Search

Combinational immunotherapy of dendritic cell (DC) vaccines and anti‐programmed cell death protein 1 antibodies (aPD1) has been regarded as a promising strategy for cancer treatment because it not only induces tumor‐specific T cell immune responses, but also prevents failure of T cell functions by the immune suppressive milieu of tumors. Microneedles have emerged as an innovative platform for efficient transdermal immunotherapies. However, co‐delivery of DC vaccines and aPD1 via microneedles has not been studied since conventional microneedle platforms are unsuitable for fragile therapeutics like living cells and antibodies. This study employs our newly invented cryomicroneedles (cryoMNs) to co‐deliver DC vaccines and aPD1 for the combinational immunotherapy. CryoMNs are fabricated by stepwise cryogenic micromoulding of cryogenic medium with pre‐suspended DCs and aPD1, which are further integrated with a homemade handle for convenient application. The viability of DCs in cryoMNs remains above 85%. CryoMNs are mechanically strong enough to insert into porcine and mouse skin, successfully releasing DCs and aPD1 inside skin tissue after melting. Co‐delivery of ovalbumin (OVA)‐pulsed DCs (OVA‐DCs) and aPD1 via cryoMNs induced higher antigen‐specific cellular immune responses compared with the mono‐delivery of OVA‐DCs or aPD1. Finally, administration with cryoMNs co‐encapsulated with OVA‐DCs and aPD1 increases the infiltration of effector T cells in the tumor, resulting in stronger anti‐tumor therapeutic efficacy in both prophylactic and therapeutic melanoma models compared with administration with cryoMNs loaded with OVA‐DCs or aPD1. This study demonstrates the great potential of cryoMNs as a co‐delivery system of therapeutic cells and biomacromolecules for combinational therapies. [ABSTRACT FROM AUTHOR]

Plasmacytoid dendritic cells (pDCs), a subtype of DC, possess unique developmental, morphological, and functional traits that have sparked much debate over the years whether they should be categorized as DCs. The digestive system has the greatest mucosal tissue overall, and the pDC therein is responsible for shaping the adaptive and innate immunity of the gastrointestinal tract, resisting pathogen invasion through generating type I interferons, presenting antigens, and participating in immunological responses. Therefore, its alleged importance in the gut has received a lot of attention in recent years, and a fresh functional overview is still required. Here, we summarize the current understanding of mouse and human pDCs, ranging from their formation and different qualities compared with related cell types to their functional characteristics in intestinal disorders, including colon cancer, infections, autoimmune diseases, and intestinal graft‐versus‐host disease. The purpose of this review is to convey our insights, demonstrate the limits of existing research, and lay a theoretical foundation for the rational development and use of pDCs in future clinical practice. HIGHLIGHTS: pDCs are a subset of dendritic cells, and transcription factors play a crucial role in the process.pDCs contribute to intestinal immune responses by generating interferon (IFN) and presenting antigens.pDCs guard the intestinal mucosa and protect against the invasion of microbiota and pathogens in the gut, playing a pivotal role in gut infection and colon cancer. [ABSTRACT FROM AUTHOR]

In a companion article to this study,1 the successful programming of a JAWSII dendritic cell ( DC) line's antigen uptake and processing was demonstrated based on pre-treatment of DCs with a specific 'cocktail' of select chemokines. Chemokine pre-treatment modulated cytokine production before and after DC maturation [by lipopolysaccharide (LPS)]. After DC maturation, it induced an antigen uptake and processing capacity at levels 36% and 82% higher than in immature DCs, respectively. Such programming proffers a potential new approach to enhance vaccine efficiency. Unfortunately, simply enhancing antigen uptake does not guarantee the desired activation and proliferation of lymphocytes, e.g. CD4+ T cells. In this study, phenotype changes and antigen presentation capacity of chemokine pre-treated murine bone marrow-derived DCs were examined in long-term co-culture with antigen-specific CD4+ T cells to quantify how chemokine pre-treatment may impact the adaptive immune response. When a model antigen, ovalbumin ( OVA), was added after intentional LPS maturation of chemokine-treated DCs, OVA-biased CD4+ T-cell proliferation was initiated from ~ 100% more undivided naive T cells as compared to DCs treated only with LPS. Secretion of the cytokines interferon-γ, interleukin-1β, interleukin-2 and interleukin-10 in the CD4+ T cell : DC co-culture (with or without chemokine pre-treatment) were essentially the same. Chemokine programming of DCs with a 7 : 3 ratio of CCL3 : CCL19 followed by LPS treatment maintained partial immature phenotypes of DCs, as indicated by surface marker ( CD80 and CD86) expression over time. Results here and in our companion paper suggest that chemokine programming of DCs may provide a novel immunotherapy strategy to obviate the natural endocytosis limit of DC antigen uptake, thus potentially increasing DC-based vaccine efficiency. [ABSTRACT FROM AUTHOR]

Please cite this paper as: Leishmaniasis, contact hypersensitivity and graft-versus-host disease: understanding the role of dendritic cell subsets in balancing skin immunity and tolerance. Experimental Dermatology 2010; 19: 760-771. Abstract: Dendritic cells (DC) are key elements of the immune system. In peripheral tissues, they function as sentinels taking up and processing antigens. After migration to the draining lymph nodes, the DC either present antigenic peptides by themselves or transfer them to lymph node-resident DC. The skin is the primary interface between the body and the environment and host's various DC subsets, including dermal DC (dDC) and Langerhans cells (LC). Because of their anatomical position in the epidermis, LC are believed to be responsible for induction of adaptive cutaneous immune responses. The functions of LC and dDC in the skin immune system in vivo are manifold, and it is still discussed controversially whether the differentiation of T-cell subtypes (e.g. effector T cells and regulatory T cells) may be initiated by distinct DC subtypes. As skin DC are able to promote or downmodulate immune responses, we chose different skin diseases (cutaneous leishmaniasis, contact hypersensitivity, UV radiation-induced suppression, and graft-versus-host disease) to describe the biological interactions between different DC subtypes and T cells that lead to the development of efficient or unwanted immune responses. A detailed knowledge about the immune modulatory capacity of different cutaneous DC subsets might be helpful to specifically target these cells through the skin during therapeutic interventions. [ABSTRACT FROM AUTHOR]

In the early phases of an immune response, T cells of appropriate antigen specificity become activated by antigen-presenting cells in secondary lymphoid organs. Two-photon microscopy imaging experiments have shown that this stimulation occurs in distinct stages during which T cells exhibit different motilities and interactions with dendritic cells (DCs). In this paper, we utilize the Cellular Potts Model, a model formalism that takes cell shapes and cellular interactions explicitly into account, to simulate the dynamics of, and interactions between, T cells and DCs in the lymph node paracortex. Our three-dimensional simulations suggest that the initial decrease in T-cell motility after antigen appearance is due to ‘stop signals’ transmitted by activated DCs to T cells. The long-lived interactions that occur at a later stage can only be explained by the presence of both stop signals and a high adhesion between specific T cells and antigen-bearing DCs. Furthermore, our results indicate that long-lasting contacts with T cells are promoted when DCs retract dendrites that detect a specific contact at lower velocities than other dendrites. Finally, by performing long simulations (after prior fitting to short time scale data) we are able to provide an estimate of the average contact duration between T cells and DCs.Immunology and Cell Biology (2007) 85, 306–314. doi:10.1038/sj.icb.7100054; published online 10 April 2007 [ABSTRACT FROM AUTHOR]

Nerve growth factor (NGF) was originally considered as a trophic factor for peripheral sympathetic and sensory neurones; however, recent reports indicate that NGF may induce proliferation of immune and hacmatopoietic cells. Histochemical studies conducted in human spleen and lymph nodes have suggested the presence of NGF receptor (NGF-R) immunoreactive elements in secondary follicles; however the nature. of the cells bearing the NGF-R in lymphoid tissue has not been determined. In this paper we report the results of an immunohistochemical study conducted on mucosa associated lymphoid tissue. Using a specific monoclonal antibody to human NGF-R (mAb 20.4) we observed an NGF-R-immunoreactive population in all secondary lymphoid follicles examined. Double immunostaining revealed that this population was composed of follicular dendritic cells (FDC); lymphoid cells within the germinal centres did not appear to be 204 immunoreactive. Cell suspensions from tonsillar follicles also contained NGF-R immunopositive dendritic cells which were enriched by a 20.4 labelled magnetic bead procedure, revealing cells with the morphological characteristics of FDC. Mononuclear cells from human peripheral blood did not contain any NGF-R-immunoreactive elements using our techniques. [ABSTRACT FROM AUTHOR]

Dendritic cells (DCs)‐based tumor vaccines have the advantages of high safety and rapid activation of T cells, and have been approved for clinical tumor treatment. However, the conventional DC vaccines have some severe problems, such as poor activation of DCs in vitro, low level of antigen presentation, reduced cell viability, and difficulty in targeting lymph nodes in vivo, resulting in poor clinical therapeutic effects. In this research, magnetic nanoparticles Fe3O4@Ca/MnCO3 were prepared and used to actively and efficiently deliver antigens to the cytoplasm of DCs, promote antigen cross‐presentation and DC activation, and finally enhance the cellular immune response of DC vaccines. The results show that the magnetic nanoparticles can actively and quickly deliver antigens to the cytoplasm of DCs by regulating the magnetic field, and achieve cross‐presentation of antigens. At the same time, the nanoparticles degradation product Mn2+ enhanced immune stimulation through the interferon gene stimulating protein (STING) pathway, and another degradation product Ca2+ ultimately promoted cellular immune response by increasing autophagy. The DC vaccine constructed with the magnetic nanoparticles can more effectively migrate to the lymph nodes, promote the proliferation of CD8+ T cells, prolong the time of immune memory, and produce higher antibody levels. Compared with traditional DC vaccines, cytoplasmic antigen delivery with the magnetic nanoparticles provides a new idea for the construction of novel DC vaccines. [ABSTRACT FROM AUTHOR]

Background: Dendritic cells (DCs) mediate divergent immune effects by activating T cells or negatively regulating the immune response to promote immune tolerance. They perform specific functions determined by their tissue distribution and maturation state. Traditionally, immature and semimature DCs were described to have immunosuppressive effects, leading to immune tolerance. Nonetheless, recent research has demonstrated that mature DCs can also suppress the immune response under certain circumstances. Main body: Mature DCs enriched in immunoregulatory molecules (mregDCs) have emerged as a regulatory module across species and tumour types. Indeed, the distinct roles of mregDCs in tumour immunotherapy have sparked the interest of researchers in the field of single‐cell omics. In particular, these regulatory cells were found to be associated with a positive response to immunotherapy and a favourable prognosis. Conclusion: Here, we provide a general overview of the latest and most notable advances and recent findings regarding the basic features and complex roles of mregDCs in nonmalignant diseases and the tumour microenvironment. We also emphasise the important clinical implications of mregDCs in tumours. [ABSTRACT FROM AUTHOR]

With the rapid growth of advanced nanoengineering strategies, there are great implications for therapeutic immunostimulators formulated in nanomaterials to combat cancer. It is crucial to direct immunostimulators to the right tissue and specific immune cells at the right time, thereby orchestrating the desired, potent, and durable immune response against cancer. The flexibility of nanoformulations in size, topology, softness, and multifunctionality allows precise regulation of nano‐immunological activities for enhanced therapeutic effect. To grasp the modulation of immune response, research efforts are needed to understand the interactions of immune cells at lymph organs and tumor tissues, where the nanoformulations guide the immunostimulators to function on tissue specific subsets of immune cells. In this review, recent advanced nanoformulations targeting specific subset of immune cells, such as dendritic cells (DCs), T cells, monocytes, macrophages, and natural killer (NK) cells are summarized and discussed, and clinical development of nano‐paradigms for targeted cancer immunotherapy is highlighted. Here the focus is on the targeting nanoformulations that can passively or actively target certain immune cells by overcoming the physiobiological barriers, instead of directly injecting into tissues. The opportunities and remaining obstacles for the clinical translation of immune cell targeting nanoformulations in cancer therapy are also discussed. [ABSTRACT FROM AUTHOR]

Presents several papers at an international workshop on the role of dendritic and Langerhans cells in immunoregulation in Oslo, Norway. Initiation and regulation of immune responses; Importance of class II antigens for the restriction of local immune responses; Advances in the basic understanding of local immune reactions.

Dendritic cells (DCs) are crucial for the appropriate initiation of adaptive immune responses. During inflammation, DCs capture antigens, mature, and migrate to lymphoid tissues to present foreign material to naïve T cells. These cells get activated and differentiate either into pathogen‐specific cytotoxic CD8+ T cells that destroy infected cells or into CD4+ T helper cells that, among other effector functions, orchestrate antibody production by B cells. DC‐mediated antigen presentation is equally important in non‐inflammatory conditions. Here, DCs mediate induction of tolerance by presenting self‐antigens or harmless environmental antigens and induce differentiation of regulatory T cells or inactivation of self‐reactive immune cells. Detailed insights into the biology of DCs are, therefore, crucial for the development of novel vaccines as well as the prevention of autoimmune diseases. As in many other life science areas, our understanding of DC biology would be extremely restricted without bioimaging, a compilation of methods that visualize biological processes. Spatiotemporal tracking of DCs relies on various imaging tools, which not only enable insights into their positioning and migration within tissues or entire organs but also allow visualization of subcellular and molecular processes. This review aims to provide an overview of the imaging toolbox and to provide examples of diverse imaging techniques used to obtain fundamental insights into DC biology. [ABSTRACT FROM AUTHOR]

Background: High‐altitude therapy has been used as add‐on treatment for allergic asthma with considerable success. However, the underlying mechanisms remain unclear. In order to investigate the possible therapeutic effects of high‐altitude therapy on allergic asthma, we utilized a new in vivo mouse model. Methods: Mice were treated with house dust mite (HDM) extract over 4 weeks and co‐exposed to 10% oxygen (Hyp) or room air for the final 2 weeks. Experimental asthma was assessed by airway hyper‐responsiveness, mucus hypersecretion and inflammatory cell recruitment. Isolated immune cells from mouse and allergic patients were stimulated in vitro with HDM under Hyp and normoxia in different co‐culture systems to analyse the adaptive immune response. Results: Compared to HDM‐treated mice in room air, HDM‐treated Hyp‐mice displayed ameliorated mucosal hypersecretion and airway hyper‐responsiveness. The attenuated asthma phenotype was associated with strongly reduced activation of antigen‐presenting cells (APCs), effector cell infiltration and cytokine secretion. In vitro, hypoxia almost completely suppressed the HDM‐induced adaptive immune response in both mouse and human immune cells. While hypoxia did not affect effector T‐cell responses per‐se, it interfered with antigen‐presenting cell (APC) differentiation and APC/effector cell crosstalk. Conclusions: Hypoxia‐induced reduction in the Th2‐response to HDM ameliorates allergic asthma in vivo. Hypoxia interferes with APC/T‐cell crosstalk and confers an unresponsive phenotype to APCs. [ABSTRACT FROM AUTHOR]

A major challenge for the development of anticancer vaccines is the induction of a safe and effective immune response, particularly mediated by CD8+ T lymphocytes, in an adjuvant‐free manner. In this respect, we present a simple strategy to improve the specific CD8+ T cell responses using KFE8 nanofibers bearing a Class I (Kb)‐restricted peptide epitope (called E. nanofibers) without the use of adjuvant. We demonstrate that incorporation of Tat, a cell‐penetrating peptide (CPP) of the HIV transactivator protein, into E. nanofibers remarkably enhanced tumor‐specific CD8+ T cell responses. E. nanofibers containing 12.5% Tat peptide (E.Tat12.5 nanofiber) increased antigen cross‐presentation by bone marrow‐derived dendritic cells as compared with E. nanofibers, or E. nanofibers containing 25 or 50% the Tat peptide. Uptake of KFE8.Tat12.5 nanofibers by dendritic cells (DCs) was significantly increased compared with KFE8 nanofiber lacking Tat. Peritoneal and lymph node DCs of mice immunized with E.Tat12.5 nanofibers exhibited increased presentation of the H2kb‐epitope (reminiscent for cross‐presentation) compared with DCs obtained from E. nanofiber vaccinated mice. Tetrameric and intracellular cytokine staining revealed that vaccination with E.Tat12.5 triggered a robust and specific CD8+ T lymphocyte response, which was more pronounced than in mice vaccinated with E. nanofibers alone. Furthermore, E.Tat12.5 nanofibers were more potent than E. nanofiber to induce antitumor immune response and tumor‐infiltrating IFN‐γ CD8 T lymphocyte. In terms of cancer vaccine development, we propose that harnessing the nanofiber‐based vaccine platform with incorporated Tat peptide could present a simple and promising strategy to induce highly effective antitumor immune response. [ABSTRACT FROM AUTHOR]

Human metapneumovirus (HMPV) is a leading cause of lower respiratory tract infection (LRTI) in pediatric and geriatric populations. We recently found that two PDZ‐binding motifs of the M2‐2 protein, 29‐DEMI‐32 and 39‐KEALSDGI‐46, play a significant role in mediating HMPV immune evasion in airway epithelial cells (AECs). However, their role in the overall pulmonary responses to HMPV infection has not been investigated. In this study, we found that two recombinant HMPVs (rHMPV) lacking the individual M2‐2 PDZ‐binding motif are attenuated in mouse lungs. Mice infected with mutants produce more cytokines/chemokines in bronchoalveolar lavage (BAL) fluid compared to mice infected with wild‐type rHMPV. In addition, both mutants are able to enhance the pulmonary recruitment of dendritic cells (DCs) and T cells and induce effective protections against the HMPV challenge. The DC maturation is also significantly improved by the motif mutation. Taken together, our data provide proof‐of‐principle for two live‐attenuated M2‐2 mutants to be promising HMPV vaccine candidates that are effective in inducing higher pulmonary innate immunity and generating protection against HMPV infection. Highlights: HMPV is a major pathogen causing hospitalization in children with bronchiolitis and pneumonia. The infection does not induce long‐lasting immunity. Herein, we identified two M2‐2 mutants which are effective in inducing higher pulmonary innate immunity and producing protection against HMPV infection. [ABSTRACT FROM AUTHOR]

Allergic responses are characterized by the activation of a specific subset of effector CD4+ T cells, the T‐helper type 2 (Th2) cells, that respond to harmless environmental antigens causing inflammation and pathology. Th2 cells are also found in the context of parasite infections, where they can mediate parasite clearance and expulsion, and support tissue repair. The process that leads to the activation of Th2 cells in vivo is incompletely understood: while it has become clear that "conventional" dendritic cells are essential antigen‐presenting cells for the initiation of Th2 immune responses, the molecules that are expressed by dendritic cells exposed to allergens, and the mediators that are produced as a consequence and signal to naïve CD4+ T cells to promote their development into effector Th2, remain to be defined. Here we summarize recent developments in the identification of the dendritic cell subsets involved in Th2 responses, review potential mechanisms proposed to explain the generation of these immune responses, and discuss the direct and indirect signals that condition dendritic cells to drive the development of Th2 responses during allergen or parasite exposure. [ABSTRACT FROM AUTHOR]

Summary: Release of granulysin by γδ T cells contributes to tumour cell killing. A cytolytic 9000 MW isoform of granulysin kills tumour cells directly, whereas a 15 000 MW precursor has been hypothesized to cause both the maturation and migration of dendritic cell (DC) populations. Recruiting DC to a tumour is beneficial as these cells initiate adaptive immune responses, which contribute to the eradication of malignancies. In this study, Vδ2+γδ T cells were activated by stimulation of peripheral blood mononuclear cells with zoledronic acid or Bacillus Calmette–Guérin (BCG), or were isolated and cultured with tumour targets. Although a large proportion of resting Vδ2+γδ T cells expressed 15 000 MW granulysin, 9000 MW granulysin expression was induced only after stimulation with BCG. Increased levels of activation and granulysin secretion were also observed when Vδ2+γδ T cells were cultured with the human B‐cell lymphoma line Daudi. High concentrations of recombinant 15 000 MW granulysin caused migration and maturation of immature DC, and also initiated fugetaxis in mature DC. Conversely, low concentrations of recombinant 15 000 MW granulysin resulted in migration of mature DC, but not immature DC. Our data therefore support the hypothesis that Vδ2+γδ T cells can release granulysin, which may modulate recruitment of DC, initiating adaptive immune responses. [ABSTRACT FROM AUTHOR]

It is known that aging decreases natural resistance to viral diseases due to dysfunctional innate and adaptive immune responses, but the nature of these dysfunctions, particularly in regard to innate immunity, is not well understood. We have previously shown that C57BL/6J (B6) mice lose their natural resistance to footpad infection with ectromelia virus (ECTV) due to impaired maturation and recruitment of natural killer (NK) cells to the draining popliteal lymph node (dLN). More recently, we have also shown that in young B6 mice infected with ECTV, the recruitment of NK cells is dependent on a complex cascade whereby migratory dendritic cells (mDCs) traffic from the skin to the dLN, where they produce CCL2 and CCL7 to recruit inflammatory monocytes (iMOs). In the dLN, mDCs also upregulate NKG2D ligands to induce interferon gamma (IFN‐γ) expression by group 1 innate lymphoid cells (G1‐ILCs), mostly NK in cells but also some ILC1. In response to the IFN‐γ, the incoming uninfected iMOs secret CXCL9 to recruit the critical NK cells. Here, we show that in aged B6 mice, the trafficking of mDCs to the dLN in response to ECTV is decreased, resulting in impaired IFN‐γ expression by G1‐ILCs, reduced accumulation of iMOs, and attenuated CXCL9 production by iMOs, which likely contributes to decrease in NK cell recruitment. Together, these data indicate that defects in the mDC response to viral infection during aging result in a reduced innate immune response in the dLN and contribute to increased susceptibility to viral disease in the aged. [ABSTRACT FROM AUTHOR]

Background and Purpose: Myeloid-derived suppressor cells (MDSCs) represent a major obstacle to cancer treatment, as they negatively regulate anti-tumour immunity through the suppression of tumour-specific T lymphocytes. Thus, the efficacy of immunotherapies may be improved by targeting MDSCs. In this study, we assessed the ability of hydrogen sulfide (H2 S), a gasotransmitter whose anti-cancer effects are well known, to inhibit the accumulation and immunosuppressive functions of MDSCs in melanoma.Experimental Approach: Effects of H2 S on the host immune response to cancer were evaluated using an in vivo syngeneic model of murine melanoma. B16F10-melanoma-bearing mice were treated with the H2 S donor, diallyl trisulfide (DATS) and analysed for content of MDSCs, dendritic cells (DCs) and T cells. Effects of H2 S on expression of immunosuppressive genes in MDSCs and on T cell proliferation were evaluated.Key Results: In melanoma-bearing mice, DATS inhibited tumour growth, and this effect was associated with a reduction in the frequency of MDSCs in the spleen, in the blood as well as in the tumour micro-environment. In addition, we found that CD8+ T cells and DCs were increased. Furthermore, DATS reduced the immuno-suppressive activity of MDSCs, restoring T cell proliferation.Conclusions and Implications: The H2 S donor compound, DATS, inhibited the expansion and the suppressive functions of MDSCs, suggesting a novel role for H2 S as a modulator of MDSCs in cancer. Therefore, H2 S donors may provide a novel approach for enhancing the efficacy of melanoma immunotherapy.Linked Articles: This article is part of a themed section on Hydrogen Sulfide in Biology & Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.4/issuetoc. [ABSTRACT FROM AUTHOR]

Cystic fibrosis (CF) is caused by mutations to the CF transmembrane conductance regulator (CFTR) gene. CFTR is known to be expressed on multiple immune cell subtypes, dendritic cells, monocytes/macrophages, neutrophils and lymphocytes. We hypothesized that the lack of CFTR expression on peripheral blood innate immune cells would result in an altered cell profile in the periphery and that this profile would reflect lung pathology. We performed a flow cytometric phenotypic investigation of innate immune cell proportions in peripheral blood collected from 17 CF patients and 15 age‐matched healthy controls. We observed significant differences between CF patients and controls in the relative proportions of natural killer (NK) cells, monocytes and their subsets, with significant correlations observed between proportions of NK and monocyte cell subsets and lung function (forced expiratory volume in 1 sec, % predicted; FEV1% predicted) in CF patients. This study demonstrates the widespread nature of immune dysregulation in CF and provides a basis for identification of potential therapeutic targets. Modulation of the distinct CF‐related immune cell phenotype identified could also be an important biomarker for evaluating CFTR‐targeted drug efficacy. [ABSTRACT FROM AUTHOR]

Retinoids, vitamin A and its natural and synthetic analogues have various functions, including being involved in cell proliferation and differentiation and participating in the formation of vertebrate morphology. In addition, they may activate certain tumour suppressor genes that then act as tumour inhibitors. In the past decades, retinoids have been regarded as promising chemotherapeutic and chemopreventive agents; however, their mechanisms are still not fully understood. Immune cells that participate in or are associated with the immune response play vital roles in the initiation and development of many cancers. Interestingly, recent studies have demonstrated that retinoids can also exert various effects on immune cells including macrophages, T cells and dendritic cells in tumour tissues to execute anti-tumour actions, providing new insights into chemoprevention and chemotherapeutics. In this review, we focus on the effects of retinoids on immune cells in the tumour, which may provide new approaches for antineoplastic strategies. [ABSTRACT FROM AUTHOR]

Abstract: Dendritic cells (DCs) are a diverse family of cells that play a crucial role in linking our innate and adaptive immune system to initiate adequate T‐cell responses. They respond to pathogens by triggering the appropriate adaptive immune response that is required to clear invaders while balancing the need to limit tissue damage as a result of inflammation. Perturbation in DC regulation results in abnormal T‐cell homeostasis, leading to development of autoimmune diseases and aberrant responses to pathogens. In recent years, it has become clear that the DC family is more complex than initially thought in terms of their identification, homeostasis and functions. In this review, we discuss recent findings that improve our understanding of development, and functional specializations of conventional and plasmacytoid DCs. [ABSTRACT FROM AUTHOR]

Background Allergy and allergic asthma are significant health burdens in developed countries and are increasing in prevalence. Dendritic cells ( DCs) initiate immune responses to common aeroallergens, and ADAM10 has been demonstrated to be important for the development of adaptive responses. This study's objective was to understand the role of ADAM10 on DCs in the development of allergic and anaphylactic responses. Methods In this study, we used mouse models of allergic airway inflammation (house dust mice and Alternaria alternata) and OVA-induced models of active anaphylaxis to determine the DC-specific function of ADAM10 and Notch signaling. To examine TH1 and TH17 immunity infection with Anaplasma phagocytophilum and Citrobacter rodentium respectively, were used. Results Mice, which have ADAM10 deleted from DCs, have dramatic reductions in IgE production and do not develop significant TH2 immune responses. Further, ADAM10 DC−/− mice are resistant to IgE-mediated anaphylaxis. This response is selective for TH2 immunity as TH1 and TH17 immunity is largely unaffected. Notch1, a known ADAM10 substrate, when knocked out of DCs (Notch1 DC−/−) demonstrated a similar reduction in anaphylaxis and IgE. Without ADAM10 and Notch1 signaling, DCs were unable to make cytokines that stimulate TH2 cells and cytokines. Anaphylaxis and allergic lung inflammation were restored in ADAM10 DC−/− with the overexpression of the Notch1-intracellular domain, confirming the role of Notch signaling. Conclusions Targeting ADAM10 and Notch1 on DCs represent a novel strategy for modulating TH2 immune responses and IgE production. [ABSTRACT FROM AUTHOR]

Efferocytosis, or clearance of apoptotic cells (ACs), by dendritic cells (DCs) leads to immune response suppression and tolerance to self-antigens. However, efferocytosis of infected apoptotic cells (IACs) leads to the production of a mixed pro- and anti-inflammatory cytokine milieu. We examined the DC phenotype and ability to migrate after phagocytosis of ACs or IACs and observed higher levels of CD86 and CCR7 expression in DCs, as well as enhanced migration capacity following efferocytosis of IACs. Interestingly, higher levels of interleukin-1 β, interleukin-10 and prostaglandin E2 (PGE2) were also produced in this context. Blockage of IAC recognition led to an impaired maturation profile and PGE2 production, which may have contributed to reduced CD86 and CCR7 expression and migration capacity. These data contribute to the understanding of how efferocytosis of sterile or infected cells may regulate the adaptive immune response, although the precise role of PGE2 in this process requires further investigation. [ABSTRACT FROM AUTHOR]

There is a current lack of effective mucosal vaccines against major gastroenteric pathogens and particularly against Helicobacter pylori, which causes a chronic infection that can lead to peptic ulcers and gastric cancer in a subpopulation of infected individuals. Mucosal CD4+ T-cell responses have been shown to be essential for vaccine-induced protection against H. pylori infection. The current study addresses the influence of the adjuvant and site of mucosal immunization on early CD4+ T-cell priming to H. pylori antigens. The vaccine formulation consisted of H. pylori lysate antigens and mucosal adjuvants, cholera toxin ( CT) or a detoxified double-mutant heat-labile enterotoxin from Escherichia coli (dm LT), which were administered by either the sublingual or intragastric route. We report that in vitro, adjuvants CT and dm LT induce up-regulation of pro-inflammatory gene expression in purified dendritic cells and enhance the H. pylori-specific CD4+ T-cell response including interleukin-17A ( IL-17A), interferon- γ ( IFN- γ) and tumour necrosis factor- α ( TNF- α) secretion. In vivo, sublingual immunization led to an increased frequency of IL-17A+, IFN- γ+ and TNF- α+ secreting CD4+ T cells in the cervical lymph nodes compared with in the mesenteric lymph nodes after intragastric immunization. Subsequently, IL-17A+ cells were visualized in the stomach of sublingually immunized and challenged mice. In summary, our results suggest that addition of an adjuvant to the vaccine clearly activated dendritic cells, which in turn, enhanced CD4+ T-cell cytokines IL-17A, IFN- γ and TNF- α responses, particularly in the cervical lymph nodes after sublingual vaccination. [ABSTRACT FROM AUTHOR]

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

Background Food protein-induced enterocolitis ( FPIES) is an uncommon, non-IgE-mediated food allergy that usually debuts in infancy with profuse vomiting, lethargy, and pallor 2-4 h following ingestion of the offending food. Its immune mechanism is not known. We aimed to describe the clinical features and outcome of children with fish- FPIES as well as to investigate on cellular immune response implicated. Methods Prospective and follow-up clinical study of children with FPIES by fish over a period between 2004 and 2013 was conducted. Measurement in vitro of both cytokine production in peripheral blood mononuclear cells ( PBMCs) and expression of HLA- DR in monocyte-derived dendritic cells stimulated with fish extracts. Results Sixteen children (seven male and nine female) were included, with a mean age of onset at 10 months. Diagnosis was established after a median of 4 reactions. Twelve patients were treated in emergency room, and two were admitted in intensive care. Patch tests were positive in six patients. Skin prick tests ( SPTs) and specific IgE to all fish tested were negative. Only three children reached tolerance at a mean age of 4.5 years. Eight children avoided fish because of positive oral food challenge ( OFC) after 6 years of age. Other patients have not been challenged because of parent refusal to OFC or a recent diagnosis. TNF-α was increased in patients, and a significant elevation of the HLA- DR marker was also observed in these patients vs. control donors. Conclusions FPIES caused by fish in many cases presents with severe clinical manifestations. Patch test has poor diagnostic value, and OFC is the gold standard to test tolerance. The cytokine TNF-α may be implicated in the clinical symptoms. Higher expression of HLA- DR in dendritic cells has also been detected in our patients. [ABSTRACT FROM AUTHOR]

Understanding the regulation of T-cell responses during inflammation and auto-immunity is fundamental for designing efficient therapeutic strategies against immune diseases. In this regard, prostaglandin E2 (PGE2) is mostly considered a myeloid-derived immunosuppressive molecule. We describe for the first time that T cells secrete PGE2 during T-cell receptor stimulation. In addition, we show that autocrine PGE2 signaling through EP receptors is essential for optimal CD4+ T-cell activation in vitro and in vivo, and for T helper 1 (Th1) and regulatory T cell differentiation. PGE2 was found to provide additive co-stimulatory signaling through AKT activation. Intravital multiphoton microscopy showed that triggering EP receptors in T cells is also essential for the stability of T cell--dendritic cell (DC) interactions and Th-cell accumulation in draining lymph nodes (LNs) during inflammation. We further demonstrated that blocking EP receptors in T cells during the initial phase of collagen-induced arthritis in mice resulted in a reduction of clinical arthritis. This could be attributable to defective T-cell activation, accompanied by a decline in activated and interferon-γ-producing CD4+ Th1 cells in draining LNs. In conclusion, we prove that T lymphocytes secret picomolar concentrations of PGE2, which in turn provide additive co-stimulatory signaling, enabling T cells to attain a favorable activation threshold. PGE2 signaling in T cells is also required for maintaining long and stable interactions with DCs within LNs. Blockade of EP receptors in vivo impairs T-cell activation and development of T cell-mediated inflammatory responses. This may have implications in various pathophysiological settings. [ABSTRACT FROM AUTHOR]

Aims Primary central nervous system ( CNS) diffuse large B-cell lymphoma ( PCNSL) is an ominous disease with a poor prognosis. The brain is an immune-privileged sanctuary, and this may contribute to an ineffective host immune response and thus a poorer outcome. The aim of this study was therefore to study the difference in the immune composition in PCNSL and non- CNS diffuse large B-cell lymphoma ( DLBCL), and the role of the immune response in PCNSL prognosis. Methods and results Thirty-two biopsy specimens of PCNSL and 30 specimens of low-stage non- CNS DLBCL from immunocompetent patients formed the study group. The density and distribution of immune cells, including dendritic cells (dendritic cell-specific lysosomal-associated membrane protein-positive and S100-positive), effector/memory T cells ( CD45 RO-positive), and cytotoxic T cells (granzyme B-positive), and the expression of HLA- DR by lymphoma cells, were evaluated immunohistochemically. PCNSL patients showed poorer overall survival ( P = 0.032). On comparison of the PCNSL and DLBCL biopsy specimens, the PCNSL cells showed less HLA- DR expression ( P = 0.003), and there were fewer S100-positive cells ( P < 0.01), and effector T cells ( P = 0.026) infiltrating PCNSL than infiltrating DLBCL. For PCNSL patients, fewer cytotoxic T cells in the background constituted a poor prognostic factor ( P = 0.004). Intratumoral S100-positive cell infiltration was positively correlated with T-cell infiltration, and a T-cell rimming pattern. Conclusions In PCNSL, the baseline antitumour immune response is less as compared with non- CNS DLBCL, and this response may play a role in the poorer prognosis. Adjuvant dendritic cell and T-cell immunotherapy may further boost treatment responses in PCNSL patients. [ABSTRACT FROM AUTHOR]

Targeting of antigens to the endocytic uptake receptor DEC205 resulted in enhanced antigen presentation by dendritic cells ( DCs). In combination with adjuvants for DC maturation, proteins coupled to an antibody against DEC205 induced strong pathogen-specific immune responses, whereas without additional adjuvant tolerance could be induced. As less is known about DNA vaccines encoding DEC205-targeted antigens, we explored the immunogenicity and efficacy of a dendritic cell-targeted DNA vaccine against influenza A virus ( IAV) delivered by electroporation. Although coupling of haemagglutinin to a single-chain antibody against DEC205 enhanced antigen presentation on MHC class II and activation of T-cell receptor-transgenic CD4 T cells, the T-cell responses induced by the targeted DNA vaccine in wild-type BALB/c mice were significantly reduced compared with DNA encoding non-targeted antigens. Consistently, these mice were less protected against an IAV infection. Adoptive transfer experiments were performed to assess the fate of the antigen-specific T cells in animals vaccinated with DNA encoding DEC205-targeted antigens. By this, we could exclude the general deletion of antigen-specific T cells as cause for the reduced efficacy, but observed a local expansion of antigen-specific regulatory T cells, which could suppress the activation of effector cells. In conclusion, DNA vaccines encoding DEC205-targeted antigens induce peripheral tolerance rather than immunity in our study. Finally, we evaluated our DNA vaccines as prophylactic or therapeutic treatment in an allergen-induced asthma mouse model. [ABSTRACT FROM AUTHOR]

The outcome of a cutaneous immune response is critically dependent upon the ability of dendritic cells ( DC) to migrate from skin to the draining lymph nodes - a process that is influenced by the cutaneous tissue microenvironment. Here, the role of fibroblasts - a major component of the dermal microenvironment - on the migratory capacity of monocyte-derived DC (Mo DC) was investigated in a 3D collagen I matrix. Indeed, dermal fibroblasts supported the migration of pre-activated Mo DC through a 3D collagen I matrix. Activation of human Mo DC resulted in the release of TNFα and IL-1β that in turn stimulated MMP-1 (human collagenase) and PGE2 secretion by human dermal fibroblasts. Transmigration assays confirmed the importance of fibroblast-derived MMP-1 and PGE2 for the migration of Mo DC through a 3D collagen I matrix. Finally, in mice initiation of inflammation by induction of an irritant contact dermatitis or a psoriasis-like skin inflammation, the expression of the PGE2 generating cox-2 and the mouse collagen I degrading enzyme matrix metalloproteinases ( MMP)-13 was strongly up-regulated. Our study indicates that Mo DC are able to instruct dermal fibroblasts resulting in enhanced migratory capability of Mo DC, thus highlighting the role of a crosstalk of DC with their stromal microenvironment for the control of cutaneous immune responses. [ABSTRACT FROM AUTHOR]

Inflammatory immune responses are mediated by signaling molecules that are both produced by and recognized across highly heterogeneous cell populations. As such, the study of inflammation using traditional immunostimulants is complicated by paracrine and autocrine signaling, which obscures the origin of a propagating response. To address this challenge, we developed a small-molecule probe that can photosensitize immune cells, thus allowing light-mediated inflammation. This probe was used to control the origin of inflammation using light. Following this motif, inflammation was initiated from fibroblasts or dendritic cells. The contributions of fibroblasts and dendritic cells in initiating inflammation in heterogeneous co-culture are reported, thus providing insights into the future development of vaccines and treatment of inflammation. [ABSTRACT FROM AUTHOR]

Type I interferon ( IFN), mainly produced by dendritic cells ( DCs), is critical in the host defence against tick-transmitted pathogens. Here, we report that salivary cysteine protease inhibitor from the hard tick Ixodes scapularis, sialostatin L2, affects IFN-β mediated immune reactions in mouse dendritic cells. Following IFN receptor ligation, the Janus activated kinases/signal transducer and activator of transcription ( JAK/ STAT) pathway is activated. We show that sialostatin L2 attenuates phosphorylation of STATs in spleen dendritic cells upon addition of recombinant IFN-β. LPS-stimulated dendritic cells release IFN-β which in turn leads to the induction of IFN-stimulated genes ( ISG) through JAK/ STAT pathway activation. The induction of two ISG, interferon regulatory factor 7 ( IRF-7) and IP-10, was suppressed by sialostatin L2 in LPS-stimulated dendritic cells. Finally, the interference of sialostatin L2 with IFN action led to the enhanced replication of tick-borne encephalitis virus in DC. In summary, we present here that tick salivary cystatin negatively affects IFN-β responses which may consequently increase the pathogen load after transmission via tick saliva. [ABSTRACT FROM AUTHOR]

Autophagy is a major cellular pathway, which at basal levels regulates and maintains the cytoplasmic environment through the capture, isolation and digestion of intracellular materials in a specialized structure called an autophagosome. The unique ability of autophagy to degrade large targets, such as damaged and surplus organelles, intracellular microbes and protein aggregates, has made it a prime focus in inflammation and microbial research. Indeed, autophagy has been shown to be involved in a number of infectious and inflammatory pathologies, by which it may confer protection against intracellular microbes, be targeted by microbes for evasion or be hijacked for microbe biogenesis. In addition, autophagy helps regulate the intracellular and global immune response to both extracellular and intracellular pathogens. Here we review the current literature on the interactions between autophagy and HIV among different immune cells and discuss new research that re-emphasizes the role of inflammation in HIV-mediated CD4+ T cell death. [ABSTRACT FROM AUTHOR]

A role for complement, particularly the classical pathway, in the regulation of immune responses is well documented. Deficiencies in C1q or C4 predispose to autoimmunity, while deficiency in C3 affects the suppression of contact sensitization and generation of oral tolerance. Complement components including C3 have been shown to be required for both B-cell and T-cell priming. The mechanisms whereby complement can mediate these diverse regulatory effects are poorly understood. Our previous work, using the mouse minor histocompatibility (HY) model of skin graft rejection, showed that both C1q and C3 were required for the induction of tolerance following intranasal peptide administration. By comparing tolerance induction in wild-type C57BL/6 and C1q-, C3-, C4- and C5-deficient C57BL/6 female mice, we show here that the classical pathway components including C3 are required for tolerance induction, whereas C5 plays no role. C3-deficient mice failed to generate a functional regulatory T (Treg) -dendritic cell (DC) tolerogenic loop required for tolerance induction. This was related to the inability of C3-deficient DC to up-regulate the arginine-consuming enzyme, inducible nitric oxide synthase ( Nos-2), in the presence of antigen-specific Treg cells and peptide, leading to reduced Treg cell generation. Our findings demonstrate that the classical pathway and C3 play a critical role in the peptide-mediated induction of tolerance to HY by modulating DC function. [ABSTRACT FROM AUTHOR]

The Notch signalling pathway is involved in multiple cellular processes and has been recently indicated to modulate the host immune response. However, the role of the Notch pathway in dengue virus ( DENV) infection remains unknown. Our study has screened the expression profile of Notch receptors, ligands and target genes in human monocytes, macrophages and dendritic cells in response to DENV infection. The real-time PCR data showed that Notch ligand Dll1 was significantly induced in DENV-infected monocytes; and receptor Notch4, ligands Dll1 and Dll4, and target Hes1 were dramatically enhanced in DENV-infected macrophages and dendritic cells. In macrophages, induction of Dll1 and Dll4 mediated by DENV2 was increased by treatment with interferon- β ( IFN- β), and was impaired by neutralization of IFN- β. The DENV-induced Dll1 and Dll4 expression level was decreased by silencing key innate immune molecules, including Toll-like receptor 3 (TLR3), MyD88, RIG-I and IPS-I. In IFN-receptor-depleted macrophages, the Dll1 and Dll4 induction was significantly alleviated. Functionally, activation of Notch signalling by Dll1 in CD4+ T cells enhanced the expression of a T helper type 1 ( Th1) cytokine IFN- γ, while Notch activation in macrophages had no direct effect on replication of DENV. Our data revealed that the expressions of Notch ligands in antigen-presenting cells were differentially induced by DENV via innate immune signalling, which is important for Th1/ Th2 differentiation during adaptive immune response. [ABSTRACT FROM AUTHOR]

The M2 subset of macrophages has a critical role to play in host tissue repair, tissue fibrosis and modulation of adaptive immunity during helminth infection. Infection with the helminth, Fasciola hepatica, is associated with M2 macrophages in its mammalian host, and this response is mimicked by its excretory-secretory products (Fh ES). The tegumental coat of F. hepatica (FhTeg) is another major source of immune-modulatory molecules; we have previously shown that FhTeg can modulate the activity of both dendritic cells and mast cells inhibiting their ability to prime a Th1 immune response. Here, we report that FhTeg does not induce Th2 immune responses but can induce M2-like phenotype in vivo that modulates cytokine production from CD4+ cells in response to anti- CD3 stimulation. FhTeg induces a RELMα expressing macrophage population in vitro, while in vivo, the expression of Arg1 and Ym-1/2 but not RELMα in FhTeg-stimulated macrophages was STAT6 dependent. To support this finding, FhTeg induces RELMα expression in vivo prior to the induction of IL-13. FhTeg can induce IL-13-producing peritoneal macrophages following intraperitoneal injection This study highlights the important role of FhTeg as an immune-modulatory source during F. hepatica infection and sheds further light on helminth-macrophage interactions. [ABSTRACT FROM AUTHOR]

The activation of dendritic cells ( DCs) is necessary to initiate immune responses. Angiotensin II ( Ang II) can enhance the maturation and activation of DCs, but the mechanisms are still unclear. Ubiquitin-activating enzyme ( E1/ Uba1) is the common first step in ubiquitylation, which decides whether or not the modified protein is ultimately degraded by the proteasome. This study aimed to investigate the role of E1 in Ang II-induced activation of DCs and the underlying mechanisms. First, we showed that Ang II stimulation significantly up-regulated E1 expression in DCs. Moreover, Ang II treatment markedly induced phenotypic maturation, the secretion of cytokines and the immunostimulatory capacity of DCs. In contrast, inhibition of E1 by a small molecule inhibitor, 4 [4-(5-nitro-furan-2-ylmethylene)-3, 5-dioxo-pyrazolidin-1-yl]-benzoic acid ethyl ester ( PYR41), markedly attenuated these effects. Mechanistically, PYR41 treatment markedly decreased K63-linked ubiquitination of tumour necrosis factor receptor-associated factor 6 and nuclear factor- κ B essential modulator, inhibited proteasomal degradation of nuclear factor- κ B inhibitor α and mitogen-activated protein kinase phosphatase 1 thereby resulting in activation of nuclear factor- κ B, extracellular signal-regulated kinase 1/2 and signal transducer and activator of transcription 1 signalling pathways in DCs induced by Ang II. Taken together, our results demonstrate a novel role of E1 in Ang II-induced activation of DCs, and inhibition of E1 activity might be a potential therapeutic target for DC-mediated autoimmune diseases. [ABSTRACT FROM AUTHOR]

Background The natural course of Helicobacter pylori infection, as well as the success of antibiotic eradication is determined by the immune response to bacteria. The aim of the study is to investigate how different Helicobacter pylori isolates influence the dendritic cells maturation and antigen-presenting function in order to elucidate the differences between Helicobacter pylori strains, isolated from the patients with successful antibiotic eradication therapy or repeated eradication failure. Materials and Methods Dendritic cells maturation and antigen presentation were monitored by flow cytometry analysis of the major histocompatibility complex class II ( MHC-II), Toll-like receptor ( TLR) and costimulatory molecules expression, and by determining cytokine secretion. Results Dendritic cells stimulated with Helicobacter pylori isolated from patients with repeated antibiotic eradication failure expressed less human leukocyte antigen ( HLA-DR), CD86, TLR-2, and interleukin-8 ( IL-8) compared to Helicobacter pylori strains susceptible to antibiotic therapy; the latter expressed lower production of IL-10. Polymyxin B inhibition of lipopolysaccharide reduces IL-8 secretion in the group of Helicobacter pylori strains susceptible to antibiotic therapy. The differences in IL-8 secretion between both groups are lipopolysaccharide dependent, while the differences in secretion of IL-10 remain unchanged after lipopolysaccharide inhibition. Inhibitor of cathepsin X Mab 2F12 reduced the secretion of IL-6, and the secretion was significantly lower in the group of Helicobacter pylori strains isolated from patients with repeated antibiotic eradication failure. Conclusion Helicobacter pylori strains, susceptible/resistant to antibiotic eradication therapy, differ in their capability to induce DCs maturation and antigen-presenting function. [ABSTRACT FROM AUTHOR]

γδ T cells contribute to immunosurveillance of pathogenic infections and malignant transformations; however, mechanisms of activation have yet to be fully defined. In this study we demonstrate a novel mechanism by which human Vδ2+ γδ T cells are activated by the model pathogen Bacillus Calmette Guérin (BCG). We show in vitro that Vδ2 cell cytokine production and cytotoxic activity in response to BCG are dependent on both dendritic cells (DCs) and memory CD4+ αβ T cells (CD4 T cells). We found that Vδ2 cells are indirectly activated by BCG in an interleukin (IL)-12p70-dependent manner, and that DC production of the IL-12p70 responsible for Vδ2 cell activation requires Toll-like receptor 2/4 ligands from BCG and interferon (IFN)-γ from memory CD4 T cells. Our data suggest that Vδ2 cell responses to BCG are dependent on the activation of IFN-γ-producing memory CD4 T cells, and provide novel insight into the complex interplay between cells of the innate and adaptive immune response. [ABSTRACT FROM AUTHOR]

Trichuris muris is an intestinal nematode that invades the colonic epithelium triggering a mucosal inflammation. Vitamin A and its active metabolite retinoic acid are strongly linked with the modulation of gut immune responses. Here, we describe the temporal changes in the expression of aldehyde dehydrogenase (ALDH) enzymes, responsible for converting dietary-absorbed vitamin A into the immuno-modulatory retinoic acid in lamina propria leucocytes post-infection. We show that ALDH enzymes are expressed by both colonic macrophages and dendritic cells. Further, during an on-going T. muris infection, ALDH expression is repressed from uninfected levels and only recovers to normal levels following expulsion of the parasite. These results suggest that local regulation of cellular levels of retinoic acid is an important component of infection-driven inflammation. [ABSTRACT FROM AUTHOR]

The skin is under constant assault by environmental factors and microbes. Innate immune cells in epidermis and dermis regulate immune responses against pathogens while maintaining tolerance against commensal bacteria and autoantigens. The introduction of intravital imaging approaches, in particular multiphoton microscopy, has enabled studying the cellular and molecular regulation of cutaneous immunity in real time within intact skin. Here, we discuss recent advances in our understanding of innate immune cell behaviour in the skin, as unravelled by intravital microscopy, with emphasis on the function of myeloid cells, including dendritic cells, neutrophils and monocytes. [ABSTRACT FROM AUTHOR]

Background Myeloid (m) and plasmacytoid (p) dendritic cells ( DCs) regulate immune responses to allergens, whereas it remains unclear whether abnormal DC function characterizes patients with airway allergy and whether putative dysfunction exists only in target organs. To evaluate DC function from patients with allergic rhinitis ( AR), we assessed nasal, cutaneous as well as blood DCs after in vivo and in vitro allergen challenge, respectively. Methods DCs were immunostained in nasal and skin tissues, and cytokine expression was assessed by dual immunofluorescence. Cytokine production and regulation of cocultured peripheral CD4+ T cells were assayed by ELISA. Results In AR patients, local allergen challenge resulted in increases in pDC and mDC numbers at 8 h in the nasal mucosa and at 8-48 h in the skin. Defects in IL-10 and IFN-α were observed in both organs from AR. Blood mDCs from AR exhibited reduced IL-10 and IL-12 expression. The capacity of activated pDCs from AR to produce IFN-α and to trigger IL-10 by allogeneic CD4+ T cells was diminished, whereas mDCs from these patients supported Th2- and Th17-cell differentiation. Conclusion In allergic rhinitis, DCs are altered not only locally but also in the systemic circulation. mDCs and pDCs increased in airway and skin tissues exposed to the allergen and displayed reduced production of IL-10 and 'type 1 signals' (IL-12, IFN-α) both locally and in blood. Functional studies showed that this results in preferential Th2/Th17-cell polarization and impaired generation by blood DCs of IL-10+ T cells, linking systemic DC dysfunction and biased T-cell responses. [ABSTRACT FROM AUTHOR]

Dendritic cells (DCs) have a pivotal role in instructing antigen-specific immune responses, processing and presenting antigens to CD4+ and CD8+ T cells and producing factors capable to modulate the quality of T-cell responses. In this review, we will provide an historic overview on the identification of the mechanisms controlling lymphocyte migration into the largest immune organ of the body: the gut, and we will describe how in recent years an unexpected role for DCs has emerged as the architects in programming gut-homing immune cells. Specifically, we will review how intestinal DCs utilize the dietary vitamin A metabolite retinoic acid (RA) to program gut-homing lymphocytes and how intestinal DCs acquire the unique capacity to become RA producers. [ABSTRACT FROM AUTHOR]

Dendritic cells ( DCs) play an essential role in immunity against bacteria by phagocytosis and by eliciting adaptive immune responses. Previously, we demonstrated that human monocyte-derived DCs ( MDDCs) express a high content of cell surface α2,6-sialylated glycans. However, the relative role of these sialylated structures in phagocytosis of bacteria has not been reported. Here, we show that treatment with a sialidase significantly improved the capacity of both immature and mature MDDCs to phagocytose Escherichia coli. Desialylated MDDCs had a significantly more mature phenotype, with higher expression of MHC molecules and interleukin ( IL)-12, tumour necrosis factor-α, IL-6 and IL-10 cytokines, and nuclear factor-κB activation. T lymphocytes primed by desialylated MDDCs expressed more interferon-γ when compared with priming by sialylated MDDCs. Improved phagocytosis required E. coli sialic acids, indicating a mechanism of host-pathogen interaction dependent on sialic acid moieties. The DCs harvested from mice deficient in the ST6 Gal.1 sialyltransferase showed improved phagocytosis capacity, demonstrating that the observed sialidase effect was a result of the removal of α2,6-sialic acid. The phagocytosis of different pathogenic E. coli isolates was also enhanced by sialidase, which suggests that modifications on MDDC sialic acids may be considered in the development of MDDC-based antibacterial therapies. Physiologically, our findings shed new light on mechanisms that modulate the function of both immature and mature MDDCs, in the context of host-bacteria interaction. Hence, with particular relevance to DC-based therapies, the engineering of α2,6-sialic acid cell surface is a novel possibility to fine tune DC phagocytosis and immunological potency. [ABSTRACT FROM AUTHOR]

The lung constantly interacts with the environment through thousands of liters of air that are inhaled daily. This continually transports toxic chemicals and particles or pathogenic microorganisms deep into the respiratory system, posing a challenge to physicochemical barriers and the local immune system. Thus, complex structures and mechanisms have evolved to recognize and fend off environmental dangers while at the same time allowing efficient gas exchange. Here we review our current knowledge regarding cellular mechanisms of the immune system in context with the highly specialized anatomical features of the airways and especially the alveolar compartment. The focus is on fungal and viral infections, merging anatomical aspects well known to pulmonologists with fundamental immunological concepts. We discuss the specialized morphological constraints of immune cells compressed under a continuous layer of the surfactant lining within alveoli as well as the importance of functional polarization of respiratory tract epithelia. Furthermore, we summarize the different types of innate and adaptive immune cells and their relative contribution to lung homeostasis with respect to localization. Finally, we provide a list of currently unresolved questions with high relevance for the field that might serve as food for thought regarding future research directions. [ABSTRACT FROM AUTHOR]

DCs (dendritic cells) are the strongest professional APCs (antigen-presenting cells) to initiate immune responses against pathogens, but they are usually incompetent in initiating efficient immune responses in the progress of solid tumours. We have shown that Notch signalling plays a pivotal role in DC-dependent anti-tumour immunity. Compared with the control DCs, OP9-DL1 (Delta-like1) cell co-cultured DCs gained increased tumour suppression activity when inoculated together with tumour cells. This was probably due to the activation of Notch signalling in DCs enhancing their ability to evoke anti-tumour immune responses in solid tumours. Indeed, the OP9-DL1 cell co-cultured DCs expressed higher levels of MHC I, MHC II, CXCR4 (CXC chemokine receptor 4), CCR7 (CC chemokine receptor 7), IL-6 (interleukin 6), IL-12 and TNFα (tumour necrosis factor α), and a lower level of IL-10 than control DCs, resulting in more efficient DC migration and T-cell activation in vivo and in vitro. T-cells stimulated by OP9-DL1 cells co-cultured DCs more efficiently; and were cytotoxic against tumour cells, in contrast with control DCs. These results indicated that up-regulation of Notch signalling in DCs by co-culturing with OP9-DL1 cells enhances DC-dependent anti-tumour immune reactions, making the Notch signalling pathway a target for the establishment of the DC-based anti-tumour immunotherapies. [ABSTRACT FROM AUTHOR]

To cite this article: Calderón MA, Simons FER, Malling H-J, Lockey RF, Moingeon P, Demoly P. Sublingual allergen immunotherapy: mode of action and its relationship with the safety profile. Allergy 2012; 67: 302-311. Abstract Allergen immunotherapy reorients inappropriate immune responses in allergic patients. Sublingual allergen immunotherapy (SLIT) has been approved, notably in the European Union, as an effective alternative to subcutaneous allergen immunotherapy (SCIT) for allergic rhinitis patients. Compared with SCIT, SLIT has a better safety profile. This is possibly because oral antigen-presenting cells (mostly Langerhans and myeloid dendritic cells) exhibit a tolerogenic phenotype, despite constant exposure to danger signals from food and microbes. This reduces the induction of pro-inflammatory immune responses leading to systemic allergic reactions. Oral tissues contain relatively few mast cells and eosinophils (mostly located in submucosal areas) and, in comparison with subcutaneous tissue, are less likely to give rise to anaphylactic reactions. SLIT-associated immune responses include the induction of circulating, allergen-specific Th1 and regulatory CD4+ T cells, leading to clinical tolerance. Although 40-75% of patients receiving SLIT experience mild, transient local reactions in the oral mucosa, these primary reactions rarely necessitate dose reduction or treatment interruption. We discuss 11 published case reports of anaphylaxis (all nonfatal) diagnosed according to the World Allergy Organization criteria and relate this figure to the approximately 1 billion SLIT doses administered worldwide since 2000. Anaphylaxis risk factors associated with SCIT and/or SLIT should be characterized further. [ABSTRACT FROM AUTHOR]

Ebolaviruses naturally infect a wide variety of cells including macrophages and dendritic cells (DCs), and the resulting cytokine and interferon-α/β (IFN) responses of infected cells are thought to influence viral pathogenesis. The VP35 protein impairs RIG-I-like receptor-dependent signaling to inhibit IFN production, and this function has been suggested to promote the ineffective host immune response characteristic of ebolavirus infection. To assess the impact of VP35 on innate immunity in biologically relevant primary cells, we used a recombinant Newcastle disease virus encoding VP35 (NDV/VP35) to infect macrophages and conventional DCs, which primarily respond to RNA virus infection via RIG-I-like pathways. VP35 suppressed not only IFN but also tumor necrosis factor (TNF)-α secretion, which are normally produced from these cells upon NDV infection. Additionally, in cells susceptible to the activity of VP35, IRF7 activation is impaired. In contrast, NDV/VP35 infection of plasmacytoid DCs, which activate IRF7 and produce IFN through TLR-dependent signaling, leads to robust IFN production. When plasmacytoid DCs deficient for TLR signaling were infected, NDV/VP35 was able to inhibit IFN production. Consistent with this, VP35 was less able to inhibit TLR-dependent versus RIG-I-dependent signaling in vitro. These data demonstrate that ebolavirus VP35 suppresses both IFN and cytokine production in multiple primary human cell types. However, cells that utilize the TLR pathway can circumvent this inhibition, suggesting that the presence of multiple viral sensors enables the host to overcome viral immune evasion mechanisms. [ABSTRACT FROM AUTHOR]

Summary Many parasitic helminth infections induce Th2-type immune responses and engage the regulatory network. In this study, we specifically investigated the influence of antigens derived from different life stages of the helminth Trichinella spiralis on the polarization of naive CD4+ T cells by dendritic cells. Results obtained from C57BL/6 mice showed that T. spiralis derived antigens have the capacity to induce bone marrow-derived dendritic cells to acquire an incompletely mature phenotype that promotes a significant proliferation of naive CD4+ T cells and a mixed Th1/Th2 cytokine profile with the predominance of Th2 cytokines. Increased production of IL-4, IL-9, IL-10 and IL-13 accompanied increased IFN-γ. Furthermore, dendritic cells pulsed with T. spiralis antigens did not induce an increase in the population of Foxp3+ T regulatory cells. Although other helminth antigens have demonstrated the capacity to induce de novo generation of Foxp3+ T regulatory cells, here our in vitro studies provide no evidence that T. spiralis antigens have this capacity. [ABSTRACT FROM AUTHOR]