but could not induce proliferation of OVA-specific OTI and OTII T cells unless specific peptide antigen was added in culture. Some proliferation of naïve, OVA-specific OTI T cells, but not OTII T cells, was observed in the tumor-draining LN of mice carrying B16.OVA tumors, however, this was not improved by PC61 treatment. Experiments using RAG1−/− hosts adoptively transferred with OTI and CD25-depleted OTII cells also failed to show improved OTI and OTII T cell proliferation in vivo compared to C57BL/6 hosts. We conclude that the defective presentation of B16.OVA tumor antigen by tumor-infiltrating dendritic cells and in the tumor-draining lymph node is not due to the presence of “natural” CD4+CD25+ Treg. PMID:21390236

  4. A Human Trypanosome Suppresses CD8+ T Cell Priming by Dendritic Cells through the Induction of Immune Regulatory CD4+ Foxp3+ T Cells

    PubMed Central

    Ersching, Jonatan; Basso, Alexandre Salgado; Kalich, Vera Lucia Garcia; Bortoluci, Karina Ramalho

    2016-01-01

    Although CD4+ Foxp3+ T cells are largely described in the regulation of CD4+ T cell responses, their role in the suppression of CD8+ T cell priming is much less clear. Because the induction of CD8+ T cells during experimental infection with Trypanosoma cruzi is remarkably delayed and suboptimal, we raised the hypothesis that this protozoan parasite actively induces the regulation of CD8+ T cell priming. Using an in vivo assay that eliminated multiple variables associated with antigen processing and dendritic cell activation, we found that injection of bone marrow-derived dendritic cells exposed to T. cruzi induced regulatory CD4+ Foxp3+ T cells that suppressed the priming of transgenic CD8+ T cells by peptide-loaded BMDC. This newly described suppressive effect on CD8+ T cell priming was independent of IL-10, but partially dependent on CTLA-4 and TGF-β. Accordingly, depletion of Foxp3+ cells in mice infected with T. cruzi enhanced the response of epitope-specific CD8+ T cells. Altogether, our data uncover a mechanism by which T. cruzi suppresses CD8+ T cell responses, an event related to the establishment of chronic infections. PMID:27332899

  5. A Human Trypanosome Suppresses CD8+ T Cell Priming by Dendritic Cells through the Induction of Immune Regulatory CD4+ Foxp3+ T Cells.

    PubMed

    Ersching, Jonatan; Basso, Alexandre Salgado; Kalich, Vera Lucia Garcia; Bortoluci, Karina Ramalho; Rodrigues, Maurício M

    2016-06-01

    Although CD4+ Foxp3+ T cells are largely described in the regulation of CD4+ T cell responses, their role in the suppression of CD8+ T cell priming is much less clear. Because the induction of CD8+ T cells during experimental infection with Trypanosoma cruzi is remarkably delayed and suboptimal, we raised the hypothesis that this protozoan parasite actively induces the regulation of CD8+ T cell priming. Using an in vivo assay that eliminated multiple variables associated with antigen processing and dendritic cell activation, we found that injection of bone marrow-derived dendritic cells exposed to T. cruzi induced regulatory CD4+ Foxp3+ T cells that suppressed the priming of transgenic CD8+ T cells by peptide-loaded BMDC. This newly described suppressive effect on CD8+ T cell priming was independent of IL-10, but partially dependent on CTLA-4 and TGF-β. Accordingly, depletion of Foxp3+ cells in mice infected with T. cruzi enhanced the response of epitope-specific CD8+ T cells. Altogether, our data uncover a mechanism by which T. cruzi suppresses CD8+ T cell responses, an event related to the establishment of chronic infections. PMID:27332899

  6. Thymic regulatory T cell niche size is dictated by limiting interleukin 2 from antigen-bearing dendritic cells and feedback competition

    PubMed Central

    Weist, Brian M.; Kurd, Nadia; Boussier, Jeremy; Chan, Shiao Wei; Robey, Ellen A.

    2015-01-01

    Thymic regulatory T (Treg) cell production requires interleukin 2 (IL-2) and agonist TCR ligands, and is controlled by competition for a limited developmental niche, but the thymic sources of IL-2 and the factors that limit access to the niche are poorly understood. Here we show that IL-2 produced by antigen-bearing dendritic cells plays a key role in Treg cell development, and that existing Treg cells limit new Treg cell development by competing for IL-2. . Our data suggest that antigen-presenting cells that can provide both IL-2 and a TCR ligand comprise the thymic niche, and that competition by existing Treg cells for a limited supply of IL-2 provides negative feedback for new Treg cell production. PMID:25939026

  7. Binding immunoglobulin protein-treated peripheral blood monocyte-derived dendritic cells are refractory to maturation and induce regulatory T-cell development.

    PubMed

    Corrigall, Valerie M; Vittecoq, Olivier; Panayi, Gabriel S

    2009-10-01

    Binding immunoglobulin protein (BiP) has been shown previously to have immunomodulatory functions. Herein we investigated whether BiP could affect the differentiation of monocytes into dendritic cells (DCs) and thence the development of regulatory T cells. Peripheral blood monocyte-derived DCs were matured with lipopolysaccharide in the presence or absence of BiP. DC development and T-cell changes were monitored by flow cytometry and regulatory T-cell function was measured by uptake of tritiated thymidine. More BiP-treated DCs (DC((BiP))s) expressed amounts of intracellular indoleamine 2,3-dioxygenase (IDO) and cell surface leucocyte immunoglobulin-like receptor subfamily B member 1 (LILRB1), retained CD14 expression but down-regulated expression of human leucocyte antigen (HLA)-DR and CD86, and produced copious amounts of interleukin (IL)-10, when compared with control DCs. T cells co-cultured with DC((BiP))s developed regulatory function with increased surface expression of CD4(+) CD25(hi) CD27(hi) but with no concomitant increase in forkhead box P3 (Foxp3). These T cells also showed significantly higher levels of intracellular cytotoxic T-lymphocyte antigen (CTLA)-4. The latter could be inhibited by the presence of the IDO inhibitor 1 methyl tryptophan. The addition of neutralizing anti-IL-10 antibody or the specific mitogen-activated protein kinase (MAPK) p38 inhibitor SB203580 reversed the inhibition of DC differentiation by BiP. In conclusion, BiP is an immunomodulator able to arrest inflammation through induction of tolerogenic DCs and subsequent generation of T regulatory cells. PMID:19740378

  8. Retinoic acid treated human dendritic cells induce T regulatory cells via the expression of CD141 and GARP which is impaired with age.

    PubMed

    Agrawal, Sudhanshu; Ganguly, Sreerupa; Tran, Alexander; Sundaram, Padmaja; Agrawal, Anshu

    2016-06-01

    Aged subjects display increased susceptibility to mucosal diseases. Retinoic Acid (RA) plays a major role in inducing tolerance in the mucosa. RA acts on Dendritic cells (DCs) to induce mucosal tolerance. Here we compared the response of DCs from aged and young individuals to RA with a view to understand the role of DCs in age-associated increased susceptibility to mucosal diseases. Our investigations revealed that compared to young DCs, RA stimulated DCs from aged subjects are defective in inducing IL-10 and T regulatory cells. Examinations of the underlying mechanisms indicated that RA exposure led to the upregulation of CD141 and GARP on DCs which rendered the DCs tolerogenic. CD141(hi), GARP(+) DCs displayed enhanced capacity to induce T regulatory cells compared to CD141(lo) and GARP(-) DCs. Unlike RA stimulated DCs from young, DCs from aged subjects exhibited diminished upregulation of both CD141 and GARP. The percentage of DCs expressing CD141 and GARP on RA treatment was significantly reduced in DCs from aged individuals. Furthermore, the remaining CD141(hi), GARP(+) DCs from aged individuals were also deficient in inducing T regs. In summary, reduced response of aged DCs to RA enhances mucosal inflammation in the elderly, increasing their susceptibility to mucosal diseases. PMID:27244900

  9. Retinoic acid treated human dendritic cells induce T regulatory cells via the expression of CD141 and GARP which is impaired with age

    PubMed Central

    Agrawal, Sudhanshu; Ganguly, Sreerupa; Tran, Alexander; Sundaram, Padmaja; Agrawal, Anshu

    2016-01-01

    Aged subjects display increased susceptibility to mucosal diseases. Retinoic Acid (RA) plays a major role in inducing tolerance in the mucosa. RA acts on Dendritic cells (DCs) to induce mucosal tolerance. Here we compared the response of DCs from aged and young individuals to RA with a view to understand the role of DCs in age-associated increased susceptibility to mucosal diseases. Our investigations revealed that compared to young DCs, RA stimulated DCs from aged subjects are defective in inducing IL-10 and T regulatory cells. Examinations of the underlying mechanisms indicated that RA exposure led to the upregulation of CD141 and GARP on DCs which rendered the DCs tolerogenic. CD141hi, GARP+ DCs displayed enhanced capacity to induce T regulatory cells compared to CD141lo and GARP− DCs. Unlike RA stimulated DCs from young, DCs from aged subjects exhibited diminished upregulation of both CD141 and GARP. The percentage of DCs expressing CD141 and GARP on RA treatment was significantly reduced in DCs from aged individuals. Furthermore, the remaining CD141hi, GARP+ DCs from aged individuals were also deficient in inducing T regs. In summary, reduced response of aged DCs to RA enhances mucosal inflammation in the elderly, increasing their susceptibility to mucosal diseases. PMID:27244900

  10. Myeloid Dendritic Cells (DCs) of Mice Susceptible to Paracoccidioidomycosis Suppress T Cell Responses whereas Myeloid and Plasmacytoid DCs from Resistant Mice Induce Effector and Regulatory T Cells

    PubMed Central

    Pina, Adriana; Frank de Araujo, Eliseu; Felonato, Maíra; Loures, Flávio V.; Feriotti, Claudia; Bernardino, Simone; Barbuto, José Alexandre M.

    2013-01-01

    The protective adaptive immune response in paracoccidioidomycosis, a mycosis endemic among humans, is mediated by T cell immunity, whereas impaired T cell responses are associated with severe, progressive disease. The early host response to Paracoccidioides brasiliensis infection is not known since the disease is diagnosed at later phases of infection. Our laboratory established a murine model of infection where susceptible mice reproduce the severe disease, while resistant mice develop a mild infection. This work aimed to characterize the influence of dendritic cells in the innate and adaptive immunity of susceptible and resistant mice. We verified that P. brasiliensis infection induced in bone marrow-derived dendritic cells (DCs) of susceptible mice a prevalent proinflammatory myeloid phenotype that secreted high levels of interleukin-12 (IL-12), tumor necrosis factor alpha, and IL-β, whereas in resistant mice, a mixed population of myeloid and plasmacytoid DCs secreting proinflammatory cytokines and expressing elevated levels of secreted and membrane-bound transforming growth factor β was observed. In proliferation assays, the proinflammatory DCs from B10.A mice induced anergy of naïve T cells, whereas the mixed DC subsets from resistant mice induced the concomitant proliferation of effector and regulatory T cells (Tregs). Equivalent results were observed during pulmonary infection. The susceptible mice displayed preferential expansion of proinflammatory myeloid DCs, resulting in impaired proliferation of effector T cells. Conversely, the resistant mice developed myeloid and plasmacytoid DCs that efficiently expanded gamma interferon-, IL-4-, and IL-17-positive effector T cells associated with increased development of Tregs. Our work highlights the deleterious effect of excessive innate proinflammatory reactions and provides new evidence for the importance of immunomodulation during pulmonary paracoccidioidomycosis. PMID:23340311

  11. Reduced Dendritic Cells Expressing CD200R1 in Children with Inflammatory Bowel Disease: Correlation with Th17 and Regulatory T Cells

    PubMed Central

    Elshal, Mohamed F.; Aldahlawi, Alia M.; Saadah, Omar I.; McCoy, J. Philip

    2015-01-01

    Loss of tolerance of the adaptive immune system towards indigenous flora contributes to the development of inflammatory bowel diseases (IBD). Defects in dendritic cell (DC)-mediated innate and adoptive immune responses are conceivable. The aim of this study was to investigate the expression of the inhibitory molecules CD200R1 and their ligand CD200 on DCs, to clarify the role of the DCs in the pathogenesis of IBD. Thirty-seven pediatric IBD patients (23 with Crohn’s disease (CD) and 14 with ulcerative colitis (UC)) with mean age 13.25 ± 2.9 years were included. Fourteen age-matched healthy pediatric volunteers (five males and nine females) served as a control group (HC). The percentage of CD11c+ myeloid dendritic cells (mDCs) and CD123+ plasmacytoid DCs (pDCs) expressing CD200R1 and CD200 were evaluated in peripheral blood using flow cytometry and were correlated with routine biochemical, serological markers, serum levels of cytokines and with the percentages of circulating regulatory T cells (Treg) and CD4+ producing IL-17 (Th17). IBD patients showed a significant decrease in the percentage of pDCs and mDCs expressing CD200R1 compared to that of HC. Patients with UC showed increased expressions of the CD200 molecule on pDCs as compared to HC. DCs expressing CD200R1 were found to be correlated positively with Treg and negatively with TH17 and erythrocyte sedimentation rate (ESR). Our findings suggest that IBD is associated with dysregulation in the CD200R1/CD200 axis and that the decrease in DCs expressing CD200R1 may contribute to the imbalance of Th17 and Treg cells and in the pathogenesis of IBD. PMID:26690123

  12. Early exposure of interferon-γ inhibits signal transducer and activator of transcription-6 signalling and nuclear factor κB activation in a short-term monocyte-derived dendritic cell culture promoting ‘FAST’ regulatory dendritic cells

    PubMed Central

    Rojas-Canales, D; Krishnan, R; Jessup, C F; Coates, P T

    2012-01-01

    Interferon (IFN)-γ is a cytokine with immunomodulatory properties, which has been shown previously to enhance the generation of tolerogenic dendritic cells (DC) when administered early ex vivo in 7-day monocyte-derived DC culture. To generate tolerogenic DC rapidly within 48 h, human monocytes were cultured for 24 h with interleukin (IL)-4 and granulocyte–macrophage colony-stimulating factor (GM-CSF) in the presence (IFN-γ-DC) or absence of IFN-γ (500 U/ml) (UT-DC). DC were matured for 24 h with TNF-α and prostaglandin E2 (PGE2). DC phenotype, signal transducer and activator of transcription-6 (STAT-6) phosphorylation and promotion of CD4+CD25+CD127neg/lowforkhead box P3 (FoxP3)hi T cells were analysed by flow cytometry. DC nuclear factor (NF)-κB transcription factor reticuloendotheliosis viral oncogene homologue B (RELB) and IL-12p70 protein expression were also determined. Phenotypically, IFN-γ-DC displayed reduced DC maturation marker CD83 by 62% and co-stimulation molecules CD80 (26%) and CD86 (8%). IFN-γ treatment of monocytes inhibited intracellular STAT6, RELB nuclear translocation and IL-12p70 production. IFN-γ-DC increased the proportion of CD4+CD25+CD127neg/lowfoxp3hi T cells compared to UT-DC from 12 to 23%. IFN-γ-DC primed T cells inhibited antigen-specific, autologous naive T cell proliferation by 70% at a 1:1 naive T cells to IFN-γ-DC primed T cell ratio in suppression assays. In addition, we examined the reported paradoxical proinflammatory effects of IFN-γ and confirmed in this system that late IFN-γ exposure does not inhibit DC maturation marker expression. Early IFN-γ exposure is critical in promoting the generation of regulatory DC. Early IFN-γ modulated DC generated in 48 h are maturation arrested and promote the generation of antigen-specific regulatory T cells, which may be clinically applicable as a novel cellular therapy for allograft rejection. PMID:22288588

  13. Imperatorin exerts antiallergic effects in Th2-mediated allergic asthma via induction of IL-10-producing regulatory T cells by modulating the function of dendritic cells.

    PubMed

    Lin, Chu-Lun; Hsiao, George; Wang, Ching-Chiung; Lee, Yueh-Lun

    2016-08-01

    Imperatorin is a furanocoumarin compound which exists in many medicinal herbs and possesses various biological activities. Herein, we investigated the antiallergic effects of imperatorin in asthmatic mice and explored the immunomodulatory actions of imperatorin on immune cells. We used a murine model of ovalbumin (OVA)-induced asthma to evaluate the therapeutic potential of imperatorin. Additionally, bone marrow-derived dendritic cells (DCs; BMDCs) were used to clarify whether imperatorin exerts an antiallergic effect through altering the ability of DCs to regulate T cells. Oral administration of imperatorin to OVA-sensitized and -challenged mice decreased serum OVA-specific immunoglobulin E (IgE) production, attenuated the airway hyperresponsiveness (AHR), and alleviated airway inflammation in a dose-dependent manner. Notably, secretions of Th2 cytokines and chemokines were reduced, and numbers of interleukin (IL)-10-producing regulatory T cells (Tregs) increased in imperatorin-treated mice. Imperatorin inhibited proinflammatory cytokines and IL-12 production but enhanced IL-10 secretion by lipopolysaccharide (LPS)-stimulated BMDCs. Compared to fully mature DCs, imperatorin-treated DCs expressed high levels of the inducible costimulatory ligand (ICOSL) and Jagged1 molecules, and had the regulatory capacity to promote the generation of IL-10-producing CD4(+) T cells in vitro. Additionally, imperatorin directly suppressed activated CD4(+) T-cell proliferation and cytokine production. Imperatorin may possess therapeutic potential against Th2-mediated allergic asthma not only via stimulating DC induction of Tregs but also via direct inhibition of Th2 cell activation. These findings provide new insights into how imperatorin affects the Th2 immune response and the development of imperatorin as a Treg-type immunomodulatory agent to treat allergic asthma. PMID:27185659

  14. Suppression of allergic inflammation by allergen-DNA-modified dendritic cells depends on the induction of Foxp3+ Regulatory T cells.

    PubMed

    Wu, Kui; Bi, Yuttian; Sun, Kun; Xia, Junbo; Wang, Yan; Wang, Changzheng

    2008-02-01

    CD4(+)CD25(+)Foxp3(+)Regulatory T cells (Tregs) play important roles in regulating allergic inflammation. To analyse if allergen-DNA-modified dendritic cells (DC) can suppress allergic responses and what roles Treg cells play in DC-based allergen-specific immunotherapy. Immature DC were transfected with retrovirus encoding Der p2 DNA, and administered to mice that sensitized and challenged with Der p2 protein. After Treg cells were depleted with anti-CD25 mAb, mice were re-challenged to observe the airway inflammation, and Treg cells in spleen CD4(+) T cells. And responses of spleen CD4(+) T cells to Der p2 were determined. Co-culture of naïve CD4(+) T cells with allergen-modified DC induced Foxp3+ Tregs. Sensitized and challenged mice developed allergic airway inflammation and Th2 responses, and decreased Foxp3(+) Tregs. Treatment with allergen-modified-DC suppressed airway inflammation and Th2 responses, and increased IL-10 and IFN-gamma production and Foxp3(+) Tregs significantly; and eliminated the responses of CD4(+) T cells to allergen. Administration of anit-CD25 mAb eliminated all the effects of modified-DC except for the increasing of IFN-gamma. Allergen-modified DC can induce immune tolerance to allergens and reverse the established Th2 responses induced by allergen, with dependence on the induction of Foxp3(+) Tregs. PMID:18201369

  15. The indoleamine 2,3-dioxygenase pathway is essential for human plasmacytoid dendritic cell-induced adaptive T regulatory cell generation.

    PubMed

    Chen, Wei; Liang, Xueqing; Peterson, Amanda J; Munn, David H; Blazar, Bruce R

    2008-10-15

    Human plasmacytoid dendritic cells (PDCs) can drive naive, allogeneic CD4(+)CD25(-) T cells to differentiate into CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs). However, the intracellular mechanism or mechanisms underlying PDC-induced Treg generation are unknown. In this study, we show that human PDCs express high levels of IDO, an intracellular enzyme that catabolizes tryptophan degradation. Triggering of TLR 9 with CpG oligodeoxynucleotides activates PDCs to up-regulate surface expression of B7 ligands and HLA-DR Ag, but also significantly increases the expression of IDO and results in the generation of inducible Tregs from CD4(+)CD25(-) T cells with potent suppressor cell function. Blocking IDO activity with the pharmacologic inhibitor 1-methyl-D-tryptophan significantly abrogates PDC-driven inducible Treg generation and suppressor cell function. Adding kynurenine, the immediate downstream metabolite of tryptophan, bypasses the 1-methyl-D-tryptophan effect and restores PDC-driven Treg generation. Our results demonstrate that the IDO pathway is essential for PDC-driven Treg generation from CD4(+)CD25(-) T cells and implicate the generation of kynurenine pathway metabolites as the critical mediator of this process. PMID:18832696

  16. TLR2 dependent induction of vitamin A metabolizing enzymes in dendritic cells promotes T regulatory responses and inhibits TH-17 mediated autoimmunity

    PubMed Central

    Manicassamy, Santhakumar; Ravindran, Rajesh; Deng, Jiusheng; Oluoch, Herold; Denning, Timothy L; Kasturi, Sudhir Pai; Rosenthal, Kristen M.; Evavold, Brian D.; Pulendran, Bali

    2009-01-01

    Immune sensing of a microbe occurs via multiple receptors. How signals from different receptors are coordinated to yield a specific immune response is poorly understood. We demonstrate that the different pathogen recognition receptors, TLR2 and dectin-1, recognizing the same microbial stimulus, stimulate distinct innate and adaptive responses. TLR2 signaling induced splenic dendritic cells (DCs) to express the retinoic acid (RA) metabolizing enzyme Raldh2 and IL-10, and to metabolize vitamin A and stimulate Foxp3+ T regulatory cells (Treg cells). RA acted on DCs to induce Socs3 expression, which suppressed activation of p38 MAPK and pro-inflammatory cytokines. Consistent with this, TLR2 signaling induced Treg cells, and suppressed IL-23 and TH-17/ TH-1 mediated autoimmune responses in vivo. In contrast, dectin-1 signaling mostly induced IL-23 and pro-inflammatory cytokines, and augmented TH-17/ TH-1 mediated autoimmune responses in vivo. These data define a new mechanism for the systemic induction of RA and immune suppression against autoimmunity. PMID:19252500

  17. Toll-like receptor 2-dependent induction of vitamin A-metabolizing enzymes in dendritic cells promotes T regulatory responses and inhibits autoimmunity.

    PubMed

    Manicassamy, Santhakumar; Ravindran, Rajesh; Deng, Jiusheng; Oluoch, Herold; Denning, Timothy L; Kasturi, Sudhir Pai; Rosenthal, Kristen M; Evavold, Brian D; Pulendran, Bali

    2009-04-01

    Immune sensing of a microbe occurs via multiple receptors. How signals from different receptors are coordinated to yield a specific immune response is poorly understood. We show that two pathogen recognition receptors, Toll-like receptor 2 (TLR2) and dectin-1, recognizing the same microbial stimulus, stimulate distinct innate and adaptive responses. TLR2 signaling induced splenic dendritic cells (DCs) to express the retinoic acid metabolizing enzyme retinaldehyde dehydrogenase type 2 and interleukin-10 (IL-10) and to metabolize vitamin A and stimulate Foxp3(+) T regulatory cells (T(reg) cells). Retinoic acid acted on DCs to induce suppressor of cytokine signaling-3 expression, which suppressed activation of p38 mitogen-activated protein kinase and proinflammatory cytokines. Consistent with this finding, TLR2 signaling induced T(reg) cells and suppressed IL-23 and T helper type 17 (T(H)17) and T(H)1-mediated autoimmune responses in vivo. In contrast, dectin-1 signaling mostly induced IL-23 and proinflammatory cytokines and augmented T(H)17 and T(H)1-mediated autoimmune responses in vivo. These data define a new mechanism for the systemic induction of retinoic acid and immune suppression against autoimmunity. PMID:19252500

  18. Human dendritic cells acquire a semimature phenotype and lymph node homing potential through interaction with CD4+CD25+ regulatory T cells.

    PubMed

    Bayry, Jagadeesh; Triebel, Frédéric; Kaveri, Srini V; Tough, David F

    2007-04-01

    Interactions between dendritic cells (DC) and T cells are known to involve the delivery of signals in both directions. We sought to characterize the effects on human DC of contact with different subsets of activated CD4+ T cells. The results showed that interaction with CD25(high)CD4+ regulatory T cells (Tregs) caused DC to take on very different properties than contact with naive or memory phenotype T cells. Whereas non-Tregs stimulated DC maturation, culture with Tregs produced DC with a mixed phenotype. By many criteria, Tregs inhibited DC maturation, inducing down-regulation of costimulatory molecules and T cell stimulatory activity. However, DC exposed to Tregs also showed some changes typically associated with DC maturation, namely, increased expression of CCR7 and MHC class II molecules, and gained the ability to migrate in response to the CCR7 ligand CCL19. Both soluble factors and cell-associated molecules were shown to be involved in Treg modulation of DC, with lymphocyte activation gene 3 (LAG-3) playing a predominant role in driving maturation-associated changes. The data show that Tregs induce the generation of semimature DC with the potential to migrate into lymphoid organs, suggesting a possible mechanism by which Tregs down-modulate immune responses. PMID:17371975

  19. Regulatory T-Cell-Mediated Suppression of Conventional T-Cells and Dendritic Cells by Different cAMP Intracellular Pathways

    PubMed Central

    Rueda, Cesar M.; Jackson, Courtney M.; Chougnet, Claire A.

    2016-01-01

    Regulatory T-cells (Tregs) mediate their suppressive action by acting directly on conventional T-cells (Tcons) or dendritic cells (DCs). One mechanism of Treg suppression is the increase of cyclic adenosine 3′,5′-monophosphate (cAMP) levels in target cells. Tregs utilize cAMP to control Tcon responses, such as proliferation and cytokine production. Tregs also exert their suppression on DCs, diminishing DC immunogenicity by downmodulating the expression of costimulatory molecules and actin polymerization at the immunological synapse. The Treg-mediated usage of cAMP occurs through two major mechanisms. The first involves the Treg-mediated influx of cAMP in target cells through gap junctions. The second is the conversion of adenosine triphosphate into adenosine by the ectonucleases CD39 and CD73 present on the surface of Tregs. Adenosine then binds to receptors on the surface of target cells, leading to increased intracellular cAMP levels in these targets. Downstream, cAMP can activate the canonical protein kinase A (PKA) pathway and the exchange protein activated by cyclic AMP (EPAC) non-canonical pathway. In this review, we discuss the most recent findings related to cAMP activation of PKA and EPAC, which are implicated in Treg homeostasis as well as the functional alterations induced by cAMP in cellular targets of Treg suppression. PMID:27313580

  20. CD8α+β− and CD8α+β+ plasmacytoid dendritic cells induce Foxp3+ regulatory T cells and prevent the induction of airway hyperreactivity

    PubMed Central

    Lombardi, Vincent; Speak, Anneliese O.; Kerzerho, Jérôme; Szely, Natacha; Akbari, Omid

    2012-01-01

    Dendritic cells (DCs) control the balance between protection against pathogens and tolerance to innocuous or self-antigens. Here, we demonstrate for the first time that mouse plasmacytoid DCs (pDCs) can be segregated into three distinct populations, exhibiting phenotypic and functional differences, according to their surface expression of CD8α or CD8β as CD8α−β−, CD8α+β− or CD8α+β+. In a mouse model of lung inflammation, adoptive transfer of CD8α+β− or CD8α+β+ pDCs prevents the development of airway hyperreactivity. The tolerogenic features of these subsets are associated with increased production of retinoic acid, which leads to the enhanced induction of Foxp3+ regulatory T cells compared to CD8α−β− pDCs. Our data thus identify subsets of pDCs with potent tolerogenic functions that may contribute to the maintenance of tolerance in mucosal sites such as the lungs. PMID:22472775

  1. Chlamydia pneumoniae infection induced allergic airway sensitization is controlled by regulatory T-cells and plasmacytoid dendritic cells.

    PubMed

    Crother, Timothy R; Schröder, Nicolas W J; Karlin, Justin; Chen, Shuang; Shimada, Kenichi; Slepenkin, Anatoly; Alsabeh, Randa; Peterson, Ellena; Arditi, Moshe

    2011-01-01

    Chlamydia pneumoniae (CP) is associated with induction and exacerbation of asthma. CP infection can induce allergic airway sensitization in mice in a dose- and time-dependent manner. Allergen exposure 5 days after a low dose (mild-moderate), but not a high dose (severe) CP infection induces antigen sensitization in mice. Innate immune signals play a critical role in controlling CP infection induced allergic airway sensitization, however these mechanisms have not been fully elucidated. Wild-type, TLR2-/-, and TLR4-/- mice were infected intranasally (i.n.) with a low dose of CP, followed by i.n. exposure to human serum albumin (HSA) and challenged with HSA 2 weeks later. Airway inflammation, immunoglobulins, eosinophils, and goblet cells were measured. Low dose CP infection induced allergic sensitization in TLR2-/- mice, but not in TLR4-/- mice, due to differential Treg responses in these genotypes. TLR2-/- mice had reduced numbers of Tregs in the lung during CP infection while TLR4-/- mice had increased numbers. High dose CP infection resulted in an increase in Tregs and pDCs in lungs, which prevented antigen sensitization in WT mice. Depletion of Tregs or pDCs resulted in allergic airway sensitization. We conclude that Tregs and pDCs are critical determinants regulating CP infection-induced allergic sensitization. Furthermore, TLR2 and TLR4 signaling during CP infection may play a regulatory role through the modulation of Tregs. PMID:21695198

  2. Peptidoglycan recognition protein 1 enhances experimental asthma by promoting Th2 and Th17 and limiting regulatory T cell and plasmacytoid dendritic cell responses.

    PubMed

    Park, Shin Yong; Jing, Xuefang; Gupta, Dipika; Dziarski, Roman

    2013-04-01

    Asthma is a common inflammatory disease involving cross-talk between innate and adaptive immunity. We reveal that antibacterial innate immunity protein, peptidoglycan recognition protein (Pglyrp)1, is involved in the development of allergic asthma. Pglyrp1(-/-) mice developed less severe asthma than wild-type (WT) mice following sensitization with house dust mite (allergen) (HDM). HDM-sensitized Pglyrp1(-/-) mice, compared with WT mice, had diminished bronchial hyperresponsiveness (lung airway resistance); numbers of eosinophils, neutrophils, lymphocytes, and macrophages in bronchoalveolar lavage fluid and lungs; inflammatory cell infiltrates in the lungs around bronchi, bronchioles, and pulmonary arteries and veins; lung remodeling (mucin-producing goblet cell hyperplasia and metaplasia and smooth muscle hypertrophy and fibrosis); levels of IgE, eotaxins, IL-4, IL-5, and IL-17 in the lungs; and numbers of Th2 and Th17 cells and expression of their marker genes in the lungs. The mechanism underlying this decreased sensitivity of Pglyrp1(-/-) mice to asthma was increased generation and activation of CD8α(+)β(+) and CD8α(+)β(-) plasmacytoid dendritic cells (pDC) and increased recruitment and activity of regulatory T (Treg) cells in the lungs. In vivo depletion of pDC in HDM-sensitized Pglyrp1(-/-) mice reversed the low responsive asthma phenotype of Pglyrp1(-/-) mice to resemble the more severe WT phenotype. Thus, Pglyrp1(-/-) mice efficiently control allergic asthma by upregulating pDC and Treg cells in the lungs, whereas in WT mice, Pglyrp1 is proinflammatory and decreases pDC and Treg cells and increases proasthmatic Th2 and Th17 responses. Blocking Pglyrp1 or enhancing pDC in the lungs may be beneficial for prevention and treatment of asthma. PMID:23420883

  3. Clonorchis sinensis-derived total protein attenuates airway inflammation in murine asthma model by inducing regulatory T cells and modulating dendritic cell functions.

    PubMed

    Jeong, Young-Il; Kim, Seung Hyun; Ju, Jung Won; Cho, Shin Hyeong; Lee, Won Ja; Park, Jin Wook; Park, Yeong-Min; Lee, Sang Eun

    2011-04-22

    Asthma is characterized by Th2-mediated inflammation, resulting in airway hyperresponsiveness (AHR) through airway remodeling. Recent epidemiological and experimental reports have suggested an inverse relationship between the development of allergy and helminth infections. Infection by Clonorchis sinensis, a liver fluke that resides in the bile duct of humans, is endemic predominantly in Asia including Korea and China. Using a murine model for asthma, we investigated the effects of C. sinensis-derived total protein (Cs-TP) on allergen-induced airway inflammation and the mechanism underlying the protective effects of Cs-TP administration on asthma. Treatment with Cs-TP attenuated OVA-induced airway inflammation and methacholine-induced AHR, as well as eosinophilia development, lymphocyte infiltration into the lung, and goblet cell metaplasia. This protective effect of Cs-TP is associated with markedly reduced OVA-specific IgE and Th1/Th2 cytokine production. Moreover, Cs-TP increased the number of CD4(+)CD25(+)Foxp3(+) regulatory T (Treg) cells as well as their suppressive activity. In fact, proliferation of OVA-restimulated splenocytes was suppressed significantly. Cs-TP also inhibited the expression of such co-stimulatory molecules as CD80, CD86, and CD40 in LPS- or OVA-stimulated dendritic cells (DCs), suggesting that Cs-TP could interfere with the capacity of airway DCs to prime naïve T cells. These data demonstrate the capacity of C. sinensis to ameliorate allergic asthma and broaden our understanding of the paradoxical relationship between the allergic immune response and helminth infection. PMID:21440530

  4. Low-dose temozolomide before dendritic-cell vaccination reduces (specifically) CD4+CD25++Foxp3+ regulatory T-cells in advanced melanoma patients

    PubMed Central

    2013-01-01

    Background In cancer immunotherapy, dendritic cells (DCs) play a fundamental role in the dialog between innate and adaptive immune response, but several immunosuppressive mechanisms remain to be overcome. For example, a high number of CD4+CD25++Foxp3+ regulatory T-cells (Foxp3+Tregs) have been observed in the peripheral blood and tumor microenvironment of cancer patients. On the basis of this, we conducted a study on DC-based vaccination in advanced melanoma, adding low-dose temozolomide to obtain lymphodepletion. Methods Twenty-one patients were entered onto our vaccination protocol using autologous DCs pulsed with autologous tumor lysate and keyhole limpet hemocyanin. Patients received low-dose temozolomide before vaccination and 5 days of low-dose interleukin-2 (IL-2) after vaccination. Circulating Foxp3+Tregs were evaluated before and after temozolomide, and after IL-2. Results Among the 17 evaluable patients we observed 1 partial response (PR), 6 stable disease (SD) and 10 progressive disease (PD). The disease control rate (PR+SD = DCR) was 41% and median overall survival was 10 months. Temozolomide reduced circulating Foxp3+Treg cells in all patients. A statistically significant reduction of 60% was observed in Foxp3+Tregs after the first cycle, whereas the absolute lymphocyte count decreased by only 14%. Conversely, IL-2 increased Foxp3+Treg cell count by 75.4%. Of note the effect of this cytokine, albeit not statistically significant, on the DCR subgroup led to a further 33.8% reduction in Foxp3+Treg cells. Conclusions Our results suggest that the combined immunological therapy, at least as far as the DCR subgroup is concerned, effectively reduced the number of Foxp3+Treg cells, which exerted a blunting effect on the growth-stimulating effect of IL-2. However, this regimen, with its current modality, would not seem to be capable of improving clinical outcome. PMID:23725550

  5. Regulation of IFN regulatory factor-7 and IFN-alpha production by enveloped virus and lipopolysaccharide in human plasmacytoid dendritic cells.

    PubMed

    Dai, Jihong; Megjugorac, Nicholas J; Amrute, Sheela B; Fitzgerald-Bocarsly, Patricia

    2004-08-01

    Human plasmacytoid dendritic cells (PDC) are a major source of IFN-alpha upon exposure to enveloped viruses and TLR-7 and TLR-9 ligands. Although IFN regulatory factor-7 (IRF-7) is known to play an essential role in virus-activated transcription of IFN-alpha genes, the molecular mechanisms of IFN-alpha production in human PDC remain poorly understood. We and others have recently reported high constitutive levels of IRF-7 expression in PDC as compared with other PBMC. In this study, we demonstrate that both LPS and HSV up-regulate the expression of IRF-7 in PDC, and that this enhancement of IRF-7 is dependent on NF-kappa B activation. The NF-kappa B inhibitors MG132 and pyrrolidinedithiocarbamate efficiently inhibited the induction of IRF-7 by HSV or LPS, and also down-regulated the constitutive expression of IRF-7 in PDC and blocked the HSV-induced production of IFN-alpha. In addition, we found that nuclear translocation of IRF-7 occurred rapidly in response to HSV stimulation, but not in response to LPS, which is consistent with the stimulation of IFN-alpha production by virus and not by LPS. Although LPS by itself was not able to induce IFN-alpha production, it led to rapid up-regulation of TLR-4 on PDC and increased the magnitude and accelerated the kinetics of HSV-induced IFN-alpha production in PDC, providing a mechanism that might be operative in a scenario of mixed infection. In contrast to the current concept of IFN-alpha regulation established in cell lines, this study strongly supports the immediate availability of high constitutive levels of IRF-7 expression in PDC, and suggests an activation required for IRF-7 that contributes to IFN-alpha production in virus-stimulated PDC. PMID:15265881

  6. Dendritic cell-specific disruption of TGFβ receptor II leads to altered regulatory T-cell phenotype and spontaneous multi-organ autoimmunity

    PubMed Central

    Ramalingam, Rajalakshmy; Larmonier, Claire B.; Thurston, Robert D.; Midura-Kiela, Monica T.; Zheng, Song Guo; Ghishan, Fayez K.; Kiela, Pawel R.

    2012-01-01

    In vitrodata and transgenic mouse models suggest a role for TGFβ signaling in dendritic cells (DC) to prevent autoimmunity primarily through maintenance of DCs in their immature and tolerogenic state characterized by low expression of MHCII and co-stimulatory molecules, and increased expression of indoleamine 2,3-dioxygenase (IDO), among others. To test whether a complete lack of TGFβ signaling in DCs predisposes mice to spontaneous autoimmunity, and to verify the mechanisms implicated previously in vitro, we generated conditional knock-out mice with Cre-mediated DC-specific deletion of Tgfbr2 (DC-Tgfbr2 KO). DC-Tgfbr2 KO mice die before 15 weeks of age with multi-organ autoimmune inflammation and spontaneous activation of T and B cells. Interestingly, there were no significant differences in the expression of MHCII, co-stimulatory molecules, or IDO in secondary lymphoid organ DCs, although Tgfbr2-deficient DCs were more pro-inflammatory in vitro and in vivo. DC-Tgfbr2 KO showed attenuated FoxP3 expression in regulatory T cells (Tregs) and abnormal expansion of CD25−FoxP3+ Tregs in vivo. Tgfbr2-deficient DCs secreted elevated levels of IFNγ and were not capable of directing antigen-specific Treg conversion unless in the presence of anti-IFNγ blocking antibody. Adoptive transfer of iTregs into DC-Tgfbr2 KO mice partially rescued the phenotype. Therefore, in vivo, TGFβ signaling in DCs is critical in the control of autoimmunity through both Treg dependent and independent mechanisms, but it does not affect MHCII and co-stimulatory molecule expression. PMID:22972928

  7. Clonorchis sinensis-derived total protein attenuates airway inflammation in murine asthma model by inducing regulatory T cells and modulating dendritic cell functions

    SciTech Connect

    Jeong, Young-Il; Kim, Seung Hyun; Ju, Jung Won; Cho, Shin Hyeong; Lee, Won Ja; Park, Jin Wook; Park, Yeong-Min; Lee, Sang Eun

    2011-04-22

    Highlights: {yields} Treatment with Clonorchis sinensis-derived total protein attenuates OVA-induced airway inflammation and AHR to methacholine. {yields} Induction of CD4{sup +}CD25{sup +}Foxp3{sup +} T cells and IL-10 along with suppression of splenocyte proliferation by C. sinensis-derived total protein. {yields} C. sinensis-derived total protein interferes with the expression of co-stimulatory molecules in DCs. -- Abstract: Asthma is characterized by Th2-mediated inflammation, resulting in airway hyperresponsiveness (AHR) through airway remodeling. Recent epidemiological and experimental reports have suggested an inverse relationship between the development of allergy and helminth infections. Infection by Clonorchis sinensis, a liver fluke that resides in the bile duct of humans, is endemic predominantly in Asia including Korea and China. Using a murine model for asthma, we investigated the effects of C. sinensis-derived total protein (Cs-TP) on allergen-induced airway inflammation and the mechanism underlying the protective effects of Cs-TP administration on asthma. Treatment with Cs-TP attenuated OVA-induced airway inflammation and methacholine-induced AHR, as well as eosinophilia development, lymphocyte infiltration into the lung, and goblet cell metaplasia. This protective effect of Cs-TP is associated with markedly reduced OVA-specific IgE and Th1/Th2 cytokine production. Moreover, Cs-TP increased the number of CD4{sup +}CD25{sup +}Foxp3{sup +} regulatory T (Treg) cells as well as their suppressive activity. In fact, proliferation of OVA-restimulated splenocytes was suppressed significantly. Cs-TP also inhibited the expression of such co-stimulatory molecules as CD80, CD86, and CD40 in LPS- or OVA-stimulated dendritic cells (DCs), suggesting that Cs-TP could interfere with the capacity of airway DCs to prime naive T cells. These data demonstrate the capacity of C. sinensis to ameliorate allergic asthma and broaden our understanding of the paradoxical

  8. Regulation of calcium signaling in dendritic cells by 1,25-dihydroxyvitamin D3.

    PubMed

    Shumilina, Ekaterina; Xuan, Nguyen Thi; Matzner, Nicole; Bhandaru, Madhuri; Zemtsova, Irina M; Lang, Florian

    2010-06-01

    Dendritic cells (DCs) are antigen-presenting cells that provide a link between innate and adaptive immunity. Ca(2+)-dependent signaling plays a central regulatory role in DC responses to diverse antigens. DCs are a primary target of 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)], a secosteroid hormone, that, in addition to its well-established action on Ca(2+) homeostasis, possesses immunomodulatory properties. Surprisingly, nothing is known about its effects on DC cytosolic Ca(2+) activity. The present study explored whether 1,25(OH)(2)D(3) modifies the intracellular Ca(2+) concentration ([Ca(2+)](i)) in DCs. Here we show that mouse DCs expressed K(+)-independent (NCX1-3) and K(+)-dependent (NCKX1, 3, 4, and 5) Na(+)/Ca(2+) exchangers. Acute application of LPS (100 ng/ml) to DCs increased [Ca(2+)](i), an effect significantly blunted by prior incubation with 1,25(OH)(2)D(3). 1,25(OH)(2)D(3) increased the membrane abundance of the NCKX1 protein, up-regulated the K(+)- and Na(+)-dependent Ca(2+) entry and enhanced the K(+)-dependent Na(+)/Ca(2+) exchanger currents. The NCKX blocker 3',4'-dichlorobenzamyl (DBZ) reversed the inhibitory effect of 1,25(OH)(2)D(3) on the LPS-induced increase of [Ca(2+)](i). Expression of the costimulatory molecule CD86 was down-regulated by 1,25(OH)(2)D(3), an effect reversed by DBZ. In summary, 1,25(OH)(2)D(3) blunts the LPS-induced increase in [Ca(2+)](i) by stimulation of Na(+)/Ca(2+) exchanger-dependent Ca(2+) extrusion, an effect that contributes to 1,25(OH)(2)D(3)-mediated immunosuppression. The results disclose completely novel mechanisms in the regulation of DC maturation and function. PMID:20124438

  9. 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.

  10. 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.

  11. Dendrite Model

    NASA Technical Reports Server (NTRS)

    1999-01-01

    Dr. Donald Gilles, the Discipline Scientist for Materials Science in NASA's Microgravity Materials Science and Applications Department, demonstrates to Carl Dohrman a model of dendrites, the branch-like structures found in many metals and alloys. Dohrman was recently selected by the American Society for Metals International as their 1999 ASM International Foundation National Merit Scholar. The University of Illinois at Urbana-Champaign freshman recently toured NASA's materials science facilities at the Marshall Space Flight Center.

  12. Uptake of donor lymphocytes treated with 8-methoxypsoralen and ultraviolet A light by recipient dendritic cells induces CD4{sup +}CD25{sup +}Foxp3{sup +} regulatory T cells and down-regulates cardiac allograft rejection

    SciTech Connect

    Zheng, De-Hua; Dou, Li-Ping; Wei, Yu-Xiang; Du, Guo-Sheng; Zou, Yi-Ping; Song, Ji-Yong; Zhu, Zhi-Dong; Cai, Ming; Qian, Ye-Yong; Shi, Bing-Yi

    2010-05-14

    Extracorporeal photopheresis (ECP) is an effective immunomodulatory therapy and has been demonstrated to be beneficial for graft-vs-host disease and solid-organ allograft rejection. ECP involves reinfusion of a patient's autologous peripheral blood leukocytes treated ex vivo with 8-methoxypsoralen and UVA light radiation (PUVA). Previous studies focused only on ECP treatment of recipient immune cells. Our study is the first to extend the target of ECP treatment to donor immune cells. The results of in vitro co-culture experiments demonstrate uptake of donor PUVA-treated splenic lymphocytes (PUVA-SPs) by recipient immature dendritic cells (DCs). Phagocytosis of donor PUVA-SPs does not stimulate phenotype maturation of recipient DCs. In the same co-culture system, donor PUVA-SPs enhanced production of interleukin-10 and interferon-{gamma} by recipient DCs and impaired the subsequent capability of recipient DCs to stimulate recipient naive T cells. Phagocytosis of donor PUVA-SP (PUVA-SP DCs) by recipient DCs shifted T-cell responses in favor of T helper 2 cells. Infusion of PUVA-SP DCs inhibited cardiac allograft rejection in an antigen-specific manner and induced CD4{sup +}CD25{sup high}Foxp3{sup +} regulatory T cells. In conclusion, PUVA-SP DCs simultaneously deliver the donor antigen and the regulatory signal to the transplant recipient, and thus can be used to develop a novel DC vaccine for negative immune regulation and immune tolerance induction.

  13. Identification of a novel basic helix-loop-helix-PAS factor, NXF, reveals a Sim2 competitive, positive regulatory role in dendritic-cytoskeleton modulator drebrin gene expression.

    PubMed

    Ooe, Norihisa; Saito, Koichi; Mikami, Nobuyoshi; Nakatuka, Iwao; Kaneko, Hideo

    2004-01-01

    Sim2, a basic helix-loop-helix (bHLH)-PAS transcriptional repressor, is thought to be involved in some symptoms of Down's syndrome. In the course of searching for hypothetical Sim2 relatives, we isolated another bHLH-PAS factor, NXF. NXF was a novel gene and was selectively expressed in neuronal tissues. While no striking homolog of NXF was found in vertebrates, a Caenorhabditis elegans putative transcription factor, C15C8.2, showed similarity in the bHLH-PAS domain. NXF had an activation domain as a transcription activator, and Arnt-type bHLH-PAS subfamily members were identified as the heterodimer partners of NXF. The NXF/Arnt heterodimer was capable of binding and activating a subset of Sim2/Arnt target DNA variants, and Sim2 could compete with the NXF activity on the elements. We showed that Drebrin had several such NXF/Arnt binding elements on the promoter, which could be direct or indirect cross talking points between NXF (activation) and Sim2 (repression) action. Drebrin has been reported to be engaged in dendritic-cytoskeleton modulation at synapses, and such a novel NXF signaling system on neural gene promoter may be a molecular target of the adverse effects of Sim2 in the mental retardation of Down's syndrome. PMID:14701734

  14. Dominating expression of negative regulatory factors downmodulates major histocompatibility complex Class-II expression on dendritic cells in chronic hepatitis C infection

    PubMed Central

    Tomer, Shallu; Chawla, Yogesh K; Duseja, Ajay; Arora, Sunil K

    2016-01-01

    AIM: To elucidate the molecular mechanisms leading to development of functionally impaired dendritic cells (DCs) in chronic hepatitis C (CHC) patients infected with genotype 3 virus. METHODS: This prospective study was conducted on the cohorts of CHC individuals identified as responders or non-responders to antiviral therapy. Myeloid DCs were isolated from the peripheral blood of each subject using CD1c (BDCA1)+ DC isolation Kit. Monocytes from healthy donor were cultured with DC growth factors such as IL-4 and GM-CSF either in the presence or absence of hepatitis C virus (HCV) viral proteins followed by LPS stimulation. Phenotyping was done by flowcytometry and gene expression profiling was evaluated by real-time PCR. RESULTS: Non-responders [sustained virological response (SVR)-ve] to conventional antiviral therapy had significantly higher expression of genes associated with interferon responsive element such as IDO1 and PD-L1 (6-fold) and negative regulators of JAK-STAT pathway such as SOCS (6-fold) as compared to responders (SVR+ve) to antiviral therapy. The down-regulated genes in non-responders included factors involved in antigen processing and presentation mainly belonging to major histocompatibility complex (MHC) Class-II family as HLA-DP, HLA-DQ (2-fold) and superoxide dismutase (2-fold). Cells grown in the presence of HCV viral proteins had genes down-regulated for factors involved in innate response, interferon signaling, DC maturation and co-stimulatory signaling to T-cells, while the genes for cytokine signaling and Toll-like receptors (4-fold) were up-regulated as compared to cells grown in absence of viral proteins. CONCLUSION: Underexpressed MHC class-II genes and upregulated negative regulators in non-responders indicate diminished capacity to present antigen and may constitute mechanism of functionally defective state of DCs. PMID:27298560

  15. Human Dendritic Cell DC-SIGN and TLR-2 Mediate Complementary Immune Regulatory Activities in Response to Lactobacillus rhamnosus JB-1

    PubMed Central

    Konieczna, Patrycja; Schiavi, Elisa; Ziegler, Mario; Groeger, David; Healy, Selena; Grant, Ray; O’Mahony, Liam

    2015-01-01

    The microbiota is required for optimal host development and ongoing immune homeostasis. Lactobacilli are common inhabitants of the mammalian large intestine and immunoregulatory effects have been described for certain, but not all, strains. The mechanisms underpinning these protective effects are beginning to be elucidated. One such protective organism is Lactobacillus rhamnosus JB-1 (Lb. rhamnosus JB-1). Lb. murinus has no such anti-inflammatory protective effects and was used as a comparator organism. Human monocyte-derived dendritic cells (MDDCs) were co-incubated with bacteria and analysed over time for bacterial adhesion and intracellular processing, costimulatory molecule expression, cytokine secretion and induction of lymphocyte polarization. Neutralising antibodies were utilized to identify the responsible MDDC receptors. Lb. rhamnosus JB-1 adhered to MDDCs, but internalization and intracellular processing was significantly delayed, compared to Lb. murinus which was rapidly internalized and processed. Lb. murinus induced CD80 and CD86 expression, accompanied by high levels of cytokine secretion, while Lb. rhamnosus JB-1 was a poor inducer of costimulatory molecule expression and cytokine secretion. Lb. rhamnosus JB-1 primed MDDCs induced Foxp3 expression in autologous lymphocytes, while Lb. murinus primed MDDCs induced Foxp3, T-bet and Ror-γt expression. DC-SIGN was required for Lb. rhamnosus JB-1 adhesion and influenced IL-12 secretion, while TLR-2 influenced IL-10 and IL-12 secretion. Here we demonstrate that the delayed kinetics of bacterial processing by MDDCs correlates with MDDC activation and stimulation of lymphocytes. Thus, inhibition or delay of intracellular processing may be a novel strategy by which certain commensals may avoid the induction of proinflammatory responses. PMID:25816321

  16. Human dendritic cell DC-SIGN and TLR-2 mediate complementary immune regulatory activities in response to Lactobacillus rhamnosus JB-1.

    PubMed

    Konieczna, Patrycja; Schiavi, Elisa; Ziegler, Mario; Groeger, David; Healy, Selena; Grant, Ray; O'Mahony, Liam

    2015-01-01

    The microbiota is required for optimal host development and ongoing immune homeostasis. Lactobacilli are common inhabitants of the mammalian large intestine and immunoregulatory effects have been described for certain, but not all, strains. The mechanisms underpinning these protective effects are beginning to be elucidated. One such protective organism is Lactobacillus rhamnosus JB-1 (Lb. rhamnosus JB-1). Lb. murinus has no such anti-inflammatory protective effects and was used as a comparator organism. Human monocyte-derived dendritic cells (MDDCs) were co-incubated with bacteria and analysed over time for bacterial adhesion and intracellular processing, costimulatory molecule expression, cytokine secretion and induction of lymphocyte polarization. Neutralising antibodies were utilized to identify the responsible MDDC receptors. Lb. rhamnosus JB-1 adhered to MDDCs, but internalization and intracellular processing was significantly delayed, compared to Lb. murinus which was rapidly internalized and processed. Lb. murinus induced CD80 and CD86 expression, accompanied by high levels of cytokine secretion, while Lb. rhamnosus JB-1 was a poor inducer of costimulatory molecule expression and cytokine secretion. Lb. rhamnosus JB-1 primed MDDCs induced Foxp3 expression in autologous lymphocytes, while Lb. murinus primed MDDCs induced Foxp3, T-bet and Ror-γt expression. DC-SIGN was required for Lb. rhamnosus JB-1 adhesion and influenced IL-12 secretion, while TLR-2 influenced IL-10 and IL-12 secretion. Here we demonstrate that the delayed kinetics of bacterial processing by MDDCs correlates with MDDC activation and stimulation of lymphocytes. Thus, inhibition or delay of intracellular processing may be a novel strategy by which certain commensals may avoid the induction of proinflammatory responses. PMID:25816321

  17. Depletion of Regulatory T Cells Induces High Numbers of Dendritic Cells and Unmasks a Subset of Anti-Tumour CD8+CD11c+ PD-1lo Effector T Cells.

    PubMed

    Goudin, Nicolas; Chappert, Pascal; Mégret, Jérome; Gross, David-Alexandre; Rocha, Benedita; Azogui, Orly

    2016-01-01

    Natural regulatory T (Treg) cells interfere with multiple functions, which are crucial for the development of strong anti-tumour responses. In a model of 4T1 mammary carcinoma, depletion of CD25+Tregs results in tumour regression in Balb/c mice, but the mechanisms underlying this process are not fully understood. Here, we show that partial Treg depletion leads to the generation of a particular effector CD8 T cell subset expressing CD11c and low level of PD-1 in tumour draining lymph nodes. These cells have the capacity to migrate into the tumour, to kill DCs, and to locally regulate the anti-tumour response. These events are concordant with a substantial increase in CD11b+ resident dendritic cells (DCs) subsets in draining lymph nodes followed by CD8+ DCs. These results indicate that Treg depletion leads to tumour regression by unmasking an increase of DC subsets as a part of a program that optimizes the microenvironment by orchestrating the activation, amplification, and migration of high numbers of fully differentiated CD8+CD11c+PD1lo effector T cells to the tumour sites. They also indicate that a critical pattern of DC subsets correlates with the evolution of the anti-tumour response and provide a template for Treg depletion and DC-based therapy. PMID:27341421

  18. Depletion of Regulatory T Cells Induces High Numbers of Dendritic Cells and Unmasks a Subset of Anti-Tumour CD8+CD11c+ PD-1lo Effector T Cells

    PubMed Central

    Goudin, Nicolas; Chappert, Pascal; Mégret, Jérome; Gross, David-Alexandre; Rocha, Benedita

    2016-01-01

    Natural regulatory T (Treg) cells interfere with multiple functions, which are crucial for the development of strong anti-tumour responses. In a model of 4T1 mammary carcinoma, depletion of CD25+Tregs results in tumour regression in Balb/c mice, but the mechanisms underlying this process are not fully understood. Here, we show that partial Treg depletion leads to the generation of a particular effector CD8 T cell subset expressing CD11c and low level of PD-1 in tumour draining lymph nodes. These cells have the capacity to migrate into the tumour, to kill DCs, and to locally regulate the anti-tumour response. These events are concordant with a substantial increase in CD11b+ resident dendritic cells (DCs) subsets in draining lymph nodes followed by CD8+ DCs. These results indicate that Treg depletion leads to tumour regression by unmasking an increase of DC subsets as a part of a program that optimizes the microenvironment by orchestrating the activation, amplification, and migration of high numbers of fully differentiated CD8+CD11c+PD1lo effector T cells to the tumour sites. They also indicate that a critical pattern of DC subsets correlates with the evolution of the anti-tumour response and provide a template for Treg depletion and DC-based therapy. PMID:27341421

  19. Isothermal Dendritic Growth Experiment - PVA Dendrites

    NASA Technical Reports Server (NTRS)

    1997-01-01

    The Isothermal Dendritic Growth Experiment (IDGE), flown on three Space Shuttle missions, is yielding new insights into virtually all industrially relevant metal and alloy forming operations. IDGE used transparent organic liquids that form dendrites (treelike structures) similar to those inside metal alloys. Comparing Earth-based and space-based dendrite growth velocity, tip size and shape provides a better understanding of the fundamentals of dentritic growth, including gravity's effects. Shalowgraphic images of pivalic acid (PVA) dendrites forming from the melt show the subtle but distinct effects of gravity-driven heat convection on dentritic growth. In orbit, the dendrite grows as its latent heat is liberated by heat conduction. This yields a blunt dendrite tip. On Earth, heat is carried away by both conduction and gravity-driven convection. This yields a sharper dendrite tip. In addition, under terrestrial conditions, the sidebranches growing in the direction of gravity are augmented as gravity helps carry heat out of the way of the growing sidebranches as opposed to microgravity conditions where no augmentation takes place. IDGE was developed by Rensselaer Polytechnic Institute and NASA/Glenn Research Center. Advanced follow-on experiments are being developed for flight on the International Space Station. Photo Credit: NASA/Glenn Research Center

  20. Free dendritic growth

    NASA Technical Reports Server (NTRS)

    Glicksman, M. E.

    1984-01-01

    Free dendritic growth refers to the unconstrained development of crystals within a supercooled melt, which is the classical 'dendrite problem'. Great strides have been taken in recent years in both the theoretical understanding of dendritic growth and its experimental status. The development of this field will be sketched, showing that transport theory and interfacial thermodynamics (capillarity theory) were sufficient ingredients to develop a truly predictive model of dendrite formation. The convenient, but incorrect, notion of 'maximum velocity' was used for many years to estimate the behavior of dendritic transformations until supplanted by modern dynamic stability theory. The proper combinations of transport theory and morphological stability seem to able to predict the salient aspects of dendritic growth, especially in the neighborhood of the tip. The overall development of cast microstructures, such as equiaxed zone formation, rapidly solidified microstructures, etc., also seems to contain additional non-deterministic features which lie outside the current theories discussed here.

  1. The PD-L1/CD86 ratio is increased in dendritic cells co-infected with porcine circovirus type 2 and porcine reproductive and respiratory syndrome virus, and the PD-L1/PD-1 axis is associated with anergy, apoptosis, and the induction of regulatory T-cells in porcine lymphocytes.

    PubMed

    Richmond, O; Cecere, T E; Erdogan, E; Meng, X J; Piñeyro, P; Subramaniam, S; Todd, S M; LeRoith, T

    2015-11-18

    Porcine circovirus type 2 (PCV2) and porcine reproductive and respiratory syndrome virus (PRRSV) continue to have a negative economic impact on global swine production operations. Host immune modulations that potentiate disease during PCV2 and/or PRRSV infections are important areas of ongoing research. In this study, we evaluated the expression levels of PD-L1, CD86, and IL-10 in order to phenotype dendritic cells following viral infection with PCV2b and/or PRRSV. The results showed that the inhibitory marker PD-L1 was significantly increased in monocyte derived dendritic cells (MoDC) in both singular PCV2 infection and PCV2/PRRSV co-infections. MoDC expression of stimulatory marker CD86 was significantly increased during singular PCV2 infections, while it was significantly decreased in the treatment groups co-infected with both PCV2 and PRRSV. IL-10 production was highest among MoDCs that were co-infected with PCV2 and PRRSV. These results indicate that dendritic cells develop a regulatory phenotype following PCV2/PRRSV co-infections. We further investigated the role of the PD-L1/PD-1 axis in lymphocyte anergy, apoptosis, and the induction of regulatory T-cells in porcine mononuclear cell populations. Lymphocyte populations with normal PD-1 expression had higher percentages of anergic, apoptotic lymphocytes and CD4(+)CD25(HIGH)FoxP3(+) regulatory T-cells when compared to a PD-1 deficient lymphocyte population. These results implicate the PD-L1/PD-1 axis in negative regulation of lymphocyte responses in pigs. PMID:26446939

  2. Dendritic Growth Investigators

    NASA Technical Reports Server (NTRS)

    2000-01-01

    Representatives of NASA materials science experiments supported the NASA exhibit at the Rernselaer Polytechnic Institute's Space Week activities, April 5 through 11, 1999. From left to right are: Angie Jackman, project manager at NASA's Marshall Space Flight Center for dendritic growth experiments; Dr. Martin Glicksman of Rennselaer Polytechnic Instutute, Troy, NY, principal investigator on the Isothermal Dendritic Growth Experiment (IDGE) that flew three times on the Space Shuttle; and Dr. Matthew Koss of College of the Holy Cross in Worcester, MA, a co-investigator on the IDGE and now principal investigator on the Transient Dendritic Solidification Experiment being developed for the International Space Station (ISS). The image at far left is a dendrite grown in Glicksman's IDGE tests aboard the Shuttle. Glicksman is also principal investigator for the Evolution of Local Microstructures: Spatial Instabilities of Coarsening Clusters.

  3. On the dendrites and dendritic transitions in undercooled germanium

    SciTech Connect

    Lau, C.F.; Kui, H.W. . Dept. of Physics)

    1993-07-01

    Undercooled molten Ge was allowed to solidify at initial bulk undercoolings, [Delta]T, from 10 to 200C under dehydrated boron oxide flux. It turned out that in addition to the (211) twin dendrite found by Billig and the (100) twin-free dendrite discovered by Devaud and Turnbill, there is a third novel twin dendrite, the (110) twin dendrite. The twin planes in a (110) dendrite always appear in multiple numbers and the orientation is (111). These different kinds of dendrites exist at different initial interfacial undercoolings and the transition temperatures for (110) to (211), (211) to (100) are [Delta]T = 61 and 93C, respectively.

  4. Isothermal Dendritic Growth Experiment - SCN Dendrites

    NASA Technical Reports Server (NTRS)

    1995-01-01

    The Isothermal Dendritic Growth Experiment (IDGE), flown on three Space Shuttle missions, is yielding new insights into virtually all industrially relevant metal and alloy forming operations. IDGE used transparent organic liquids that form dendrites (treelike structures) similar to the crystals that form inside metal alloys. Comparing Earth-based and space-based dentrite growth velocity, tip size and shape provid a better understanding of the fundamentals of dentritic growth, including gravity's effects. These shadowgraphic images show succinonitrile (SCN) dentrites growing in a melt (liquid). The space-grown crystals also have cleaner, better defined sidebranches. IDGE was developed by Rensselaer Polytechnic Institude (RPI) and NASA/ Glenn Research Center(GRC). Advanced follow-on experiments are being developed for flight on the International Space Station. Photo gredit: NASA/Glenn Research Center

  5. 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

  6. Dendritic Polymers for Theranostics

    PubMed Central

    Ma, Yuan; Mou, Quanbing; Wang, Dali; Zhu, Xinyuan; Yan, Deyue

    2016-01-01

    Dendritic polymers are highly branched polymers with controllable structures, which possess a large population of terminal functional groups, low solution or melt viscosity, and good solubility. Their size, degree of branching and functionality can be adjusted and controlled through the synthetic procedures. These tunable structures correspond to application-related properties, such as biodegradability, biocompatibility, stimuli-responsiveness and self-assembly ability, which are the key points for theranostic applications, including chemotherapeutic theranostics, biotherapeutic theranostics, phototherapeutic theranostics, radiotherapeutic theranostics and combined therapeutic theranostics. Up to now, significant progress has been made for the dendritic polymers in solving some of the fundamental and technical questions toward their theranostic applications. In this review, we briefly summarize how to control the structures of dendritic polymers, the theranostics-related properties derived from their structures and their theranostics-related applications. PMID:27217829

  7. Lithium Dendrite Formation

    SciTech Connect

    2015-03-06

    Scientists at the Department of Energy’s Oak Ridge National Laboratory have captured the first real-time nanoscale images of lithium dendrite structures known to degrade lithium-ion batteries. The ORNL team’s electron microscopy could help researchers address long-standing issues related to battery performance and safety. Video shows annular dark-field scanning transmission electron microscopy imaging (ADF STEM) of lithium dendrite nucleation and growth from a glassy carbon working electrode and within a 1.2M LiPF6 EC:DM battery electrolyte.

  8. Stability of dendritic arrays

    NASA Technical Reports Server (NTRS)

    Warren, James A.; Langer, J. S.

    1990-01-01

    An approximate method for studying steady-state properties and linear stability of the dendritic arrays that are formed in directional solidification of alloys is proposed. This analysis is valid at high growth rates where the primary spacing between dendrites is larger than the velocity-dependent solutal diffusion length. A neutral stability boundary is computed and it is found that, in the situations where the results should be valid, the experimental data of Somboonsuk, et al. (1984) lie in the stable region, well away from the boundary.

  9. Isothermal Dendritic Growth Experiment Video

    NASA Technical Reports Server (NTRS)

    1997-01-01

    This video, captured during the Isothermal Dendritic Growth Experiment (IDGE) flown on STS-87 as a part of the fourth United States Microgravity payload, shows the growth of a dendrite, and the surface solidification that occurred on the front and back windows of the growth chamber. Dendrites are tiny, tree like structures that form as metals solidify.

  10. Transport Processes in Dendritic Crystallization

    NASA Technical Reports Server (NTRS)

    Glicksman, M. E.

    1984-01-01

    Free dentritic growth refers to the unconstrained development of crystals within a supercooled melt, which is the classical dendrite problem. The development of theoretical understanding of dendritic growth and its experimental status is sketched showing that transport theory and interfacial thermodynamics (capillarity theory) are insufficient ingredients to develop a truly predictive model of dendrite formation. The convenient, but incorrect, notion of maximum velocity was used for many years to estimate the behavior of dendritic transformations until supplanted by modern dynamic stability theory. The proper combinations of transport theory and morphological stability seem to be able to predict the salient aspects of dendritic growth, especially in the neighborhood of the tip.

  11. Modification of dendritic development.

    PubMed

    Feria-Velasco, Alfredo; del Angel, Alma Rosa; Gonzalez-Burgos, Ignacio

    2002-01-01

    Since 1890 Ramón y Cajal strongly defended the theory that dendrites and their processes and spines had a function of not just nutrient transport to the cell body, but they had an important conductive role in neural impulse transmission. He extensively discussed and supported this theory in the Volume 1 of his extraordinary book Textura del Sistema Nervioso del Hombre y de los Vertebrados. Also, Don Santiago significantly contributed to a detailed description of the various neural components of the hippocampus and cerebral cortex during development. Extensive investigation has been done in the last Century related to the functional role of these complex brain regions, and their association with learning, memory and some limbic functions. Likewise, the organization and expression of neuropsychological qualities such as memory, exploratory behavior and spatial orientation, among others, depend on the integrity and adequate functional activity of the cerebral cortex and hippocampus. It is known that brain serotonin synthesis and release depend directly and proportionally on the availability of its precursor, tryptophan (TRY). By using a chronic TRY restriction model in rats, we studied their place learning ability in correlation with the dendritic spine density of pyramidal neurons in field CA1 of the hippocampus during postnatal development. We have also reported alterations in the maturation pattern of the ability for spontaneous alternation and task performance evaluating short-term memory, as well as adverse effects on the density of dendritic spines of hippocampal CA1 field pyramidal neurons and on the dendritic arborization and the number of dendritic spines of pyramidal neurons from the third layer of the prefrontal cortex using the same model of TRY restriction. The findings obtained in these studies employing a modified Golgi method, can be interpreted as a trans-synaptic plastic response due to understimulation of serotoninergic receptors located in the

  12. Silicon dendritic web material

    NASA Technical Reports Server (NTRS)

    Meier, D. L.; Campbell, R. B.; Sienkiewicz, L. J.; Rai-Choudhury, P.

    1982-01-01

    The development of a low cost and reliable contact system for solar cells and the fabrication of several solar cell modules using ultrasonic bonding for the interconnection of cells and ethylene vinyl acetate as the potting material for module encapsulation are examined. The cells in the modules were made from dendritic web silicon. To reduce cost, the electroplated layer of silver was replaced with an electroplated layer of copper. The modules that were fabricated used the evaporated Ti, Pd, Ag and electroplated Cu (TiPdAg/Cu) system. Adherence of Ni to Si is improved if a nickel silicide can be formed by heat treatment. The effectiveness of Ni as a diffusion barrier to Cu and the ease with which nickel silicide is formed is discussed. The fabrication of three modules using dendritic web silicon and employing ultrasonic bonding for interconnecting calls and ethylene vinyl acetate as the potting material is examined.

  13. 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

  14. Web-dendritic ribbon growth

    NASA Technical Reports Server (NTRS)

    Hilborn, R. B., Jr.; Faust, J. W., Jr.

    1976-01-01

    A web furnace was constructed for pulling dendritic-web samples. The effect of changes in the furnace thermal geometry on the growth of dendritic-web was studied. Several attempts were made to grow primitive dendrites for use as the dendritic seed crystals for web growth and to determine the optimum twin spacing in the dendritic seed crystal for web growth. Mathematical models and computer programs were used to determine the thermal geometries in the susceptor, crucible melt, meniscus, and web. Several geometries were determined for particular furnace geometries and growth conditions. The information obtained was used in conjunction with results from the experimental growth investigations in order to achieve proper conditions for sustained pulling of two dendrite web ribbons. In addition, the facilities for obtaining the following data were constructed: twin spacing, dislocation density, web geometry, resistivity, majority charge carrier type, and minority carrier lifetime.

  15. IDGE: Isothermal Dendritic Growth Experiment

    NASA Technical Reports Server (NTRS)

    1994-01-01

    The Isothermal Dendritic Growth Experiment (IDGE) flew on STS-62 to study the microscopic, tree-like structures (dendrites) that form within metals as they solidify from molten materials. The size, shape, and orientation of these dendrites affect the strength and usefulness of metals. Data from this experiment will be used to test and improve the mathematical models that support the industrial production of metals.

  16. 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

  17. 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

  18. Hepatitis C virus core protein inhibits interferon production by a human plasmacytoid dendritic cell line and dysregulates interferon regulatory factor-7 and signal transducer and activator of transcription (STAT) 1 protein expression.

    PubMed

    Stone, Amy E L; Mitchell, Angela; Brownell, Jessica; Miklin, Daniel J; Golden-Mason, Lucy; Polyak, Stephen J; Gale, Michael J; Rosen, Hugo R

    2014-01-01

    Plasmacytoid Dendritic Cells (pDCs) represent a key immune cell population in the defense against viruses. pDCs detect viral pathogen associated molecular patterns (PAMPs) through pattern recognition receptors (PRR). PRR/PAMP interactions trigger signaling events that induce interferon (IFN) production to initiate local and systemic responses. pDCs produce Type I and Type III (IFNL) IFNs in response to HCV RNA. Extracellular HCV core protein (Core) is found in the circulation in chronic infection. This study defined how Core modulates PRR signaling in pDCs. Type I and III IFN expression and production following exposure to recombinant Core or β-galactosiade was assessed in human GEN2.2 cells, a pDC cell line. Core suppressed type I and III IFN production in response to TLR agonists and the HCV PAMP agonist of RIG-I. Core suppression of IFN induction was linked with decreased IRF-7 protein levels and increased non-phosphorylated STAT1 protein. Circulating Core protein interferes with PRR signaling by pDCs to suppress IFN production. Strategies to define and target Core effects on pDCs may serve to enhance IFN production and antiviral actions against HCV. PMID:24788809

  19. Dendritic Alloy Solidification Experiment (DASE)

    NASA Technical Reports Server (NTRS)

    Beckermann, C.; Karma, A.; Steinbach, I.; deGroh, H. C., III

    2001-01-01

    A space experiment, and supporting ground-based research, is proposed to study the microstructural evolution in free dendritic growth from a supercooled melt of the transparent model alloy succinonitrile-acetone (SCN-ACE). The research is relevant to equiaxed solidification of metal alloy castings. The microgravity experiment will establish a benchmark for testing of equiaxed dendritic growth theories, scaling laws, and models in the presence of purely diffusive, coupled heat and solute transport, without the complicating influences of melt convection. The specific objectives are to: determine the selection of the dendrite tip operating state, i.e. the growth velocity and tip radius, for free dendritic growth of succinonitrile-acetone alloys; determine the growth morphology and sidebranching behavior for freely grown alloy dendrites; determine the effects of the thermal/solutal interactions in the growth of an assemblage of equiaxed alloy crystals; determine the effects of melt convection on the free growth of alloy dendrites; measure the surface tension anisotropy strength of succinon itrile -acetone alloys establish a theoretical and modeling framework for the experiments. Microgravity experiments on equiaxed dendritic growth of alloy dendrites have not been performed in the past. The proposed experiment builds on the Isothermal Dendritic Growth Experiment (IDGE) of Glicksman and coworkers, which focused on the steady growth of a single crystal from pure supercooled melts (succinonitrile and pivalic acid). It also extends the Equiaxed Dendritic Solidification Experiment (EDSE) of the present investigators, which is concerned with the interactions and transients arising in the growth of an assemblage of equiaxed crystals (succinonitrile). However, these experiments with pure substances are not able to address the issues related to coupled heat and solute transport in growth of alloy dendrites.

  20. 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

  1. Development of dendrite polarity in Drosophila neurons

    PubMed Central

    2012-01-01

    Background Drosophila neurons have dendrites that contain minus-end-out microtubules. This microtubule arrangement is different from that of cultured mammalian neurons, which have mixed polarity microtubules in dendrites. Results To determine whether Drosophila and mammalian dendrites have a common microtubule organization during development, we analyzed microtubule polarity in Drosophila dendritic arborization neuron dendrites at different stages of outgrowth from the cell body in vivo. As dendrites initially extended, they contained mixed polarity microtubules, like mammalian neurons developing in culture. Over a period of several days this mixed microtubule array gradually matured to a minus-end-out array. To determine whether features characteristic of dendrites were localized before uniform polarity was attained, we analyzed dendritic markers as dendrites developed. In all cases the markers took on their characteristic distribution while dendrites had mixed polarity. An axonal marker was also quite well excluded from dendrites throughout development, although this was perhaps more efficient in mature neurons. To confirm that dendrite character could be acquired in Drosophila while microtubules were mixed, we genetically disrupted uniform dendritic microtubule organization. Dendritic markers also localized correctly in this case. Conclusions We conclude that developing Drosophila dendrites initially have mixed microtubule polarity. Over time they mature to uniform microtubule polarity. Dendrite identity is established before the mature microtubule arrangement is attained, during the period of mixed microtubule polarity. PMID:23111238

  2. 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

  3. 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

  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. Optimal Current Transfer in Dendrites

    PubMed Central

    Bird, Alex D.

    2016-01-01

    Integration of synaptic currents across an extensive dendritic tree is a prerequisite for computation in the brain. Dendritic tapering away from the soma has been suggested to both equalise contributions from synapses at different locations and maximise the current transfer to the soma. To find out how this is achieved precisely, an analytical solution for the current transfer in dendrites with arbitrary taper is required. We derive here an asymptotic approximation that accurately matches results from numerical simulations. From this we then determine the diameter profile that maximises the current transfer to the soma. We find a simple quadratic form that matches diameters obtained experimentally, indicating a fundamental architectural principle of the brain that links dendritic diameters to signal transmission. PMID:27145441

  6. Transient Dendritic Solidification Experiment (TDSE)

    NASA Technical Reports Server (NTRS)

    2000-01-01

    The Transient Dendritic Solidification Expepriment (TDSE) is being developed as a candidate for flight aboard the International Space Station. TDSE will study the growth of dendrites (treelike crystalline structures) in a transparent material (succinonitrile or SCN) that mimics the behavior of widely used iron-based metals. Basic work by three Space Shuttle missions of the Isothermal Dendritic Growth Expepriment (IDGE) is yielding new insights into virtually all industrially relevant metal and alloy forming operations. The TDSE is similar to IDGE, but will maintain a constant temperature while varying pressure on the dendrites. Shown here is an exploded view of major elements of TDSE. A similar view is available with labels. The principal investigator is Matthew Koss of College of the Holy Cross in Worcester, MA. Photo credit: NASA/Marshall Space Flight Center (MSFC)

  7. Transient Dendritic Solidification Experiment (TDSE)

    NASA Technical Reports Server (NTRS)

    2000-01-01

    The Transient Dendritic Solidification Experiment (TDSE) is being developed as a candidate for flight aboard the International Space Station. TDSE will study the growth of dendrites (treelike crystalline structures) in a transparent material (succinonitrile or SCN) that mimics the behavior or widely used iron-based metals. Basic work by three Space Shuttle missions of the Isothermal Dendritic Growth Experiment (IDGE) is yielding new insights into virtually all industrially relevant metal and alloy forming operations. The TDSE is similar to IDGE, but will maintain a constant temperature while varying pressure on the dendrites. Shown here is an exploded view of major elements of the TDSE. A similar view is availble without labels. The principal investigator is Matthew Koss of College of the Holy Cross in Worcester, MA. Photo credit: NASA/Marshall Space Flight Center (MSFC)

  8. 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

  9. 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

  10. Lysophosphatidic acid induces osteocyte dendrite outgrowth

    SciTech Connect

    Karagiosis, Sue A.; Karin, Norm J.

    2007-05-25

    A method was developed to measure dendrite formation in bone cells. Lysophosphatidic acid (LPA) was found to stimulate dendrite outgrowth. It is postulated that LPA plays a role in regulating the osteocyte network in vivo.

  11. Mechanisms and Function of Dendritic Exocytosis

    PubMed Central

    Kennedy, Matthew J.; Ehlers, Michael D.

    2011-01-01

    Summary Dendritic exocytosis is required for a broad array of neuronal functions including retrograde signaling, neurotransmitter release, synaptic plasticity, and establishment of neuronal morphology. While the details of synaptic vesicle exocytosis from presynaptic terminals have been intensely studied for decades, the mechanisms of dendritic exocytosis are only now emerging. Here we review the molecules and mechanisms of dendritic exocytosis, and discuss how exocytosis from dendrites influences neuronal function and circuit plasticity. PMID:21382547

  12. An Inverse Approach for Elucidating Dendritic Function

    PubMed Central

    Torben-Nielsen, Benjamin; Stiefel, Klaus M.

    2010-01-01

    We outline an inverse approach for investigating dendritic function–structure relationships by optimizing dendritic trees for a priori chosen computational functions. The inverse approach can be applied in two different ways. First, we can use it as a “hypothesis generator” in which we optimize dendrites for a function of general interest. The optimization yields an artificial dendrite that is subsequently compared to real neurons. This comparison potentially allows us to propose hypotheses about the function of real neurons. In this way, we investigated dendrites that optimally perform input-order detection. Second, we can use it as a “function confirmation” by optimizing dendrites for functions hypothesized to be performed by classes of neurons. If the optimized, artificial, dendrites resemble the dendrites of real neurons the artificial dendrites corroborate the hypothesized function of the real neuron. Moreover, properties of the artificial dendrites can lead to predictions about yet unmeasured properties. In this way, we investigated wide-field motion integration performed by the VS cells of the fly visual system. In outlining the inverse approach and two applications, we also elaborate on the nature of dendritic function. We furthermore discuss the role of optimality in assigning functions to dendrites and point out interesting future directions. PMID:21258425

  13. Spindle-F Is the Central Mediator of Ik2 Kinase-Dependent Dendrite Pruning in Drosophila Sensory Neurons

    PubMed Central

    Lai, Yu-Ting; Chiang, Kai-Wen; Hsieh, Hsin-Lun; Wu, Yi-Ping; Ke, Jian-Ming; Lee, Myong-Chol; Liao, Shih-Sian; Shih, Hsueh-Tzu; Tang, Chiou-Yang; Yang, Shi-Bing; Cheng, Hsu-Chen; Wu, June-Tai; Jan, Yuh-Nung; Lee, Hsiu-Hsiang

    2015-01-01

    During development, certain Drosophila sensory neurons undergo dendrite pruning that selectively eliminates their dendrites but leaves the axons intact. How these neurons regulate pruning activity in the dendrites remains unknown. Here, we identify a coiled-coil protein Spindle-F (Spn-F) that is required for dendrite pruning in Drosophila sensory neurons. Spn-F acts downstream of IKK-related kinase Ik2 in the same pathway for dendrite pruning. Spn-F exhibits a punctate pattern in larval neurons, whereas these Spn-F puncta become redistributed in pupal neurons, a step that is essential for dendrite pruning. The redistribution of Spn-F from puncta in pupal neurons requires the phosphorylation of Spn-F by Ik2 kinase to decrease Spn-F self-association, and depends on the function of microtubule motor dynein complex. Spn-F is a key component to link Ik2 kinase to dynein motor complex, and the formation of Ik2/Spn-F/dynein complex is critical for Spn-F redistribution and for dendrite pruning. Our findings reveal a novel regulatory mechanism for dendrite pruning achieved by temporal activation of Ik2 kinase and dynein-mediated redistribution of Ik2/Spn-F complex in neurons. PMID:26540204

  14. Intrinsic and extrinsic mechanisms of dendritic morphogenesis.

    PubMed

    Dong, Xintong; Shen, Kang; Bülow, Hannes E

    2015-01-01

    The complex, branched morphology of dendrites is a cardinal feature of neurons and has been used as a criterion for cell type identification since the beginning of neurobiology. Regulated dendritic outgrowth and branching during development form the basis of receptive fields for neurons and are essential for the wiring of the nervous system. The cellular and molecular mechanisms of dendritic morphogenesis have been an intensely studied area. In this review, we summarize the major experimental systems that have contributed to our understandings of dendritic development as well as the intrinsic and extrinsic mechanisms that instruct the neurons to form cell type-specific dendritic arbors. PMID:25386991

  15. Wiring dendrites in layers and columns.

    PubMed

    Luo, Jiangnan; McQueen, Philip G; Shi, Bo; Lee, Chi-Hon; Ting, Chun-Yuan

    2016-06-01

    The most striking structure in the nervous system is the complex yet stereotyped morphology of the neuronal dendritic tree. Dendritic morphologies and the connections they make govern information flow and integration in the brain. The fundamental mechanisms that regulate dendritic outgrowth and branching are subjects of extensive study. In this review, we summarize recent advances in the molecular and cellular mechanisms for routing dendrites in layers and columns, prevalent organizational structures in the brain. We highlight how dendritic patterning influences the formation of synaptic circuits. PMID:27315108

  16. Advanced dendritic web growth development

    NASA Technical Reports Server (NTRS)

    Hopkins, R. H.

    1985-01-01

    A program to develop the technology of the silicon dendritic web ribbon growth process is examined. The effort is being concentrated on the area rate and quality requirements necessary to meet the JPL/DOE goals for terrestrial PV applications. Closed loop web growth system development and stress reduction for high area rate growth is considered.

  17. DENDRITIC POLYMERS AS FIRE SUPPRESSANTS

    EPA Science Inventory

    This report describes an evaluation of the applicability of one of the latest advances in polymer technology (dendritic polymers) to suppressing fires, one of the greatest survivability threats to military personnel and vehicles. Certain types of alkali and transition metal compl...

  18. 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

  19. Dendrite engineering on xenon crystals.

    PubMed

    Fell, Marco; Bilgram, Jörg

    2007-06-01

    The experimental work presented focuses on transient growth, morphological transitions, and control of xenon dendrites. Dendritic free growth is perturbed by two different mechanisms: Shaking and heating up to the melting temperature. Spontaneous and metastable multitip configurations are stabilized, coarsening is reduced, leading to a denser sidebranch growth, and a periodic tip splitting is found during perturbation by shaking. On the other hand, heating leads to controlled sidebranching and characteristic transitions of the tip shape. A deterministic behavior is found besides the random-noise-driven growth. The existence of a limit cycle is supported by the findings. Together the two perturbation mechanisms allow a "dendrite engineering"--i.e., a reproducible controlling of the crystal shape during its growth. The tip splitting for dendritic free growth is found not to be a splitting of the tip in two; rather, the respective growth velocities of the main tip and the fins change. The latter then surpass the main tip and develop into new tips. The occurrence of three- and four-tip configurations is explained with this mechanism. Finite-element calculations of the heat flow and the convective flow in the growth vessel show that the idea of a single axisymmetric toroidal convection roll across the whole growth vessel has to be dropped. The main effect of convection under Earth's gravity is the compression of the diffusive temperature field around the downward-growing tip. A model to explain the symmetry of dendritic crystals--e.g., snow crystals--is developed, based on the interaction of crystal shape and heat flow in the crystal. PMID:17677269

  20. 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

  1. 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

  2. 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

  3. Microtubule nucleation and organization in dendrites.

    PubMed

    Delandre, Caroline; Amikura, Reiko; Moore, Adrian W

    2016-07-01

    Dendrite branching is an essential process for building complex nervous systems. It determines the number, distribution and integration of inputs into a neuron, and is regulated to create the diverse dendrite arbor branching patterns characteristic of different neuron types. The microtubule cytoskeleton is critical to provide structure and exert force during dendrite branching. It also supports the functional requirements of dendrites, reflected by differential microtubule architectural organization between neuron types, illustrated here for sensory neurons. Both anterograde and retrograde microtubule polymerization occur within growing dendrites, and recent studies indicate that branching is enhanced by anterograde microtubule polymerization events in nascent branches. The polarities of microtubule polymerization events are regulated by the position and orientation of microtubule nucleation events in the dendrite arbor. Golgi outposts are a primary microtubule nucleation center in dendrites and share common nucleation machinery with the centrosome. In addition, pre-existing dendrite microtubules may act as nucleation sites. We discuss how balancing the activities of distinct nucleation machineries within the growing dendrite can alter microtubule polymerization polarity and dendrite branching, and how regulating this balance can generate neuron type-specific morphologies. PMID:27097122

  4. Method of inhibiting dislocation generation in silicon dendritic webs

    DOEpatents

    Spitznagel, John A.; Seidensticker, Raymond G.; McHugh, James P.

    1990-11-20

    A method of tailoring the heat balance of the outer edge of the dendrites adjacent the meniscus to produce thinner, smoother dendrites, which have substantially less dislocation sources contiguous with the dendrites, by changing the view factor to reduce radiation cooling or by irradiating the dendrites with light from a quartz lamp or a laser to raise the temperature of the dendrites.

  5. Thermosolutal convection during dendritic solidification

    NASA Technical Reports Server (NTRS)

    Heinrich, J. C.; Nandapurkar, P.; Poirier, D. R.; Felicelli, S.

    1989-01-01

    This paper presents a mathematical model for directional solidification of a binary alloy including a dendritic region underlying an all-liquid region. It is assumed initially that there exists a nonconvecting state with planar isotherms and isoconcentrates solidifying at a constant velocity. The stability of this system has been analyzed and nonlinear calculations are performed that show the effect of convection in the solidification process when the system is unstable. Results of calculations for various cases defined by the initial temperature gradient at the dendrite tips and varying strength of the gravitational field are presented for systems involving lead-tin alloys. The results show that the systems are stable for a gravitational constant of 0.0001 g(0) and that convection can be suppressed by appropriate choice of the container's size for higher values of the gravitational constant. It is also concluded that for the lead-tin systems considered, convection in the mushy zone is not significant below the upper 20 percent of the dendritic zone, if al all.

  6. Dendritic Ion Channel Trafficking and Plasticity

    PubMed Central

    Shah, Mala M.; Hammond, Rebecca S.; Hoffman, Dax

    2010-01-01

    Dendrites, the elaborate processes emerging from neuronal cell bodies, receive most excitatory synaptic inputs. Voltage- and calcium-gated ion channels are abundant in dendrites and modify the shape, propagation and integration of synaptic signals. These ion channels also determine intrinsic dendritic excitability and are therfore important for the induction and manifestation of Hebbian and non-Hebbian plasticity. Revealingly, dendritic channels have distinct expression patterns and biophysical properties from those present in other neuronal compartments. Recent evidence suggests that dendritic ion channels are locally regulated, perhaps contributing to different forms of plasticity. In this review, we will discuss the implications of regulating dendritic ion channel function and trafficking in the context of plasticity and information processing. PMID:20363038

  7. Annealing kinetics of electrodeposited lithium dendrites.

    PubMed

    Aryanfar, Asghar; Cheng, Tao; Colussi, Agustin J; Merinov, Boris V; Goddard, William A; Hoffmann, Michael R

    2015-10-01

    The densifying kinetics of lithium dendrites is characterized with effective activation energy of Ea ≈ 6 - 7 kcal mol(-1) in our experiments and molecular dynamics computations. We show that heating lithium dendrites for 55 °C reduces the representative dendrites length λ¯(T,t) up to 36%. NVT reactive force field simulations on three-dimensional glass phase dendrites produced by our coarse grained Monte Carlo method reveal that for any given initial dendrite morphology, there is a unique stable atomic arrangement for a certain range of temperature, combined with rapid morphological transition (∼10 ps) within quasi-stable states involving concurrent bulk and surface diffusions. Our results are useful for predicting the inherent structural characteristics of lithium dendrites such as dominant coordination number. PMID:26450322

  8. Transcranial magnetic stimulation (TMS) inhibits cortical dendrites.

    PubMed

    Murphy, Sean C; Palmer, Lucy M; Nyffeler, Thomas; Müri, René M; Larkum, Matthew E

    2016-01-01

    One of the leading approaches to non-invasively treat a variety of brain disorders is transcranial magnetic stimulation (TMS). However, despite its clinical prevalence, very little is known about the action of TMS at the cellular level let alone what effect it might have at the subcellular level (e.g. dendrites). Here, we examine the effect of single-pulse TMS on dendritic activity in layer 5 pyramidal neurons of the somatosensory cortex using an optical fiber imaging approach. We find that TMS causes GABAB-mediated inhibition of sensory-evoked dendritic Ca(2+) activity. We conclude that TMS directly activates fibers within the upper cortical layers that leads to the activation of dendrite-targeting inhibitory neurons which in turn suppress dendritic Ca(2+) activity. This result implies a specificity of TMS at the dendritic level that could in principle be exploited for investigating these structures non-invasively. PMID:26988796

  9. Isothermal dendritic growth - A low gravity experiment

    NASA Technical Reports Server (NTRS)

    Glicksman, M. E.; Hahn, R. C.; Lograsso, T. A.; Rubinstein, E. R.; Winsa, E.

    1987-01-01

    The Isothermal Dendritic Growth Experiment has been designed to test dendritic growth theory at low undercoolings, under microgravity conditions in the Space Shuttle Cargo Bay-borne Material Science Laboratory. The experiment will be essentially autonomous, although limited in-flight interaction through a computer interface is planned. A crystal growth chamber able to yield oriented single-crystal dendritic growth will be incorporated; 'seeding' the chamber with a crystal of the requisite orientation will not in itself meet this requirement.

  10. 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

  11. The involvement of actin, calcium channels and exocytosis proteins in somato-dendritic oxytocin and vasopressin release

    PubMed Central

    Tobin, Vicky; Leng, Gareth; Ludwig, Mike

    2012-01-01

    Hypothalamic magnocellular neurons release vasopressin and oxytocin not only from their axon terminals into the blood, but also from their somata and dendrites into the extracellular space of the brain, and this can be regulated independently. Differential release of neurotransmitters from different compartments of a single neuron requires subtle regulatory mechanisms. Somato-dendritic, but not axon terminal release can be modulated by changes in intracellular calcium concentration [(Ca2+)] by release of calcium from intracellular stores, resulting in priming of dendritic pools for activity-dependent release. This review focuses on our current understanding of the mechanisms of priming and the roles of actin remodeling, voltage-operated calcium channels (VOCCs) and SNARE proteins in the regulation somato-dendritic and axon terminal peptide release. PMID:22934017

  12. Precipitation dendrites in turbulent pipe flows

    NASA Astrophysics Data System (ADS)

    Angheluta, Luiza; Hawkins, Christopher; Hammer, Øyvind; Jamtveit, Bjørn

    2013-04-01

    Surface precipitation in pipelines, as well as freezing in water pipes is of great concern in many industrial applications where scaling phenomena becomes a control problem of pipe-clogging or an efficiency reduction in transport. Flow blockage often occurs even when only a small fraction is deposited non-uniformly on the walls in the form of dendrites. Dendritic patterns are commonly encountered in surface precipitation from supersaturated solutions, e.g. calcite dendrites, as well as in solidification from undercooled liquids, e.g. freezing of water into ice dendrites. We explore the mathematical similarities between precipitation and freezing processes and, in particular, investigate the effect of fluid flow on the precipitation dendrites on pipe walls. We use a phase field approach to model surface growth coupled with a lattice Boltzmann method that simulates a channel flow at varying Reynolds number. The dendrites orientation and shape depend non-trivially on the ratio between advection and diffusion, i.e. the Peclet number, as well as the Reynolds number. Roughness induced vortices near growing dendrites at high flow rates further affect the branch splitting of dendrites. We show how the transport rate in a pipeline may depend on the different dendritic morphologies, and provide estimates for the flow conditions that correspond to most efficient transport regimes.

  13. Dendrite preventing separator for secondary lithium batteries

    NASA Technical Reports Server (NTRS)

    Shen, David H. (Inventor); Surampudi, Subbarao (Inventor); Huang, Chen-Kuo (Inventor); Halpert, Gerald (Inventor)

    1993-01-01

    Dendrites are prevented from shorting a secondary lithium battery by use of a first porous separator, such as porous polypropylene, adjacent to the lithium anode that is unreactive with lithium and a second porous fluoropolymer separator between the cathode and the first separator, such as polytetrafluoroethylene, that is reactive with lithium. As the tip of a lithium dendrite contacts the second separator, an exothermic reaction occurs locally between the lithium dendrite and the fluoropolymer separator. This results in the prevention of the dendrite propagation to the cathode.

  14. Dendrite preventing separator for secondary lithium batteries

    NASA Technical Reports Server (NTRS)

    Shen, David H. (Inventor); Surampudi, Subbarao (Inventor); Huang, Chen-Kuo (Inventor); Halpert, Gerald (Inventor)

    1995-01-01

    Dendrites are prevented from shorting a secondary lithium battery by use of a first porous separator such as porous polypropylene adjacent the lithium anode that is unreactive with lithium and a second porous fluoropolymer separator between the cathode and the first separator such as polytetrafluoroethylene that is reactive with lithium. As the tip of a lithium dendrite contacts the second separator, an exothermic reaction occurs locally between the lithium dendrite and the fluoropolymer separator. This results in the prevention of the dendrite propagation to the cathode.

  15. Hierarchical assembly of diphenylalanine into dendritic nanoarchitectures.

    PubMed

    Han, Tae Hee; Oh, Jun Kyun; Lee, Gyoung-Ja; Pyun, Su-Il; Kim, Sang Ouk

    2010-09-01

    Highly ordered, multi-dimensional dendritic nanoarchitectures were created via self-assembly of diphenylalanine from an acidic buffer solution. The self-similarity of dendritic structures was characterized by examining their fractal dimensions with the box-counting method. The fractal dimension was determined to be 1.7, which demonstrates the fractal dimension of structures generated by diffusion limited aggregation on a two-dimensional substrate surface. By confining the dendritic assembly of diphenylalanine within PDMS microchannels, the self-similar dendritic growth could be hierarchically directed to create linearly assembled nanoarchitectures. Our approach offers a novel pathway for creating and directing hierarchical nanoarchitecture from biomolecular assembly. PMID:20605423

  16. Mode of dendrite growth in undercooled alloy melts

    SciTech Connect

    Li, J.; Yang, G.; Zhou, Y.

    1998-01-01

    The mode of dendrite growth in the undercooled Ni-50 at% Cu alloy was investigated. At lower undercoolings, the dendrite growth is mainly controlled by solute diffusion, and the formed dendritic morphologies are similar to those of the conventional as-cast equiaxed crystals, except that here the branches are much denser. At higher undercoolings, however, the severe solutal trapping that results from high dendrite growth velocity weakens the effect of solute diffusion on the dendrite growth. In this case, the dendrites branch in the bunching form. The dendrite spacings were measured, and the results were interpreted with the current dendrite growth theories.

  17. Early events in axon/dendrite polarization.

    PubMed

    Cheng, Pei-lin; Poo, Mu-ming

    2012-01-01

    Differentiation of axons and dendrites is a critical step in neuronal development. Here we review the evidence that axon/dendrite formation during neuronal polarization depends on the intrinsic cytoplasmic asymmetry inherited by the postmitotic neuron, the exposure of the neuron to extracellular chemical factors, and the action of anisotropic mechanical forces imposed by the environment. To better delineate the functions of early signals among a myriad of cellular components that were shown to influence axon/dendrite formation, we discuss their functions by distinguishing their roles as determinants, mediators, or modulators and consider selective degradation of these components as a potential mechanism for axon/dendrite polarization. Finally, we examine whether these early events of axon/dendrite formation involve local autocatalytic activation and long-range inhibition, as postulated by Alan Turing for the morphogenesis of patterned biological structure. PMID:22715881

  18. Vertical solidification of dendritic binary alloys

    NASA Technical Reports Server (NTRS)

    Heinrich, J. C.; Felicelli, S.; Poirier, D. R.

    1991-01-01

    Three numerical techniques are employed to analyze the influence of thermosolutal convection on defect formation in directionally solidified (DS) alloys. The finite-element models are based on the Boussinesq approximation and include the plane-front model and two plane-front models incorporating special dendritic regions. In the second model the dendritic region has a time-independent volume fraction of liquid, and in the last model the dendritic region evolves as local conditions dictate. The finite-element models permit the description of nonlinear thermosolutal convection by treating the dendritic regions as porous media with variable porosities. The models are applied to lead-tin alloys including DS alloys, and severe segregation phenomena such as freckles and channels are found to develop in the DS alloys. The present calculations and the permeability functions selected are shown to predict behavior in the dendritic regions that qualitatively matches that observed experimentally.

  19. Engineering crystals of dendritic molecules

    PubMed Central

    Lukin, Oleg; Schubert, Dirk; Müller, Claudia M.; Schweizer, W. Bernd; Gramlich, Volker; Schneider, Julian; Dolgonos, Grygoriy; Shivanyuk, Alexander

    2009-01-01

    A detailed single-crystal X-ray study of conformationally flexible sulfonimide-based dendritic molecules with systematically varied molecular architectures was undertaken. Thirteen crystal structures reported in this work include 9 structures of the second-generation dendritic sulfonimides decorated with different aryl groups, 2 compounds bearing branches of both second and first generation, and 2 representatives of the first generation. Analysis of the packing patterns of 9 compounds bearing second-generation branches shows that despite their lack of strong directive functional groups there is a repeatedly reproduced intermolecular interaction mode consisting in an anchor-type packing of complementary second-generation branches of neighbouring molecules. The observed interaction tolerates a wide range of substituents in meta- and para-positions of the peripheral arylsulfonyl rings. Quantum chemical calculations of the molecule-molecule interaction energies agree at the qualitative level with the packing preferences found in the crystalline state. The calculations can therefore be used as a tool to rationalize and predict molecular structures with commensurate and non-commensurate branches for programming of different packing modes in crystal. PMID:19549870

  20. Engineering crystals of dendritic molecules.

    PubMed

    Lukin, Oleg; Schubert, Dirk; Müller, Claudia M; Schweizer, W Bernd; Gramlich, Volker; Schneider, Julian; Dolgonos, Grygoriy; Shivanyuk, Alexander

    2009-07-01

    A detailed single-crystal X-ray study of conformationally flexible sulfonimide-based dendritic molecules with systematically varied molecular architectures was undertaken. Thirteen crystal structures reported in this work include 9 structures of the second-generation dendritic sulfonimides decorated with different aryl groups, 2 compounds bearing branches of both second and first generation, and 2 representatives of the first generation. Analysis of the packing patterns of 9 compounds bearing second-generation branches shows that despite their lack of strong directive functional groups there is a repeatedly reproduced intermolecular interaction mode consisting in an anchor-type packing of complementary second-generation branches of neighbouring molecules. The observed interaction tolerates a wide range of substituents in meta- and para-positions of the peripheral arylsulfonyl rings. Quantum chemical calculations of the molecule-molecule interaction energies agree at the qualitative level with the packing preferences found in the crystalline state. The calculations can therefore be used as a tool to rationalize and predict molecular structures with commensurate and non-commensurate branches for programming of different packing modes in crystal. PMID:19549870

  1. 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

  2. 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

  3. 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

  4. Solidification under microgravity conditions - Dendritic growth

    NASA Technical Reports Server (NTRS)

    Glicksman, M. E.; Hahn, R. C.; Lograsso, T. A.; Rubinstein, E. R.; Winsa, E.

    1987-01-01

    The experimental approach and apparatus of a zero-gravity active crystal growth experiment to test dendritic growth theory at low supercoolings are discussed. The experiment consists of 20 experimental cycles. Estimates have been made as to how low gravitational accelerations would have to be reduced to observe convection-free dendritic growth at supercoolings from 0.01-1.0 K. The experiment requires temperature control of + or - 2 mK and photographic resolution of a few microns with a depth of field of + or - 6 mm. The thermostatic bath and temperature control system, photographic system, growth chamber, and dendrite detection system are described in detail.

  5. Evidence for Eigenfrequencies in Dendritic Growth Dynamics

    NASA Astrophysics Data System (ADS)

    Lacombe, Jeffrey C.; Koss, Matthew B.; Giummarra, Cindie; Frei, Julie E.; Lupulescu, Afina O.; Glicksman, Martin E.

    Microgravity dendritic growth experiments, conducted aboard the space shuttle Columbia, are described. In-situ video images reveal that pivalic acid dendrites growing in the diffusion-controlled environment of low-earth orbit exhibit a range of transient or non-steady-state behaviors. The observed transient features of the growth process are being studied with the objective of understanding the mechanisms responsible for these behaviors. Included in these observations is possible evidence for characteristic frequencies or limit cycles in the growth behavior near the tip of the dendrites. These data, and their interpretations, will be discussed.

  6. Some aspects of the electroanatomy of dendrites.

    PubMed

    Lux, H D; Schubert, P

    1975-01-01

    An understanding of the neuronal function requires the knowledge of the electroanatomy of dendrites, which comprise the major area and receive the main input in most neurons. Some simplifying assumptions are necessary to describe the electrical characteristics of the dendritic tree. The applicability of the simplified model of a combined equivalent dendritic cylinder proposed by Rall, was tested and verified by a combined analysis of anatomic and electrical data from the same spinal motoneurons. Assuming a uniform somadendritic membrane, estimates of the specific membrane resistance (RM: 2,700 +/- 920 omegacm2) were made by relating the neuronal input resistance with the combined dendritic trunk parameter (sigmaD3/2: 320 +/- 150-10(-6) CM3/2). From these combined anatomic and electrical data the dendritic electrotonic lengths (Lgeom: 1.5 +/- 0.3 times the length constant) were derived. Comparable L values (Ltrans: 1.5 +/- 0.3) resulted independently from analysis of membrane voltage transients during current steps. The linear dendritic cable model has proved its applicability for the analysis of small voltage deflections during current step applications at the soma as well as for the analysis of the majority of minimal postsynaptic potentials (PSP's). During the transmission along the dendritic cable the PSP undergoes changes in shape. These changes often permit a determination of the distance of the dendritic input from the soma. Unfortunately, the attenuation of the dendritic signal cannot be directly assessed. Dendritic synaptic transmission can be observed in isolation in chromatolytic motoneurons because the somal synapses are peeled off from the soma by proliferating glial cells in the course of retrograde reaction. These observations support the prediction that the PSP's with relatively short rise-times and duration originate from synapses near the soma. It may be questioned as to whether the linear dendritic cable approximation also applies to the larger

  7. Tumor Targeting, Trifunctional Dendritic Wedge

    PubMed Central

    2015-01-01

    We report in vitro and in vivo evaluation of a newly designed trifunctional theranostic agent for targeting solid tumors. This agent combines a dendritic wedge with high boron content for boron neutron capture therapy or boron MRI, a monomethine cyanine dye for visible-light fluorescent imaging, and an integrin ligand for efficient tumor targeting. We report photophysical properties of the new agent, its cellular uptake and in vitro targeting properties. Using live animal imaging and intravital microscopy (IVM) techniques, we observed a rapid accumulation of the agent and its retention for a prolonged period of time (up to 7 days) in fully established animal models of human melanoma and murine mammary adenocarcinoma. This macromolecular theranostic agent can be used for targeted delivery of high boron load into solid tumors for future applications in boron neutron capture therapy. PMID:25350602

  8. 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

  9. 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

  10. 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

  11. 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

  12. 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

  13. The Protein Dendrite Arborization and Synapse Maturation 1 (Dasm-1) Is Dispensable for Dendrite Arborization▿ †

    PubMed Central

    Mishra, Archana; Knerr, Boris; Paixão, Sónia; Kramer, Edgar R.; Klein, Rüdiger

    2008-01-01

    The development of a highly branched dendritic tree is essential for the establishment of functional neuronal connections. The evolutionarily conserved immunoglobulin superfamily member, the protein dendrite arborization and synapse maturation 1 (Dasm-1) is thought to play a critical role in dendrite formation of dissociated hippocampal neurons. RNA interference-mediated Dasm-1 knockdown was previously shown to impair dendrite, but not axonal, outgrowth and branching (S. H. Shi, D. N. Cox, D. Wang, L. Y. Jan, and Y. N. Jan, Proc. Natl. Acad. Sci. USA 101:13341-13345, 2004). Here, we report the generation and analysis of Dasm-1 null mice. We find that genetic ablation of Dasm-1 does not interfere with hippocampal dendrite growth and branching in vitro and in vivo. Moreover, the absence of Dasm-1 does not affect the modulation of dendritic outgrowth induced by brain-derived neurotrophic factor. Importantly, the previously observed impairment in dendrite growth after Dasm-1 knockdown is also observed when the Dasm-1 knockdown is performed in cultured hippocampal neurons from Dasm-1 null mice. These findings indicate that the dendrite arborization phenotype was caused by off-target effects and that Dasm-1 is dispensable for hippocampal dendrite arborization. PMID:18268009

  14. 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

  15. 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

  16. 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.

  17. 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

  18. Fluctuation effects on dendritic growth morphology

    NASA Astrophysics Data System (ADS)

    Brener, E.; Ihle, T.; Müller-Krumbhaar, H.; Saito, Y.; Shiraishi, K.

    1994-03-01

    Dendrites are the typical patterns for many anisotropic growth processes. A detailed understanding of their dynamics appears to be crucial for a proper classification of various growth morphologies. In particular the morphology transitions occurring for varying anisotropy were predicted to depend upon fluctuations. In the present investigation we compare analytical and numerical results on the stability of dendrites under influence of external fluctuations. In particular we confirm the previous ideas that the dendrites are linearly stable under influence of noise even in the limit of extremely small but nonzero anisotropy. This supports the concept of a smooth change-over from compact to fractal dendrites and finally to fractal seaweed whose internal length scale was predicted to depend on noise.

  19. Dendritic spine dysgenesis in Rett syndrome

    PubMed Central

    Xu, Xin; Miller, Eric C.; Pozzo-Miller, Lucas

    2014-01-01

    Spines are small cytoplasmic extensions of dendrites that form the postsynaptic compartment of the majority of excitatory synapses in the mammalian brain. Alterations in the numerical density, size, and shape of dendritic spines have been correlated with neuronal dysfunction in several neurological and neurodevelopmental disorders associated with intellectual disability, including Rett syndrome (RTT). RTT is a progressive neurodevelopmental disorder associated with intellectual disability that is caused by loss of function mutations in the transcriptional regulator methyl CpG-binding protein 2 (MECP2). Here, we review the evidence demonstrating that principal neurons in RTT individuals and Mecp2-based experimental models exhibit alterations in the number and morphology of dendritic spines. We also discuss the exciting possibility that signaling pathways downstream of brain-derived neurotrophic factor (BDNF), which is transcriptionally regulated by MeCP2, offer promising therapeutic options for modulating dendritic spine development and plasticity in RTT and other MECP2-associated neurodevelopmental disorders. PMID:25309341

  20. Dendritic Growth in Nematic Liquid Crystals

    NASA Astrophysics Data System (ADS)

    Martin, Joshua; Garg, Shila

    2000-03-01

    The experimental study of the onset of electrohydrodynamic convection (EHC) through a dendritic growth is reported. If a magnetic Freedericksz-distorted liquid crystal of negative dielectric anisotropy is subjected to an electric field parallel to the magnetic field, EHC sets in through the nucleation of dendrites [1,2]. Measurements of tip speeds of the dendrites as a function of applied voltage at a fixed magnetic field are made. The goal is to explore the effect of the magnetic and electric fields on the dendritic growth. In addition, pattern dynamics is monitored once the final state of spatio-temporal chaos is reached by the system. [1] J. T. Gleeson, Nature 385, 511 (1997). [2] J. T. Gleeson, Physica A 239, 211 (1997). This research was supported by NSF grants DMR 9704579 and DMR 9619406.

  1. Dendritic Spine Pathology in Neurodegenerative Diseases.

    PubMed

    Herms, Jochen; Dorostkar, Mario M

    2016-05-23

    Substantial progress has been made toward understanding the neuropathology, genetic origins, and epidemiology of neurodegenerative diseases, including Alzheimer's disease; tauopathies, such as frontotemporal dementia; α-synucleinopathies, such as Parkinson's disease or dementia with Lewy bodies; Huntington's disease; and amyotrophic lateral sclerosis with dementia, as well as prion diseases. Recent evidence has implicated dendritic spine dysfunction as an important substrate of the pathogenesis of dementia in these disorders. Dendritic spines are specialized structures, extending from the neuronal processes, on which excitatory synaptic contacts are formed, and the loss of dendritic spines correlates with the loss of synaptic function. We review the literature that has implicated direct or indirect structural alterations at dendritic spines in the pathogenesis of major neurodegenerative diseases, focusing on those that lead to dementias such as Alzheimer's, Parkinson's, and Huntington's diseases, as well as frontotemporal dementia and prion diseases. We stress the importance of in vivo studies in animal models. PMID:26907528

  2. 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

  3. Free Energy and Dendritic Self-Organization

    PubMed Central

    Kiebel, Stefan J.; Friston, Karl J.

    2011-01-01

    In this paper, we pursue recent observations that, through selective dendritic filtering, single neurons respond to specific sequences of presynaptic inputs. We try to provide a principled and mechanistic account of this selectivity by applying a recent free-energy principle to a dendrite that is immersed in its neuropil or environment. We assume that neurons self-organize to minimize a variational free-energy bound on the self-information or surprise of presynaptic inputs that are sampled. We model this as a selective pruning of dendritic spines that are expressed on a dendritic branch. This pruning occurs when postsynaptic gain falls below a threshold. Crucially, postsynaptic gain is itself optimized with respect to free energy. Pruning suppresses free energy as the dendrite selects presynaptic signals that conform to its expectations, specified by a generative model implicit in its intracellular kinetics. Not only does this provide a principled account of how neurons organize and selectively sample the myriad of potential presynaptic inputs they are exposed to, but it also connects the optimization of elemental neuronal (dendritic) processing to generic (surprise or evidence-based) schemes in statistics and machine learning, such as Bayesian model selection and automatic relevance determination. PMID:22013413

  4. Transcranial magnetic stimulation (TMS) inhibits cortical dendrites

    PubMed Central

    Murphy, Sean C; Palmer, Lucy M; Nyffeler, Thomas; Müri, René M; Larkum, Matthew E

    2016-01-01

    One of the leading approaches to non-invasively treat a variety of brain disorders is transcranial magnetic stimulation (TMS). However, despite its clinical prevalence, very little is known about the action of TMS at the cellular level let alone what effect it might have at the subcellular level (e.g. dendrites). Here, we examine the effect of single-pulse TMS on dendritic activity in layer 5 pyramidal neurons of the somatosensory cortex using an optical fiber imaging approach. We find that TMS causes GABAB-mediated inhibition of sensory-evoked dendritic Ca2+ activity. We conclude that TMS directly activates fibers within the upper cortical layers that leads to the activation of dendrite-targeting inhibitory neurons which in turn suppress dendritic Ca2+ activity. This result implies a specificity of TMS at the dendritic level that could in principle be exploited for investigating these structures non-invasively. DOI: http://dx.doi.org/10.7554/eLife.13598.001 PMID:26988796

  5. 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

  6. GSK-3 signaling in developing cortical neurons is essential for radial migration and dendritic orientation

    PubMed Central

    Morgan-Smith, Meghan; Wu, Yaohong; Zhu, Xiaoqin; Pringle, Julia; Snider, William D

    2014-01-01

    GSK-3 is an essential mediator of several signaling pathways that regulate cortical development. We therefore created conditional mouse mutants lacking both GSK-3α and GSK-3β in newly born cortical excitatory neurons. Gsk3-deleted neurons expressing upper layer markers exhibited striking migration failure in all areas of the cortex. Radial migration in hippocampus was similarly affected. In contrast, tangential migration was not grossly impaired after Gsk3 deletion in interneuron precursors. Gsk3-deleted neurons extended axons and developed dendritic arbors. However, the apical dendrite was frequently branched while basal dendrites exhibited abnormal orientation. GSK-3 regulation of migration in neurons was independent of Wnt/β-catenin signaling. Importantly, phosphorylation of the migration mediator, DCX, at ser327, and phosphorylation of the semaphorin signaling mediator, CRMP-2, at Thr514 were markedly decreased. Our data demonstrate that GSK-3 signaling is essential for radial migration and dendritic orientation and suggest that GSK-3 mediates these effects by phosphorylating key microtubule regulatory proteins. DOI: http://dx.doi.org/10.7554/eLife.02663.001 PMID:25073924

  7. An evolutionarily conserved protein CHORD regulates scaling of dendritic arbors with body size

    PubMed Central

    Shimono, Kohei; Fujishima, Kazuto; Nomura, Takafumi; Ohashi, Masayoshi; Usui, Tadao; Kengaku, Mineko; Toyoda, Atsushi; Uemura, Tadashi

    2014-01-01

    Most organs scale proportionally with body size through regulation of individual cell size and/or cell number. Here we addressed how postmitotic and morphologically complex cells such as neurons scale with the body size by using the dendritic arbor of one Drosophila sensory neuron as an assay system. In small adults eclosed under a limited-nutrition condition, the wild-type neuron preserved the branching complexity of the arbor, but scaled down the entire arbor, making a “miniature”. In contrast, mutant neurons for the Insulin/IGF signaling (IIS) or TORC1 pathway exhibited “undergrowth”, which was characterized by decreases in both the branching complexity and the arbor size, despite a normal diet. These contrasting phenotypes hinted that a novel regulatory mechanism contributes to the dendritic scaling in wild-type neurons. Indeed, we isolated a mutation in the gene CHORD/morgana that uncoupled the neuron size and the body size: CHORD mutant neurons generated miniature dendritic arbors regardless of the body size. CHORD encodes an evolutionarily conserved co-chaperone of HSP90. Our results support the notion that dendritic growth and branching are controlled by partly separate mechanisms. The IIS/TORC1 pathways control both growth and branching to avert underdevelopment, whereas CHORD together with TORC2 realizes proportional scaling of the entire arbor. PMID:24643112

  8. 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

  9. Perinatal opiate treatment delays growth of cortical dendrites.

    PubMed

    Ricalde, A A; Hammer, R P

    1990-07-31

    Basilar dendritic arborizations of layer II-III pyramidal neurons in primary somatosensory cortex of 5-day-old male rats were reconstructed following perinatal morphine, morphine/naltrexone, or saline vehicle administration. Morphine treatment was observed to reduce total dendritic length. This effect was limited to higher order dendritic branches, with terminal dendrites manifesting the greatest reduction of length. The action of morphine was presumably mediated by opiate receptors, since concurrent naltrexone administration completely reversed morphine effects on dendritic length and branching. These results suggest that opiates act during late ontogenesis to affect dendritic growth in cerebral cortex. PMID:2172870

  10. Integrins establish dendrite-substrate relationships that promote dendritic self-avoidance and patterning in Drosophila sensory neurons

    PubMed Central

    Kim, Michelle E.; Shrestha, Brikha R.; Blazeski, Richard; Mason, Carol A.; Grueber, Wesley B.

    2012-01-01

    Summary Dendrites achieve characteristic spacing patterns during development to ensure appropriate coverage of territories. Mechanisms of dendrite positioning via repulsive dendrite-dendrite interactions are beginning to be elucidated, but the control, and importance, of dendrite positioning relative to their substrate is poorly understood. We found that dendritic branches of Drosophila dendritic arborization sensory neurons can be positioned either at the basal surface of epidermal cells, or enclosed within epidermal invaginations. We show that integrins control dendrite positioning on or within the epidermis in a cell autonomous manner by promoting dendritic retention on the basal surface. Loss of integrin function in neurons resulted in excessive self-crossing and dendrite maintenance defects, the former indicating a novel role for substrate interactions in self-avoidance. In contrast to a contact-mediated mechanism, we find that integrins prevent crossings that are non-contacting between dendrites in different three-dimensional positions, revealing a requirement for combined dendrite-dendrite and dendrite-substrate interactions in self-avoidance. PMID:22243748

  11. 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

  12. MicroRNA-132, -134, and -138: a microRNA troika rules in neuronal dendrites.

    PubMed

    Bicker, Silvia; Lackinger, Martin; Weiß, Kerstin; Schratt, Gerhard

    2014-10-01

    Dendritic mRNA transport and local translation in the postsynaptic compartment play an important role in synaptic plasticity, learning and memory. Local protein synthesis at the synapse has to be precisely orchestrated by a plethora of factors including RNA binding proteins as well as microRNAs, an extensive class of small non-coding RNAs. By binding to complementary sequences in target mRNAs, microRNAs fine-tune protein synthesis and thereby represent critical regulators of gene expression at the post-transcriptional level. Research over the last years identified an entire network of dendritic microRNAs that fulfills an essential role in synapse development and physiology. Recent studies provide evidence that these small regulatory molecules are highly regulated themselves, at the level of expression as well as function. The importance of microRNAs for correct function of the nervous system is reflected by an increasing number of studies linking dysregulation of microRNA pathways to neurological disorders. By focusing on three extensively studied examples (miR-132, miR-134, miR-138), this review will attempt to illustrate the complex regulatory roles of dendritic microRNAs at the synapse and their implications for pathological conditions. PMID:25008044

  13. 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

  14. Dendritic spine dysgenesis in neuropathic pain.

    PubMed

    Tan, Andrew M; Waxman, Stephen G

    2015-08-01

    Neuropathic pain is a significant unmet medical need in patients with variety of injury or disease insults to the nervous system. Neuropathic pain often presents as a painful sensation described as electrical, burning, or tingling. Currently available treatments have limited effectiveness and narrow therapeutic windows for safety. More powerful analgesics, e.g., opioids, carry a high risk for chemical dependence. Thus, a major challenge for pain research is the elucidation of the mechanisms that underlie neuropathic pain and developing targeted strategies to alleviate pathological pain. The mechanistic link between dendritic spine structure and circuit function could explain why neuropathic pain is difficult to treat, since nociceptive processing pathways are adversely "hard-wired" through the reorganization of dendritic spines. Several studies in animal models of neuropathic pain have begun to reveal the functional contribution of dendritic spine dysgenesis in neuropathic pain. Previous reports have demonstrated three primary changes in dendritic spine structure on nociceptive dorsal horn neurons following injury or disease, which accompany chronic intractable pain: (I) increased density of dendritic spines, particularly mature mushroom-spine spines, (II) redistribution of spines toward dendritic branch locations close to the cell body, and (III) enlargement of the spine head diameter, which generally presents as a mushroom-shaped spine. Given the important functional implications of spine distribution, density, and shape for synaptic and neuronal function, the study of dendritic spine abnormality may provide a new perspective for investigating pain, and the identification of specific molecular players that regulate spine morphology may guide the development of more effective and long-lasting therapies. PMID:25445354

  15. The Complete Reconfiguration of Dendritic Gold

    NASA Astrophysics Data System (ADS)

    Paneru, Govind; Flanders, Bret

    2014-03-01

    Reconfigurability-by-design is an important strategy in modern materials science, as materials with this capability could potentially be used to confer hydrophobic, lipophobic, or anti-corrosive character to substrates in a regenerative manner. The present work extends the directed electrochemical nanowire assembly (DENA) methodology, which is a technique that employs alternating voltages to grow single crystalline metallic nanowires and nano-dendrites from simple salt solutions, to enable the complete dissolution of macroscopic arrays of metallic dendrites following their growth. Our main finding is that structural reconfiguration of dendritic gold is induced by changes in the MHz-level frequencies of voltages that are applied to the dendrites. Cyclic voltammetry and micro-Raman spectroscopy have been used to show that dendritic gold grows and dissolves by the same chemical mechanisms as bulk gold. Hence, the redox chemistry that occurs at the crystal-solution interface is no different than the established electrochemistry of gold. What differs in this process and allows for reconfiguration to occur is the diffusive behavior of the gold chloride molecules in the solution adjacent to the interface. We will present a simple model that captures the physics of this behavior.

  16. Dendrites Inhibition in Rechargeable Lithium Metal Batteries

    NASA Astrophysics Data System (ADS)

    Aryanfar, Asghar

    The specific high energy and power capacities of rechargeable lithium metal (Li0) batteries are ideally suited to portable devices and are valuable as storage units for intermittent renewable energy sources. Lithium, the lightest and most electropositive metal, would be the optimal anode material for rechargeable batteries if it were not for the fact that such devices fail unexpectedly by short-circuiting via the dendrites that grow across electrodes upon recharging. This phenomenon poses a major safety issue because it triggers a series of adverse events that start with overheating, potentially followed by the thermal decomposition and ultimately the ignition of the organic solvents used in such devices. In this thesis, we developed experimental platform for monitoring and quantifying the dendrite populations grown in a Li battery prototype upon charging under various conditions. We explored the effects of pulse charging in the kHz range and temperature on dendrite growth, and also on loss capacity into detached "dead" lithium particles. Simultaneously, we developed a computational framework for understanding the dynamics of dendrite propagation. The coarse-grained Monte Carlo model assisted us in the interpretation of pulsing experiments, whereas MD calculations provided insights into the mechanism of dendrites thermal relaxation. We also developed a computational framework for measuring the dead lithium crystals from the experimental images.

  17. 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

  18. 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

  19. 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.

  20. 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

  1. Successful Isothermal Dendritic Growth Experiment (IDGE) Proves Current Theories of Dendritic Solidification are Flawed

    NASA Technical Reports Server (NTRS)

    1996-01-01

    The scientific objective of the Isothermal Dendritic Growth Experiment (IDGE) is to test fundamental assumptions about dendritic solidification of molten materials. "Dendrites"-- from the ancient Greek word for tree--are tiny branching structures that form inside molten metal alloys when they solidify during manufacturing. The size, shape, and orientation of the dendrites have a major effect on the strength, ductility (ability to be molded or shaped), and usefulness of an alloy. Nearly all of the cast metal alloys used in everyday products (such as automobiles and airplanes) are composed of thousands to millions of tiny dendrites. Gravity, present on Earth, causes convection currents in molten alloys that disturb dendritic solidification and make its precise study impossible. In space, gravity is negated by the orbiting of the space shuttle. Consequently, IDGE (which was conducted on the space shuttle) gathered the first precise data regarding undisturbed dendritic solidification. IDGE is a microgravity materials science experiment that uses an apparatus which was designed, built, tested, and operated by people from the NASA Lewis Research Center. This experiment was conceived by the principal investigator, Professor Martin E. Glicksman, from Rensselaer Polytechnic Institute in Troy, New York. The experiment was a team effort of Lewis civil servants, contractors from Aerospace Design & Fabrication Inc. (ADF), and personnel at Rensselaer.

  2. Dendritic cells, indoleamine 2,3 dioxygenase and acquired immune privilege

    PubMed Central

    Huang, Lei; Baban, Babak; Johnson, Burles A; Mellor, Andrew L.

    2013-01-01

    Dendritic cells (DCs) are specialized to stimulate T cell immunity. Paradoxically some DCs suppress T cell responses, and activate regulatory T cells. In this review we focus on a potent counter-regulatory pathway mediated by plasmacytoid DCs (pDCs) expressing the immunosuppressive enzyme indoleamine 2,3 dioxygenase (IDO). IDO-expressing pDCs inhibit effector T cell responses, activate regulatory T cells, and attenuate pro-inflammatory responses in settings of chronic inflammation that manifest in clinical syndromes such as infectious, allergic and autoimmune diseases, cancer, and transplantation. Thus IDO-expressing pDCs create immune privilege, and provide novel opportunities to improve immunotherapy in multiple disease syndromes. PMID:20367139

  3. Dendritic inhomogeneity of stainless maraging steels

    SciTech Connect

    Krasnikova, S.I.; Drobot, A.V.; Shmelev, A.Y.; Vukelich, S.B.

    1986-03-01

    The authors investigated dendritic inhomogeneity in industrial ingots 630 mm (steel I) in diameter and 500 mm (steel II) in diameter. The variation in the degree of dendritic inhomogeneity was investigated over the height of the ingots and across the sections on an MS-46 microprobe. It was established that the elements can be placed in the following order in accordance with the degree of reduction in the liquation factor: titanium, molybdenum, nickel, chromium, and cobalt. Titanium and molybdenum exhibit forward liquation in both steels, and chromium in steel II. The distribution of nickel and chromium in the steel I ingots and cobalt in the steel II ingots is unconventional. Dendritic inhomogeneity, which must be considered in assigning the heat treatment for finished articles, develops during the crystallization of stainless maraging steels.

  4. Isothermal dendritic growth: A low gravity experiment

    NASA Technical Reports Server (NTRS)

    Glicksman, M. E.; Hahn, R. C.; Lograsso, T. A.; Rubinstein, E. R.; Selleck, M. E.; Winsa, E.

    1988-01-01

    The Isothermal Dendritic Growth Experiment is an active crystal growth experiment designed to test dendritic growth theory at low undercoolings where convection prohibits such studies at 1 g. The experiment will be essentially autonomous, though limited in-flight interaction through a computer interface is planned. One of the key components of the apparatus will be a crystal growth chamber capable of achieving oriented single crystal dendritic growth. Recent work indicates that seeding the chamber with a crystal of the proper orientation will not, in and of itself, be sufficient to meet this requirement. Additional flight hardware and software required for the STS flight experiment are currently being developed at NASA Lewis Research Center and at Rensselaer Polytechnic Institute.

  5. Forward- and backpropagation in a silicon dendrite.

    PubMed

    Rasche, C; Douglas, R J

    2001-01-01

    We have developed an analog very-large-scale integrated (aVLSI) electronic circuit that emulates a compartmental model of a neuronal dendrite. The horizontal conductances of the compartmental model are implemented as a switched capacitor network. The transmembrane conductances are implemented as transconductance amplifiers. The electrotonic properties of our silicon cable are qualitatively similar to those of the ideal passive cable that is commonly used to model mathematically the electrotonic behavior of neurons. In particular the propagation of excitatory postsynaptic potentials is realistic, and we are easily able to emulate such classical synaptic integration models as direction selectivity. We are also able to emulate the backpropagation into the dendrite of single somatic spikes and bursts of spikes. Thus, this silicon dendrite is suitable for incorporation in detailed silicon neurons operating in real-time; in particular for the emulation of forward- and backpropagating electrical activities found in real neurons. PMID:18244392

  6. Convection Effects in Three-dimensional Dendritic Growth

    NASA Technical Reports Server (NTRS)

    Lu, Yili; Beckermann, C.; Karma, A.

    2003-01-01

    A phase-field model is developed to simulate free dendritic growth coupled with fluid flow for a pure material in three dimensions. The preliminary results presented here illustrate the strong influence of convection on the three-dimensional (3D) dendrite growth morphology. The detailed knowledge of the flow and temperature fields in the melt around the dendrite from the simulations allows for a detailed understanding of the convection effects on dendritic growth.

  7. 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

  8. The Isothermal Dendritic Growth Experiment (IDGE)

    NASA Technical Reports Server (NTRS)

    Glicksman, Martin E.; Koss, M. B.; Lupulescu, A. O.; LaCombe, J. C.; Frei, J. E.; Malarik, D. C.

    1999-01-01

    The Isothermal Dendritic Growth Experiment (IDGE) constituted a series of three NASA-supported microgravity experiments, all of which flew aboard the space shuttle, Columbia. This experimental space flight series was designed and operated to grow and record dendrite solidification in the absence of gravity-induced convective heat transfer, and thereby produce a wealth of benchmark-quality data for testing solidification scaling laws. The data and analysis performed on the dendritic growth speed and tip size in Succinontrie (SCN) demonstrates that although the theory yields predictions that are reasonably in agreement with experiment, there are significant discrepancies. However, some of these discrepancies can be explained by accurately describing the diffusion of heat. The key finding involves recognition that the actual three-dimensional shape of dendrites includes time-dependent side-branching and a tip region that is not a paraboloid of revolution. Thus, the role of heat transfer in dendritic growth is validated, with the caveat that a more realistic model of the dendrite then a paraboloid is needed to account for heat flow in an experimentally observed dendrite. We are currently conducting additional analysis to further confirm and demonstrate these conclusions. The data and analyses for the growth selection physics remain much less definitive. From the first flight, the data indicated that the selection parameter, sigma*, is not exactly a constant, but exhibits a slight dependence on the supercooling. Additional data from the second flight are being examined to investigate the selection of a unique dendrite speed, tip size and shape. The IDGE flight series is now complete. We are currently completing analyses and moving towards final data archiving. It is gratifying to see that the IDGE published results and archived data sets are being used actively by other scientists and engineers. In addition, we are also pleased to report that the techniques and IDGE

  9. 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

  10. Apparatus for growing a dendritic web

    DOEpatents

    Duncan, Charles S.; Piotrowski, Paul A.; Skutch, Maria E.; McHugh, James P.

    1983-06-21

    A melt system including a susceptor-crucible assembly having improved gradient control when melt replenishment is used during dendritic web growth. The improvement lies in the formation of a thermal barrier in the base of the receptor which is in the form of a vertical slot in the region of the susceptor underlying the crucible at the location of a compartmental separator dividing the crucible into a growth compartment and a melt replenishment compartment. The result achieved is a step change in temperature gradient in the melt thereby providing a more uniform temperature in the growth compartment from which the dendritic web is drawn.

  11. Dendritic microstructure in argon atomized superalloy powders

    NASA Technical Reports Server (NTRS)

    Tewari, S. N.; Kumar, Mahundra

    1986-01-01

    The dendritic microstructure of atomized nickel base superalloy powders (Ni-20 pct Cr, NIMONIC-80A, ASTROALOY, and ZHS6-K) was studied. Prealloyed vacuum induction melted ingots were argon-atomized, the powders were cooled to room temperature, and various powder-size fractions were examined by optical metallography. Linear correlations were obtained for the powder size dependence of the secondary dendrite arm spacing, following the expected d-alpha (R) to the m power dependence on the particle size for all four superalloy compositions. However, the Ni-20 pct Cr alloy, which had much coarser arm spacing as compared to the other three alloys, had a much larger value of m.

  12. Silicon dendritic web growth thermal analysis task

    NASA Technical Reports Server (NTRS)

    Richter, R.; Bhandari, P.

    1985-01-01

    A thermal analysis model is presented which describes the dendritic ribbon process. The model uses a melt-dendrite interface which projects out of the bulk melt as the basic interpretation of the ribbon production process. This is a marked departure from the interpretations of the interface phenomena which were used previously. The model was extensively illustrated with diagrams and pictures of ribbon samples. This model should have great impact on the analyses of experimental data as well as on future design modifications of ribbon-pulling equipment.

  13. [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

  14. 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.

  15. Thermosolutal convection and macrosegregation in dendritic alloys

    NASA Technical Reports Server (NTRS)

    Poirier, David R.; Heinrich, J. C.

    1993-01-01

    A mathematical model of solidification, that simulates the formation of channel segregates or freckles, is presented. The model simulates the entire solidification process, starting with the initial melt to the solidified cast, and the resulting segregation is predicted. Emphasis is given to the initial transient, when the dendritic zone begins to develop and the conditions for the possible nucleation of channels are established. The mechanisms that lead to the creation and eventual growth or termination of channels are explained in detail and illustrated by several numerical examples. A finite element model is used for the simulations. It uses a single system of equations to deal with the all-liquid region, the dendritic region, and the all-solid region. The dendritic region is treated as an anisotropic porous medium. The algorithm uses the bilinear isoparametric element, with a penalty function approximation and a Petrov-Galerkin formulation. The major task was to develop the solidification model. In addition, other tasks that were performed in conjunction with the modeling of dendritic solidification are briefly described.

  16. 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.

  17. Hyper-dendritic nanoporous zinc foam anodes

    DOE PAGESBeta

    Chamoun, Mylad; Hertzberg, Benjamin J.; Gupta, Tanya; Davies, Daniel; Bhadra, Shoham; Van Tassell, Barry.; Erdonmez, Can; Steingart, Daniel A.

    2015-04-24

    The low cost, significant reducing potential, and relative safety of the zinc electrode is a common hope for a reductant in secondary batteries, but it is limited mainly to primary implementation due to shape change. In this work we exploit such shape change for the benefit of static electrodes through the electrodeposition of hyper-dendritic nanoporous zinc foam. Electrodeposition of zinc foam resulted in nanoparticles formed on secondary dendrites in a three-dimensional network with a particle size distribution of 54.1 - 96.0 nm. The nanoporous zinc foam contributed to highly oriented crystals, high surface area and more rapid kinetics in contrastmore » to conventional zinc in alkaline mediums. The anode material presented had a utilization of ~ 88% at full depth-of-discharge at various rates indicating a superb rate-capability. The rechargeability of Zn⁰/Zn²⁺ showed significant capacity retention over 100 cycles at a 40% depth-of-discharge to ensure that the dendritic core structure was imperforated. The dendritic architecture was densified upon charge-discharge cycling and presented superior performance compared to bulk zinc electrodes.« less

  18. Hyper-dendritic nanoporous zinc foam anodes

    SciTech Connect

    Chamoun, Mylad; Hertzberg, Benjamin J.; Gupta, Tanya; Davies, Daniel; Bhadra, Shoham; Van Tassell, Barry.; Erdonmez, Can; Steingart, Daniel A.

    2015-04-24

    The low cost, significant reducing potential, and relative safety of the zinc electrode is a common hope for a reductant in secondary batteries, but it is limited mainly to primary implementation due to shape change. In this work we exploit such shape change for the benefit of static electrodes through the electrodeposition of hyper-dendritic nanoporous zinc foam. Electrodeposition of zinc foam resulted in nanoparticles formed on secondary dendrites in a three-dimensional network with a particle size distribution of 54.1 - 96.0 nm. The nanoporous zinc foam contributed to highly oriented crystals, high surface area and more rapid kinetics in contrast to conventional zinc in alkaline mediums. The anode material presented had a utilization of ~ 88% at full depth-of-discharge at various rates indicating a superb rate-capability. The rechargeability of Zn⁰/Zn²⁺ showed significant capacity retention over 100 cycles at a 40% depth-of-discharge to ensure that the dendritic core structure was imperforated. The dendritic architecture was densified upon charge-discharge cycling and presented superior performance compared to bulk zinc electrodes.

  19. 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 ...

  20. 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...

  1. 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

  2. Regulatory Physiology

    NASA Technical Reports Server (NTRS)

    Lane, Helen W.; Whitson, Peggy A.; Putcha, Lakshmi; Baker, Ellen; Smith, Scott M.; Stewart, Karen; Gretebeck, Randall; Nimmagudda, R. R.; Schoeller, Dale A.; Davis-Street, Janis

    1999-01-01

    As noted elsewhere in this report, a central goal of the Extended Duration Orbiter Medical Project (EDOMP) was to ensure that cardiovascular and muscle function were adequate to perform an emergency egress after 16 days of spaceflight. The goals of the Regulatory Physiology component of the EDOMP were to identify and subsequently ameliorate those biochemical and nutritional factors that deplete physiological reserves or increase risk for disease, and to facilitate the development of effective muscle, exercise, and cardiovascular countermeasures. The component investigations designed to meet these goals focused on biochemical and physiological aspects of nutrition and metabolism, the risk of renal (kidney) stone formation, gastrointestinal function, and sleep in space. Investigations involved both ground-based protocols to validate proposed methods and flight studies to test those methods. Two hardware tests were also completed.

  3. Regulatory Anatomy

    PubMed Central

    2015-01-01

    This article proposes the term “safety logics” to understand attempts within the European Union (EU) to harmonize member state legislation to ensure a safe and stable supply of human biological material for transplants and transfusions. With safety logics, I refer to assemblages of discourses, legal documents, technological devices, organizational structures, and work practices aimed at minimizing risk. I use this term to reorient the analytical attention with respect to safety regulation. Instead of evaluating whether safety is achieved, the point is to explore the types of “safety” produced through these logics as well as to consider the sometimes unintended consequences of such safety work. In fact, the EU rules have been giving rise to complaints from practitioners finding the directives problematic and inadequate. In this article, I explore the problems practitioners face and why they arise. In short, I expose the regulatory anatomy of the policy landscape. PMID:26139952

  4. Regulatory RNAs

    PubMed Central

    Vazquez-Anderson, Jorge; Contreras, Lydia M

    2013-01-01

    RNAs have many important functional properties, including that they are independently controllable and highly tunable. As a result of these advantageous properties, their use in a myriad of sophisticated devices has been widely explored. Yet, the exploitation of RNAs for synthetic applications is highly dependent on the ability to characterize the many new molecules that continue to be discovered by large-scale sequencing and high-throughput screening techniques. In this review, we present an exhaustive survey of the most recent synthetic bacterial riboswitches and small RNAs while emphasizing their virtues in gene expression management. We also explore the use of these RNA components as building blocks in the RNA synthetic biology toolbox and discuss examples of synthetic RNA components used to rewire bacterial regulatory circuitry. We anticipate that this field will expand its catalog of smart devices by mimicking and manipulating natural RNA mechanisms and functions. PMID:24356572

  5. RAB-10-Dependent Membrane Transport Is Required for Dendrite Arborization

    PubMed Central

    Zou, Wei; Yadav, Smita; DeVault, Laura; Jan, Yuh Nung; Sherwood, David R.

    2015-01-01

    Formation of elaborately branched dendrites is necessary for the proper input and connectivity of many sensory neurons. Previous studies have revealed that dendritic growth relies heavily on ER-to-Golgi transport, Golgi outposts and endocytic recycling. How new membrane and associated cargo is delivered from the secretory and endosomal compartments to sites of active dendritic growth, however, remains unknown. Using a candidate-based genetic screen in C. elegans, we have identified the small GTPase RAB-10 as a key regulator of membrane trafficking during dendrite morphogenesis. Loss of rab-10 severely reduced proximal dendritic arborization in the multi-dendritic PVD neuron. RAB-10 acts cell-autonomously in the PVD neuron and localizes to the Golgi and early endosomes. Loss of function mutations of the exocyst complex components exoc-8 and sec-8, which regulate tethering, docking and fusion of transport vesicles at the plasma membrane, also caused proximal dendritic arborization defects and led to the accumulation of intracellular RAB-10 vesicles. In rab-10 and exoc-8 mutants, the trans-membrane proteins DMA-1 and HPO-30, which promote PVD dendrite stabilization and branching, no longer localized strongly to the proximal dendritic membranes and instead were sequestered within intracellular vesicles. Together these results suggest a crucial role for the Rab10 GTPase and the exocyst complex in controlling membrane transport from the secretory and/or endosomal compartments that is required for dendritic growth. PMID:26394140

  6. 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

  7. Simulation of dendritic growth reveals necessary and sufficient parameters to describe the shapes of dendritic trees

    NASA Astrophysics Data System (ADS)

    Trottier, Olivier; Ganguly, Sujoy; Bowne-Anderson, Hugo; Liang, Xin; Howard, Jonathon

    For the last 120 years, the development of neuronal shapes has been of great interest to the scientific community. Over the last 30 years, significant work has been done on the molecular processes responsible for dendritic development. In our ongoing research, we use the class IV sensory neurons of the Drosophila melanogaster larva as a model system to understand the growth of dendritic arbors. Our main goal is to elucidate the mechanisms that the neuron uses to determine the shape of its dendritic tree. We have observed the development of the class IV neuron's dendritic tree in the larval stage and have concluded that morphogenesis is defined by 3 distinct processes: 1) branch growth, 2) branching and 3) branch retraction. As the first step towards understanding dendritic growth, we have implemented these three processes in a computational model. Our simulations are able to reproduce the branch length distribution, number of branches and fractal dimension of the class IV neurons for a small range of parameters.

  8. Somato-dendritic Synaptic Plasticity and Error-backpropagation in Active Dendrites.

    PubMed

    Schiess, Mathieu; Urbanczik, Robert; Senn, Walter

    2016-02-01

    In the last decade dendrites of cortical neurons have been shown to nonlinearly combine synaptic inputs by evoking local dendritic spikes. It has been suggested that these nonlinearities raise the computational power of a single neuron, making it comparable to a 2-layer network of point neurons. But how these nonlinearities can be incorporated into the synaptic plasticity to optimally support learning remains unclear. We present a theoretically derived synaptic plasticity rule for supervised and reinforcement learning that depends on the timing of the presynaptic, the dendritic and the postsynaptic spikes. For supervised learning, the rule can be seen as a biological version of the classical error-backpropagation algorithm applied to the dendritic case. When modulated by a delayed reward signal, the same plasticity is shown to maximize the expected reward in reinforcement learning for various coding scenarios. Our framework makes specific experimental predictions and highlights the unique advantage of active dendrites for implementing powerful synaptic plasticity rules that have access to downstream information via backpropagation of action potentials. PMID:26841235

  9. Evaluating Local Primary Dendrite Arm Spacing Characterization Techniques Using Synthetic Directionally Solidified Dendritic Microstructures

    NASA Astrophysics Data System (ADS)

    Tschopp, Mark A.; Miller, Jonathan D.; Oppedal, Andrew L.; Solanki, Kiran N.

    2015-10-01

    Microstructure characterization continues to play an important bridge to understanding why particular processing routes or parameters affect the properties of materials. This statement certainly holds true in the case of directionally solidified dendritic microstructures, where characterizing the primary dendrite arm spacing is vital to developing the process-structure-property relationships that can lead to the design and optimization of processing routes for defined properties. In this work, four series of simulations were used to examine the capability of a few Voronoi-based techniques to capture local microstructure statistics (primary dendrite arm spacing and coordination number) in controlled (synthetically generated) microstructures. These simulations used both cubic and hexagonal microstructures with varying degrees of disorder (noise) to study the effects of length scale, base microstructure, microstructure variability, and technique parameters on the local PDAS distribution, local coordination number distribution, bulk PDAS, and bulk coordination number. The Voronoi tesselation technique with a polygon-side-length criterion correctly characterized the known synthetic microstructures. By systematically studying the different techniques for quantifying local primary dendrite arm spacings, we have evaluated their capability to capture this important microstructure feature in different dendritic microstructures, which can be an important step for experimentally correlating with both processing and properties in single crystal nickel-based superalloys.

  10. Somato-dendritic Synaptic Plasticity and Error-backpropagation in Active Dendrites

    PubMed Central

    Schiess, Mathieu; Urbanczik, Robert; Senn, Walter

    2016-01-01

    In the last decade dendrites of cortical neurons have been shown to nonlinearly combine synaptic inputs by evoking local dendritic spikes. It has been suggested that these nonlinearities raise the computational power of a single neuron, making it comparable to a 2-layer network of point neurons. But how these nonlinearities can be incorporated into the synaptic plasticity to optimally support learning remains unclear. We present a theoretically derived synaptic plasticity rule for supervised and reinforcement learning that depends on the timing of the presynaptic, the dendritic and the postsynaptic spikes. For supervised learning, the rule can be seen as a biological version of the classical error-backpropagation algorithm applied to the dendritic case. When modulated by a delayed reward signal, the same plasticity is shown to maximize the expected reward in reinforcement learning for various coding scenarios. Our framework makes specific experimental predictions and highlights the unique advantage of active dendrites for implementing powerful synaptic plasticity rules that have access to downstream information via backpropagation of action potentials. PMID:26841235

  11. A Genome-Wide Screen for Dendritically Localized RNAs Identifies Genes Required for Dendrite Morphogenesis

    PubMed Central

    Misra, Mala; Edmund, Hendia; Ennis, Darragh; Schlueter, Marissa A.; Marot, Jessica E.; Tambasco, Janet; Barlow, Ida; Sigurbjornsdottir, Sara; Mathew, Renjith; Vallés, Ana Maria; Wojciech, Waldemar; Roth, Siegfried; Davis, Ilan; Leptin, Maria; Gavis, Elizabeth R.

    2016-01-01

    Localizing messenger RNAs at specific subcellular sites is a conserved mechanism for targeting the synthesis of cytoplasmic proteins to distinct subcellular domains, thereby generating the asymmetric protein distributions necessary for cellular and developmental polarity. However, the full range of transcripts that are asymmetrically distributed in specialized cell types, and the significance of their localization, especially in the nervous system, are not known. We used the EP-MS2 method, which combines EP transposon insertion with the MS2/MCP in vivo fluorescent labeling system, to screen for novel localized transcripts in polarized cells, focusing on the highly branched Drosophila class IV dendritic arborization neurons. Of a total of 541 lines screened, we identified 55 EP-MS2 insertions producing transcripts that were enriched in neuronal processes, particularly in dendrites. The 47 genes identified by these insertions encode molecularly diverse proteins, and are enriched for genes that function in neuronal development and physiology. RNAi-mediated knockdown confirmed roles for many of the candidate genes in dendrite morphogenesis. We propose that the transport of mRNAs encoded by these genes into the dendrites allows their expression to be regulated on a local scale during the dynamic developmental processes of dendrite outgrowth, branching, and/or remodeling. PMID:27260999

  12. A Genome-Wide Screen for Dendritically Localized RNAs Identifies Genes Required for Dendrite Morphogenesis.

    PubMed

    Misra, Mala; Edmund, Hendia; Ennis, Darragh; Schlueter, Marissa A; Marot, Jessica E; Tambasco, Janet; Barlow, Ida; Sigurbjornsdottir, Sara; Mathew, Renjith; Vallés, Ana Maria; Wojciech, Waldemar; Roth, Siegfried; Davis, Ilan; Leptin, Maria; Gavis, Elizabeth R

    2016-01-01

    Localizing messenger RNAs at specific subcellular sites is a conserved mechanism for targeting the synthesis of cytoplasmic proteins to distinct subcellular domains, thereby generating the asymmetric protein distributions necessary for cellular and developmental polarity. However, the full range of transcripts that are asymmetrically distributed in specialized cell types, and the significance of their localization, especially in the nervous system, are not known. We used the EP-MS2 method, which combines EP transposon insertion with the MS2/MCP in vivo fluorescent labeling system, to screen for novel localized transcripts in polarized cells, focusing on the highly branched Drosophila class IV dendritic arborization neurons. Of a total of 541 lines screened, we identified 55 EP-MS2 insertions producing transcripts that were enriched in neuronal processes, particularly in dendrites. The 47 genes identified by these insertions encode molecularly diverse proteins, and are enriched for genes that function in neuronal development and physiology. RNAi-mediated knockdown confirmed roles for many of the candidate genes in dendrite morphogenesis. We propose that the transport of mRNAs encoded by these genes into the dendrites allows their expression to be regulated on a local scale during the dynamic developmental processes of dendrite outgrowth, branching, and/or remodeling. PMID:27260999

  13. 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

  14. Lid for improved dendritic web growth

    DOEpatents

    Duncan, Charles S.; Kochka, Edgar L.; Piotrowski, Paul A.; Seidensticker, Raymond G.

    1992-03-24

    A lid for a susceptor in which a crystalline material is melted by induction heating to form a pool or melt of molten material from which a dendritic web of essentially a single crystal of the material is pulled through an elongated slot in the lid and the lid has a pair of generally round openings adjacent the ends of the slot and a groove extends between each opening and the end of the slot. The grooves extend from the outboard surface of the lid to adjacent the inboard surface providing a strip contiguous with the inboard surface of the lid to produce generally uniform radiational heat loss across the width of the dendritic web adjacent the inboard surface of the lid to reduce thermal stresses in the web and facilitate the growth of wider webs at a greater withdrawal rate.

  15. Asteroid core crystallization by inward dendritic growth

    NASA Technical Reports Server (NTRS)

    Haack, Henning; Scott, Edward R. D.

    1992-01-01

    The physics of the asteroid core crystallization process in metallic asteroids is investigated, with special attention given to the initial conditions for core crystallization, the manner of crystallization, the mechanisms acting in the stirring of the liquid, and the effects of elements such as sulfur on crystallization of Fe-Ni. On the basis of theoretical considerations and the published data on iron meteorites, it is suggested that the mode of crystallization in asteroid core was different from the apparent outward concentric crystallization of the earth core, in that the crystallization of asteroidal cores commenced at the base of the mantle and proceeded inward. The inward crystallization resulted in complex dendritic growth. These dendrites may have grown to lengths of hundreds of meters or perhaps even as large as the core radius, thereby dividing the core into separate magma chambers.

  16. Endoplasmic reticulum calcium stores in dendritic spines

    PubMed Central

    Segal, Menahem; Korkotian, Eduard

    2014-01-01

    Despite decades of research, the role of calcium stores in dendritic spines structure, function and plasticity is still debated. The reasons for this may have to do with the multitude of overlapping calcium handling machineries in the neuron, including stores, voltage and ligand gated channels, pumps and transporters. Also, different cells in the brain are endowed with calcium stores that are activated by different receptor types, and their differential compartmentalization in dendrites, spines and presynaptic terminals complicates their analysis. In the present review we address several key issues, including the role of calcium stores in synaptic plasticity, their role during development, in stress and in neurodegenerative diseases. Apparently, there is increasing evidence for a crucial role of calcium stores, especially of the ryanodine species, in synaptic plasticity and neuronal survival. PMID:25071469

  17. 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

  18. 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

  19. Epidermis-Derived Semaphorin Promotes Dendrite Self-Avoidance by Regulating Dendrite-Substrate Adhesion in Drosophila Sensory Neurons.

    PubMed

    Meltzer, Shan; Yadav, Smita; Lee, Jiae; Soba, Peter; Younger, Susan H; Jin, Peng; Zhang, Wei; Parrish, Jay; Jan, Lily Yeh; Jan, Yuh-Nung

    2016-02-17

    Precise patterning of dendritic arbors is critical for the wiring and function of neural circuits. Dendrite-extracellular matrix (ECM) adhesion ensures that the dendrites of Drosophila dendritic arborization (da) sensory neurons are properly restricted in a 2D space, and thereby facilitates contact-mediated dendritic self-avoidance and tiling. However, the mechanisms regulating dendrite-ECM adhesion in vivo are poorly understood. Here, we show that mutations in the semaphorin ligand sema-2b lead to a dramatic increase in self-crossing of dendrites due to defects in dendrite-ECM adhesion, resulting in a failure to confine dendrites to a 2D plane. Furthermore, we find that Sema-2b is secreted from the epidermis and signals through the Plexin B receptor in neighboring neurons. Importantly, we find that Sema-2b/PlexB genetically and physically interacts with TORC2 complex, Tricornered (Trc) kinase, and integrins. These results reveal a novel role for semaphorins in dendrite patterning and illustrate how epidermal-derived cues regulate neural circuit assembly. PMID:26853303

  20. The discovery of dendritic spines by Cajal.

    PubMed

    Yuste, Rafael

    2015-01-01

    Dendritic spines were considered an artifact of the Golgi method until a brash Spanish histologist, Santiago Ramón y Cajal, bet his scientific career arguing that they were indeed real, correctly deducing their key role in mediating synaptic connectivity. This article reviews the historical context of the discovery of spines and the reasons behind Cajal's obsession with them, all the way till his deathbed. PMID:25954162

  1. 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.

  2. The discovery of dendritic spines by Cajal

    PubMed Central

    Yuste, Rafael

    2015-01-01

    Dendritic spines were considered an artifact of the Golgi method until a brash Spanish histologist, Santiago Ramón y Cajal, bet his scientific career arguing that they were indeed real, correctly deducing their key role in mediating synaptic connectivity. This article reviews the historical context of the discovery of spines and the reasons behind Cajal's obsession with them, all the way till his deathbed. PMID:25954162

  3. A study of dendritic web silicon

    NASA Astrophysics Data System (ADS)

    Zhang, Xinyu

    Dendritic web silicon is a material used in the fabrication of large-scale terrestrial solar cells. It is grown from the thin silicon liquid film supported by bounding dendrites. The growth of long and wide web silicon with low defect density is the key to lowering the cost and increasing the efficiency of a solar cell. However, the web growth may be terminated by polycrystals, especially for the growth of wide ribbons, and high density dislocations (104 cm-2) are then found in the web silicon. In this study, chemical etching, electron channeling, atomic force microscopy and transmission X-ray topography with rotating anode and synchrotron radiation sources were used to characterize web samples that were grown under different conditions. The experimental results show that the twin planes, which are important for dendrite growth, are not required for web growth. Web is grown by step flowing from dendrite regions toward the central web region on the solid/melt interface. Web growth is strongly affected by the fluctuation of thermal profile. The web position shift during growth results in the emergence of twin planes onto the web surface. It is also found that the grain boundaries were formed due to the edge dislocations aligning in the conjunctional (11¯0) planes. The mechanisms for the formation of the edge dislocations are discussed. The surface steps introduced the high local strain by blocking the slip dislocations, which also contributes to the formation of grain boundaries. The distribution of dislocations and residual strain in the web region were studied based on the X-ray topography results. The contrast reversion in the synchrotron beam X-ray topography images was observed, which indicates the change of lattice strain during web growth. Also, from those results, a new type of edge dislocation was identified at the region under high vertical strain. Recommendations for future work are discussed based on the current conclusions.

  4. 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

  5. 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

  6. 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

  7. 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

  8. 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

  9. 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

  10. 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

  11. Microheterogeneity of calcium signalling in dendrites.

    PubMed

    Pozzo-Miller, L D; Connor, J A; Andrews, S B

    2000-05-15

    Transient changes in the intracellular concentration of free Ca2+ ([Ca2+]i) originating from voltage- or ligand-gated influx and by ligand- or Ca2+-gated release from intracellular stores, trigger or modulate many fundamental neuronal processes, including neurotransmitter release and synaptic plasticity. Of the intracellular compartments involved in Ca2+ clearance, the endoplasmic reticulum (ER) has received the most attention because it expresses Ca2+ pumps and Ca2+ channels, thus endowing it with the potential to act as both an intracellular calcium sink and store. We review here our ongoing work on the role of calcium sequestration into, and release from, ER cisterns and the role that this plays in the generation and termination of free [Ca2+]i transients in dendrites of pyramidal neurons in hippocampal slices during and after synaptic activity. These studies have been approached by combining parallel microfluorometric measurements of free cytosolic [Ca2+]i transients with energy-dispersive X-ray microanalytical measurements of total Ca content within specific dendritic compartments at the electron microscopy level. Our observations support the emerging realization that specific subsets of dendritic ER cisterns provide spatial and temporal microheterogeneity of Ca2+ signalling, acting not only as a major intracellular Ca sink involved in active clearance mechanisms after voltage- and ligand-gated Ca2+ influx, but also as an intracellular Ca2+ source that can be mobilized by a signal cascade originating at activated synapses. PMID:10811724

  12. The Isothermal Dendritic Growth Experiment Archive

    NASA Astrophysics Data System (ADS)

    Koss, Matthew

    2009-03-01

    The growth of dendrites is governed by the interplay between two simple and familiar processes---the irreversible diffusion of energy, and the reversible work done in the formation of new surface area. To advance our understanding of these processes, NASA sponsored a project that flew on the Space Shuttle Columbia is 1994, 1996, and 1997 to record and analyze benchmark data in an apparent-microgravity ``laboratory.'' In this laboratory, energy transfer by gravity driven convection was essentially eliminated and one could test independently, for the first time, both components of dendritic growth theory. The analysis of this data shows that although the diffusion of energy can be properly accounted for, the results from interfacial physics appear to be in disagreement and alternate models should receive increased attention. Unfortunately, currently and for the foreseeable future, there is no access or financial support to develop and conduct additional experiments of this type. However, the benchmark data of 35mm photonegatives, video, and all supporting instrument data are now available at the IDGE Archive at the College of the Holy Cross. This data may still have considerable relevance to researchers working specifically with dendritic growth, and more generally those working in the synthesis, growth & processing of materials, multiscale computational modeling, pattern formation, and systems far from equilibrium.

  13. 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

  14. Dendritic NMDA receptors activate axonal calcium channels

    PubMed Central

    Christie, Jason M.; Jahr, Craig E.

    2008-01-01

    Summary NMDA receptor (NMDAR) activation can alter synaptic strength by regulating transmitter release from a variety of neurons in the CNS. As NMDARs are permeable to Ca2+ and monovalent cations, they could alter release directly by increasing presynaptic Ca2+ or indirectly by axonal depolarization sufficient to activate voltage-sensitive Ca2+ channels (VSCCs). Using two-photon microscopy to measure Ca2+ excursions, we found that somatic depolarization or focal activation of dendritic NMDARs elicited small Ca2+ transients in axon varicosities of cerebellar stellate cell interneurons. These axonal transients resulted from Ca2+ entry through VSCCs that were opened by the electrotonic spread of the NMDAR-mediated depolarization elicited in the dendrites. In contrast, we were unable to detect direct activation of NMDARs on axons indicating an exclusive somatodendritic expression of functional NMDARs. In cerebellar stellate cells, dendritic NMDAR activation masquerades as a presynaptic phenomenon and may influence Ca2+-dependent forms of presynaptic plasticity and release. PMID:18957221

  15. Location-dependent synaptic plasticity rules by dendritic spine cooperativity.

    PubMed

    Weber, Jens P; Andrásfalvy, Bertalan K; Polito, Marina; Magó, Ádám; Ujfalussy, Balázs B; Makara, Judit K

    2016-01-01

    Nonlinear interactions between coactive synapses enable neurons to discriminate between spatiotemporal patterns of inputs. Using patterned postsynaptic stimulation by two-photon glutamate uncaging, here we investigate the sensitivity of synaptic Ca(2+) signalling and long-term plasticity in individual spines to coincident activity of nearby synapses. We find a proximodistally increasing gradient of nonlinear NMDA receptor (NMDAR)-mediated amplification of spine Ca(2+) signals by a few neighbouring coactive synapses along individual perisomatic dendrites. This synaptic cooperativity does not require dendritic spikes, but is correlated with dendritic Na(+) spike propagation strength. Furthermore, we show that repetitive synchronous subthreshold activation of small spine clusters produces input specific, NMDAR-dependent cooperative long-term potentiation at distal but not proximal dendritic locations. The sensitive synaptic cooperativity at distal dendritic compartments shown here may promote the formation of functional synaptic clusters, which in turn can facilitate active dendritic processing and storage of information encoded in spatiotemporal synaptic activity patterns. PMID:27098773

  16. Location-dependent synaptic plasticity rules by dendritic spine cooperativity

    PubMed Central

    Weber, Jens P.; Andrásfalvy, Bertalan K.; Polito, Marina; Magó, Ádám; Ujfalussy, Balázs B.; Makara, Judit K.

    2016-01-01

    Nonlinear interactions between coactive synapses enable neurons to discriminate between spatiotemporal patterns of inputs. Using patterned postsynaptic stimulation by two-photon glutamate uncaging, here we investigate the sensitivity of synaptic Ca2+ signalling and long-term plasticity in individual spines to coincident activity of nearby synapses. We find a proximodistally increasing gradient of nonlinear NMDA receptor (NMDAR)-mediated amplification of spine Ca2+ signals by a few neighbouring coactive synapses along individual perisomatic dendrites. This synaptic cooperativity does not require dendritic spikes, but is correlated with dendritic Na+ spike propagation strength. Furthermore, we show that repetitive synchronous subthreshold activation of small spine clusters produces input specific, NMDAR-dependent cooperative long-term potentiation at distal but not proximal dendritic locations. The sensitive synaptic cooperativity at distal dendritic compartments shown here may promote the formation of functional synaptic clusters, which in turn can facilitate active dendritic processing and storage of information encoded in spatiotemporal synaptic activity patterns. PMID:27098773

  17. Random positions of dendritic spines in human cerebral cortex.

    PubMed

    Morales, Juan; Benavides-Piccione, Ruth; Dar, Mor; Fernaud, Isabel; Rodríguez, Angel; Anton-Sanchez, Laura; Bielza, Concha; Larrañaga, Pedro; DeFelipe, Javier; Yuste, Rafael

    2014-07-23

    Dendritic spines establish most excitatory synapses in the brain and are located in Purkinje cell's dendrites along helical paths, perhaps maximizing the probability to contact different axons. To test whether spine helixes also occur in neocortex, we reconstructed >500 dendritic segments from adult human cortex obtained from autopsies. With Fourier analysis and spatial statistics, we analyzed spine position along apical and basal dendrites of layer 3 pyramidal neurons from frontal, temporal, and cingulate cortex. Although we occasionally detected helical positioning, for the great majority of dendrites we could not reject the null hypothesis of spatial randomness in spine locations, either in apical or basal dendrites, in neurons of different cortical areas or among spines of different volumes and lengths. We conclude that in adult human neocortex spine positions are mostly random. We discuss the relevance of these results for spine formation and plasticity and their functional impact for cortical circuits. PMID:25057209

  18. Random Positions of Dendritic Spines in Human Cerebral Cortex

    PubMed Central

    Morales, Juan; Benavides-Piccione, Ruth; Dar, Mor; Fernaud, Isabel; Rodríguez, Angel; Anton-Sanchez, Laura; Bielza, Concha; Larrañaga, Pedro; DeFelipe, Javier

    2014-01-01

    Dendritic spines establish most excitatory synapses in the brain and are located in Purkinje cell's dendrites along helical paths, perhaps maximizing the probability to contact different axons. To test whether spine helixes also occur in neocortex, we reconstructed >500 dendritic segments from adult human cortex obtained from autopsies. With Fourier analysis and spatial statistics, we analyzed spine position along apical and basal dendrites of layer 3 pyramidal neurons from frontal, temporal, and cingulate cortex. Although we occasionally detected helical positioning, for the great majority of dendrites we could not reject the null hypothesis of spatial randomness in spine locations, either in apical or basal dendrites, in neurons of different cortical areas or among spines of different volumes and lengths. We conclude that in adult human neocortex spine positions are mostly random. We discuss the relevance of these results for spine formation and plasticity and their functional impact for cortical circuits. PMID:25057209

  19. Molecular identity of dendritic voltage-gated sodium channels.

    PubMed

    Lorincz, Andrea; Nusser, Zoltan

    2010-05-14

    Active invasion of the dendritic tree by action potentials (APs) generated in the axon is essential for associative synaptic plasticity and neuronal ensemble formation. In cortical pyramidal cells (PCs), this AP back-propagation is supported by dendritic voltage-gated Na+ (Nav) channels, whose molecular identity is unknown. Using a highly sensitive electron microscopic immunogold technique, we revealed the presence of the Nav1.6 subunit in hippocampal CA1 PC proximal and distal dendrites. Here, the subunit density is lower by a factor of 35 to 80 than that found in axon initial segments. A gradual decrease in Nav1.6 density along the proximodistal axis of the dendritic tree was also detected without any labeling in dendritic spines. Our results reveal the characteristic subcellular distribution of the Nav1.6 subunit, identifying this molecule as a key substrate enabling dendritic excitability. PMID:20466935

  20. Special fractal growth of dendrite copper using a hydrothermal method

    NASA Astrophysics Data System (ADS)

    Zheng, Yan; Zhang, Zhejuan; Guo, Pingsheng; He, Pingang; Sun, Zhuo

    2011-08-01

    Special fractal dendrite Cu nanostructures have been synthesized through a simple hydrothermal method, and the effects of the volume ratio between glycerol and water and the concentration of H 3PO 3 on the morphologies of dendrite Cu have been studied in detail. The Field emission scanning electron microscopy (FESEM), Transmission electron microscopy (TEM) and X-ray diffraction (XRD) have been used to characterize these Cu products. The results indicate that rhombic diamond and different morphologies of fractal dendrite were prepared because of the accumulation of Cu nuclei based on the diffusion-limited aggregation (DLA) and the nucleation-limited aggregation (NLA) model. Fortunately, symmetrical leaf-like dendrite Cu nanostructures different from Cu dendrites reported before have been obtained. Additionally, an explanation for the growth of fractal dendrite Cu has been discussed carefully.

  1. Neural pattern formation in networks with dendritic structure

    NASA Astrophysics Data System (ADS)

    Bressloff, P. C.; De Souza, B.

    1998-04-01

    We present a detailed analysis of a recently proposed model of neural pattern formation that is based on the combined effect of diffusion along a neuron's dendritic tree and recurrent interactions along axo-dendritic synaptic connections. For concreteness, we consider a one-dimensional array of analog neurons with the dendritic tree idealized as a one-dimensional cable. Linear stability analysis and bifurcation theory together with numerical simulations are used to establish conditions for the onset of a Turing instability leading to the formation of stable spatial patterns of network output activity. It is shown that the presence of dendritic structure can induce dynamic (time-periodic) spatial pattern formation. Moreover, correlations between the dendritic location of a synapse and the relative positions of neurons in the network are shown to result in spatially oscillating patterns of activity along the dendrites of each neuron.

  2. Evidence for tip velocity oscillations in dendritic solidification

    NASA Astrophysics Data System (ADS)

    Lacombe, J. C.; Koss, M. B.; Frei, J. E.; Giummarra, C.; Lupulescu, A. O.; Glicksman, M. E.

    2002-03-01

    Dendritic growth experiments were conducted in the reduced-convection environment aboard the space shuttle Columbia on STS-87. Spectral analysis was performed on 30-frame/s video data during growths of isothermal dendrites. Results indicate that pivalic acid dendrites exhibit a subtle oscillatory behavior of the axial growth velocity near the tip, with a frequency component that is associated with the sidebranch formation process.

  3. Evidence for tip velocity oscillations in dendritic solidification.

    PubMed

    LaCombe, J C; Koss, M B; Frei, J E; Giummarra, C; Lupulescu, A O; Glicksman, M E

    2002-03-01

    Dendritic growth experiments were conducted in the reduced-convection environment aboard the space shuttle Columbia on STS-87. Spectral analysis was performed on 30-frame/s video data during growths of isothermal dendrites. Results indicate that pivalic acid dendrites exhibit a subtle oscillatory behavior of the axial growth velocity near the tip, with a frequency component that is associated with the sidebranch formation process. PMID:11909070

  4. 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

  5. Assessing effects on dendritic arborization using novel Sholl analyses.

    PubMed

    O'Neill, Kate M; Akum, Barbara F; Dhawan, Survandita T; Kwon, Munjin; Langhammer, Christopher G; Firestein, Bonnie L

    2015-01-01

    Determining the shape of cell-specific dendritic arbors is a tightly regulated process that occurs during development. When this regulation is aberrant, which occurs during disease or injury, alterations in dendritic shape result in changes to neural circuitry. There has been significant progress on characterizing extracellular and intrinsic factors that regulate dendrite number by our laboratory and others. Generally, changes to the dendritic arbor are assessed by Sholl analysis or simple dendrite counting. However, we have found that this general method often overlooks local changes to the arbor. Previously, we developed a program (titled Bonfire) to facilitate digitization of neurite morphology and subsequent Sholl analysis and to assess changes to root, intermediate, and terminal neurites. Here, we apply these different Sholl analyses, and a novel Sholl analysis, to uncover previously unknown changes to the dendritic arbor when we overexpress an important regulator of dendrite branching, cytosolic PSD-95 interactor (cypin), at two developmental time points. Our results suggest that standard Sholl analysis and simple dendrite counting are not sufficient for uncovering local changes to the dendritic arbor. PMID:26283921

  6. CTAB-Influenced Electrochemical Dissolution of Silver Dendrites.

    PubMed

    O'Regan, Colm; Zhu, Xi; Zhong, Jun; Anand, Utkarsh; Lu, Jingyu; Su, Haibin; Mirsaidov, Utkur

    2016-04-19

    Dendrite formation on the electrodes of a rechargeable battery during the charge-discharge cycle limits its capacity and application due to short-circuits and potential ignition. However, understanding of the underlying dendrite growth and dissolution mechanisms is limited. Here, the electrochemical growth and dissolution of silver dendrites on platinum electrodes immersed in an aqueous silver nitrate (AgNO3) electrolyte solution was investigated using in situ liquid-cell transmission electron microscopy (TEM). The dissolution of Ag dendrites in an AgNO3 solution with added cetyltrimethylammonium bromide (CTAB) surfactant was compared to the dissolution of Ag dendrites in a pure aqueous AgNO3 solution. Significantly, when CTAB was added, dendrite dissolution proceeded in a step-by-step manner, resulting in nanoparticle formation and transient microgrowth stages due to Ostwald ripening. This resulted in complete dissolution of dendrites and "cleaning" of the cell of any silver metal. This is critical for practical battery applications because "dead" lithium is known to cause short circuits and high-discharge rates. In contrast to this, in a pure aqueous AgNO3 solution, without surfactant, dendrites dissolved incompletely back into solution, leaving behind minute traces of disconnected silver particles. Finally, a mechanism for the CTAB-influenced dissolution of silver dendrites was proposed based on electrical field dependent binding energy of CTA(+) to silver. PMID:27017834

  7. Dendritic spikes enhance stimulus selectivity in cortical neurons in vivo.

    PubMed

    Smith, Spencer L; Smith, Ikuko T; Branco, Tiago; Häusser, Michael

    2013-11-01

    Neuronal dendrites are electrically excitable: they can generate regenerative events such as dendritic spikes in response to sufficiently strong synaptic input. Although such events have been observed in many neuronal types, it is not well understood how active dendrites contribute to the tuning of neuronal output in vivo. Here we show that dendritic spikes increase the selectivity of neuronal responses to the orientation of a visual stimulus (orientation tuning). We performed direct patch-clamp recordings from the dendrites of pyramidal neurons in the primary visual cortex of lightly anaesthetized and awake mice, during sensory processing. Visual stimulation triggered regenerative local dendritic spikes that were distinct from back-propagating action potentials. These events were orientation tuned and were suppressed by either hyperpolarization of membrane potential or intracellular blockade of NMDA (N-methyl-d-aspartate) receptors. Both of these manipulations also decreased the selectivity of subthreshold orientation tuning measured at the soma, thus linking dendritic regenerative events to somatic orientation tuning. Together, our results suggest that dendritic spikes that are triggered by visual input contribute to a fundamental cortical computation: enhancing orientation selectivity in the visual cortex. Thus, dendritic excitability is an essential component of behaviourally relevant computations in neurons. PMID:24162850

  8. Bent dendrite growth in undercooled Fe-B alloy melts

    NASA Astrophysics Data System (ADS)

    Karrasch, C.; Volkmann, T.; Valloton, J.; Kolbe, M.; Herlach, DM

    2016-03-01

    Dendritic growth is the main solidification mode in alloy casting. In order to control dendrite growth for materials design from the melt it is important to fully understand the influence of process conditions. This study stands as an experimental note observing bent dendrite growth in Fe-B alloys and suggesting possible explanations as induced by fluid flow, thermal, and concentrational diffusion or impurities. Electromagnetic levitation technique (EML) is used for containerless processing of undercooled melts under 1g and reduced gravity conditions in parabolic flight. Further investigations are needed to find a suitable explanation for the observed bent dendrite growth behaviour.

  9. Mapping homeostatic synaptic plasticity using cable properties of dendrites.

    PubMed

    Queenan, B N; Lee, K J; Tan, H; Huganir, R L; Vicini, S; Pak, D T S

    2016-02-19

    When chronically silenced, cortical and hippocampal neurons homeostatically upregulate excitatory synaptic function. However, the subcellular position of such changes on the dendritic tree is not clear. We exploited the cable-filtering properties of dendrites to derive a parameter, the dendritic filtering index (DFI), to map the spatial distribution of synaptic currents. Our analysis indicates that young rat cortical neurons globally scale AMPA receptor-mediated currents, while mature hippocampal neurons do not, revealing distinct homeostatic strategies between brain regions and developmental stages. The DFI presents a useful tool for mapping the dendritic origin of synaptic currents and the location of synaptic plasticity changes. PMID:26701298

  10. The Evolution of Dendrite Morphology during Isothermal Coarsening

    NASA Technical Reports Server (NTRS)

    Alkemper, Jens; Mendoza, Roberto; Kammer, Dimitris; Voorhees, Peter W.

    2003-01-01

    Dendrite coarsening is a common phenomenon in casting processes. From the time dendrites are formed until the inter-dendritic liquid is completely solidified dendrites are changing shape driven by variations in interfacial curvature along the dendrite and resulting in a reduction of total interfacial area. During this process the typical length-scale of the dendrite can change by orders of magnitude and the final microstructure is in large part determined by the coarsening parameters. Dendrite coarsening is thus crucial in setting the materials parameters of ingots and of great commercial interest. This coarsening process is being studied in the Pb-Sn system with Sn-dendrites undergoing isothermal coarsening in a Pb-Sn liquid. Results are presented for samples of approximately 60% dendritic phase, which have been coarsened for different lengths of times. Presented are three-dimensional microstructures obtained by serial-sectioning and an analysis of these microstructures with regard to interface orientation and interfacial curvatures. These graphs reflect the evolution of not only the microstructure itself, but also of the underlying driving forces of the coarsening process. As a visualization of the link between the microstructure and the driving forces a three-dimensional microstructure with the interfaces colored according to the local interfacial mean curvature is shown.