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A list of upcoming papers related to immunology is presented. They include "Mycobacterium tuberculosis HSP70 impairs maturation of dendritic cells from bone marrow precursors, induces IL-10 production and inhibits T-cell proliferation," "Triacylated lipoproteins derived from Mycoplasma pneumoniae activate NF-jB through TLR1 and TLR2," and " Sphingosine kinase inhibitor suppresses dendritic cell migration by regulating chemokine receptor expression and impairing p38 MAPK."

The article presents a list of the journal's forthcoming papers related to immunology. They include "DNA and its cationic lipid complexes induce CpG motif-dependent activation of murine dendritic cells," "Differential type I interferon activation and susceptibility of dendritic cell populations to porcine arterivirus," and "Isolated lymphoid follicle maturation induces the development of follicular dendritic cells."

The article presents a list of forthcoming research papers related to immunology. They include "DNA and its cationic lipid complexes induce CpG motif-dependent activation of murine dendritic cells," "Mature dendritic cells pulsed with exosomes stimulate efficient cytotoxic T lymphocyte responses and antitumor immunity," and "Involvement of IL-10 in exhaustion of myeloid dendritic cells and rescue by CD40 stimulation."

The article presents a list of forthcoming papers including "Immunohistochemical Analysis of Cytokines and Apoptosis in Tuberculosis Lymphadentis," by Telmina Mustafa, Stanley Mogga, Sayoki Mfinanga, Odd Mørkve and Lisbet Sviland, "Drinking a Lot Is Good for Dendritic Cells," by Christopher Norbury and "Fibrosis in Heart Disease: Understanding the Role of Transforming Growth Factor-Beta 1 in Cardiomyopathy, Valvular Disease and Arythmia," by Razi Khan and Richard Sheppard.

Presents several research works related to immunology. "Innate mechanisms for Bifidobacterium lactis to activate transient pro-inflammatory host responses in intestinal epithelial cells after the colonization of germfree rats," by Pedro Ruiz, Micha Hoffmann and Silke Szcesny; "Paired immunoglobulin-like receptors and their MHC class I recognition," by Toshiyuki Takai; "Activation of murine dendritic cells and macrophages induced by Salmonella enterica serovar Typhimurium," by Ruwani Sagarika Kalupahana, Pietro Mastroeni and Duncan Maskell.

The article presents a list of articles related to immunology. The articles include "Monocyte-Derived Dendritic Cells From Horses Differ From DC of Humans and Mice," by Susanne Mauel, Falko Steinbach and Hanns Ludwig, "Extended Sequence Preferences for Oligodeoxyribonucleotide Activity," by Peter Lenert, Adam Goeken and Robert Ashman, "On the Logic of Positive Selection," by Melvin Cohn, "CTLA-4 Interacts With Stat5 and Inhibits Stat5-Mediated Transcription," by M. Srahna, L. Van Grunsven, J. Remacle and Peter Vandenberghe, and "Peritoneal Macrophages Supress T Cell Activation by Amino Acid Catabolism," by R. Matlack, K. Yeh, L. Rosini, D. Gonzalez, J. Taylor, D. Silberman, A. Pennello and James Riggs.

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., (© 2012 Blackwell Publishing Ltd.)

It has been known for 15 years that the chicken epidermis contains ATPase+ and major histocompatibility complex class II-positive (MHCII+) dendritic cells. These cells were designated as Langerhans cells but neither their detailed phenotype nor their function was further investigated. In the present paper we demonstrate a complete overlapping of ATPase, CD45 and vimentin staining in all dendritic cells of the chicken epidermis. The CD45+ ATPase+ vimentin+ dendritic cells could be divided into three subpopulations: an MHCII+ CD3- KUL01+ and 68.1+ (monocyte-macrophage subpopulation markers) subpopulation, an MHCII- CD3- KUL01- and 68.1- subpopulation and an MHCII- CD3+ KUL01- and 68.1- subpopulation. The first population could be designated as chicken Langerhans cells. The last population represents CD4- CD8- T-cell receptor-alphabeta- and -gammadelta- natural killer cells with cytoplasmic CD3 positivity. The epidermal dendritic cells have a low proliferation rate as assessed by bromodeoxyuridine incorporation. Both in vivo and in vitro experiments showed that dendritic cells could be mobilized from the epidermis. Hapten treatment of epidermis resulted in the decrease of the frequency of epidermal dendritic cells and hapten-loaded dendritic cells appeared in the dermis or in in vitro culture of isolated epidermis. Hapten-positive cells were also found in the so-called dermal lymphoid nodules. We suggest that these dermal nodules are responsible for some regional immunological functions similar to the mammalian lymph nodes.

The ultimate outcome of T cell receptor recognition is determined by the context in which the antigen is encountered. In this fashion both antigen-presenting cells and T cells must integrate multiple environmental cues in the form of pathogen-associated molecular patterns, cytokines and accessory molecule signals. The mammalian target of rapamycin (mTOR) is an evolutionarily conserved serine/threonine kinase that plays a central role in integrating environmental signals critical to regulating metabolism and cell survival. In this paper we review the data demonstrating that mTOR integrates signals from the immune microenvironment and therefore facilitates the generation of the adaptive immune response. Specifically, we review the role of mTOR in promoting dendritic cell activation and maturation, in regulating full T cell activation versus anergy, and influencing the induction of regulatory T cells. [ABSTRACT FROM AUTHOR]

CCL25/TECK and CCL28/MEC are CC chemokines primarily expressed in thymic dendritic cells and mucosal epithelial cells. The cognate receptors of CCL25 and CCL28, CCR9 and CCR10, respectively, are mainly expressed on T and B lymphocytes. In human, mouse and pig, CCL25 and CCL28 play a key role in the segregation and the compartmentalization of the mucosal immune system through recruitment of immune cells to specific locations. However, little is known about their role in the ontogeny of the mucosal immune system during fetal development. In the present paper, we report the cloning and the sequencing of ovine CCL25, CCL28, CCR9 and CCR10 and the subsequent assessment of their mRNA expression by q-polymerase chain reaction in several tissues, including thymus, gut-associated lymphoid tissue and mammary gland, from young and adult sheep and in the fetal lamb during the development of the immune system. CCL25 mRNA was highly expressed in thymus and gut while CCL28 mRNA was more expressed in large intestine, trachea, tonsils and mammary gland, especially at the end of gestation. These results are consistent with observations in other species suggesting similar roles for these chemokines in sheep. In fetuses, mRNA of CCL25, CCL28 and their receptors are expressed early in the thymus and mucosal tissues, including the small intestine and the nasal mucosa. Furthermore, their expression increased towards the end of gestation. Consequently, we hypothesize that CCL25 and CCL28 play an important role in the lymphocyte colonization of fetal tissues, enabling the development of a functional immune system. [ABSTRACT FROM AUTHOR]

As is well known in the case of Langerhans cells, dendritic cells (DCs) play a crucial role in the initiation of immunity to simple chemicals such as noted in the contact hypersensitivity. Because DCs are scattered in non-lymphoid organs as immature cells, they must be activated to initiate primary antigen-specific immune reactions. Therefore, we hypothesized that some simple chemicals must affect the function of DCs. In this paper, we first demonstrated that human monocyte-derived DCs responded to such simple chemicals as 2, 4-dinitrochlorobenzene (DNCB), 2,4,6-trinitrochlorobenzene (TNCB), 2, 4-dinitrofluorobenzene (DNFB), NiCl2, MnCl2, CoCl2, SnCl2, and CdSO4 by augmenting their expression of CD86 or human leucocyte antigen-DR (HLA-DR), down-regulating c-Fms expression or increasing their production of tumour necrosis factor-alpha (TNF-alpha). In addition, the DCs stimulated with the chemicals demonstrated increased allogeneic T-cell stimulatory function. Next, we found that, among these chemicals, only NiCl2 and CoCl2 induced apoptosis in them. Finally, we examined the effects of these chemicals on CD86 expression by three different macrophage subsets and DCs induced from the cultures of human peripheral blood monocytes in the presence of macrophage colony-stimulating factor (M-CSF), M-CSF + interleukin-4 (IL-4), granulocyte-macrophage colony-stimulating factor (GM-CSF), and GM-CSF + IL-4, respectively. Among them, only DCs dramatically augmented their expression of CD86. These observations have revealed unique characteristics of DCs, which convert chemical stimuli to augmentation of their antigen presenting function, although their responses to different chemicals were not necessarily uniform in the phenotypic changes, cytokine production or in the induction of apoptosis.

Fluorescent contact chemical allergens provoke sensitization after application on both syngeneic and allogeneic skin grafts in mice. We attempted to determine whether the functional activity in a contact sensitization response of human skin graft was affected at the level of antigen uptake and migration. After xenogeneic skin transplantation, we examined the effect of topical exposure of the graft to rhodamine B isothiocyanate (RITC). This paper describes the migration of RITC-carrying cells and human major histocompatibility complex (MHC) class II DR (HLA-DR)+ cells, from the graft to mouse draining lymph nodes. As demonstrated by immunohistochemistry, grafting resulted in a time-dependent decrease of human HLA-DR+ and CD1a+ cells, and an increase of mouse MHC class II (Ia)+ cells within the graft. Application of RITC on a 3-week-old human skin graft showed optimal migration capability compared to 6- or 9-week-old grafts. In addition, the time-dependent increase of frequencies of RITC+ and HLA-DR+ cells in the draining lymph nodes, and the time-dependent decrease of HLA-DR+ cells in the 3-week-old human skin graft, were concurrent. Supporting these data, human cytokine interleukin-1 alpha (IL-1 alpha), IL-1 beta and tumour necrosis factor-alpha (TNF-alpha), analysis in situ revealed that cytokine production by keratinocytes, a property associated with dendritic cell migration, was preserved in the human skin graft. Thus, like dendritic cells in contact sensitization in allografted skin, dendritic cells from human xenografted skin onto nude mice are capable of migration to mouse draining lymph nodes after allergen application. Induction of contact hypersensitivity is possible in a human skin graft onto nude mice model, although the use of this ex vivo model to analyze contact sensitivity is probably limited to 3 weeks after transplantation.

We previously demonstrated that the majority ( ≥90%) of porcine ileal Peyer's patch (IPP) follicular cells are immature B cells destined to die by apoptosis, when incubated at 37°. In this paper we approached the mechanisms responsible for positive selection of porcine IPP follicular immature B-cell selection, by screening for various cell types, cytokines and polyclonal and monoclonal antibodies for promoting the survival of IPP B cells. Of these reagents, only CD3 cross-linked purified T cells from mesenteric lymph nodes were able to rescue IPP follicular B cells from apoptosis, although polyclonal anti-IPP lymphocyte antibodies delayed apoptosis. This survival effect could be reproduced simply by incubating IPP follicular B cells with soluble and cell membrane-expressed CD 154, an observation consistent with the demonstrated presence of CD40 and CD 154 on porcine IPP follicular B cells and activated T cells, respectively. The IPP follicular B cells rescued in this manner expressed a more mature surface marker phenotype. Immunohistology and fluorescence-activated cell sorter analysis demonstrated that subpopulations of IPP follicular T cells (less than 0.5%) express CD 154. Thus, perhaps unexpectedly, CD 154 on T cells may play a role in the positive selection of immature B cells in the porcine IPP. The origin and control of the activated T cells identified within the porcine IPP remains to be investigated. [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]

Anti‐CD52 antibody (anti‐CD52‐Ab) leads to a rapid depletion of T and B cells, followed by reconstitution of immune cells with tolerogenic characteristics. However, very little is known about its effect on innate immune cells. In this study, experimental autoimmune encephalomyelitis mice were administered murine anti‐CD52‐Ab to investigate its effect on dendritic cells and monocytes/macrophages in the periphery lymphoid organs and the central nervous system (CNS). Our data show that blood and splenic innate immune cells exhibited significantly increased expression of MHC‐II and costimulatory molecules, which was associated with increased capacity of activating antigen‐specific T cells, at first day but not three weeks after five daily treatment with anti‐CD52‐Ab in comparison with controls. In contrast to the periphery, microglia and infiltrating macrophages in the CNS exhibited reduced expression levels of MHC‐II and costimulatory molecules after antibody treatment at both time‐points investigated when compared to controls. Furthermore, the transit response of peripheral innate immune cells to anti‐CD52‐Ab treatment was also observed in the lymphocyte‐deficient SCID mice, suggesting the changes are not a direct consequence of the mass depletion of lymphocytes in the periphery. Our study demonstrates a dynamic and tissue‐specific modulation of the innate immune cells in their phenotype and function following the antibody treatment. The findings of differential modulation of the microglia and infiltrating macrophages in the CNS in comparison with the innate immune cells in the peripheral organs support the CNS‐specific beneficial effect of alemtuzumab treatment on inhibiting neuroinflammation in multiple sclerosis patients. [ABSTRACT FROM AUTHOR]

Conventional dendritic cells (cDC) are bone marrow‐derived immune cells that play a central role in linking innate and adaptive immunity. cDCs efficiently uptake, process and present antigen to naïve T cells, driving clonal expansion of antigen‐specific T‐cell responses. In chicken, vital reagents are lacking for the efficient and precise identification of cDCs. In this study, we have developed several novel reagents for the identification and characterization of chicken cDCs. Chicken FLT3 cDNA was cloned and a monoclonal antibody to cell surface FLT3 was generated. This antibody identified a distinct FLT3HI splenic subset which lack expression of signature markers for B cells, T cells or monocyte/macrophages. By combining anti‐FLT3 and CSF1R‐eGFP transgenic expression, three major populations within the mononuclear phagocyte system were identified in the spleen. The cDC1 subset of mammalian cDCs express the chemokine receptor XCR1. To characterize chicken cDCs, a synthetic chicken chemokine (C motif) ligand (XCL1) peptide conjugated to Alexa Fluor 647 was developed (XCL1AF647). Flow cytometry staining of XCL1AF647 on splenocytes showed that all chicken FLT3HI cells exclusively express XCR1, supporting the hypothesis that this population comprises bona fide chicken cDCs. Further analysis revealed that chicken cDCs expressed CSF1R but lacked the expression of CSF2R. Collectively, the cell surface phenotypes of chicken cDCs were partially conserved with mammalian XCR1+ cDC1, with distinct differences in CSF1R and CSF2R expression compared with mammalian orthologues. These original reagents allow the efficient identification of chicken cDCs to investigate their important roles in the chicken immunity and diseases. [ABSTRACT FROM AUTHOR]

B cells and dendritic cells, lacking functional Wiskott-Aldrich syndrome protein (WASP), have aberrant formation of membrane protrusions. We hypothesized that protrusions may play a role in antigen presentation, and consequently, that impaired antigen presentation may be an underlying factor of the immune deficiency in patients with Wiskott-Aldrich syndrome. In this paper, we investigated the antigen presentation capacity of B cells and dendritic cells from WASP knockout mice, using soluble and particulate antigen, to CD4[SUP+] T cells from T-cell receptor transgenic DO11.10 mice. As antigen we used soluble ovalbumin (OVA), a peptide thereof (amino acids 323-339) or bacteria expressing OVA. We tound that WASP-deficient B cells and dendritic cells efficiently processed and presented soluble OVA protein as well as its peptide in vitro, inducing proliferation and cytokine production from CD4[SUP+] T cells. Antigen presentation of soluble protein was efficient also in vivo, because immunization of WASP-deficient mice with OVA elicited proliferation of transferred, fluorescent-labelled, CD4[SUP+] T cells. Although we could detect uptake of bacteria in dendritic cells, processing and presentation of bacterial-expressed OVA was impaired in WASP-deficient dendritic cells. In conclusion, our data suggest that WASP is not needed for processing and presentation of soluble antigen, but that efficient presentation of particulate antigen require WASP. [ABSTRACT FROM AUTHOR]

Presents abstracts of research papers on dendritic cells, published in the December 2002 supplement of 'Immunology.' 'Dendritic cell biology,' by M. Moser; 'Investigating the MHC-restriction of CD4[sup+]CD25[sup+] regulatory T cells,' by L.R. Ambrose.

Summary: Cytomegalovirus (CMV) induction of large frequencies of highly functional memory T cells has attracted much interest in the utility of CMV‐based vaccine vectors, with exciting preclinical data obtained in models of infectious diseases and cancer. However, pathogenesis of human CMV (HCMV) remains a concern. Attenuated CMV‐based vectors, such as replication‐ or spread‐deficient viruses, potentially offer an alternative to fully replicating vectors. However, it is not well understood how CMV attenuation impacts vector immunogenicity, particularly when administered via relevant routes of immunization such as the skin. Herein, we used the murine cytomegalovirus (MCMV) model to investigate the impact of vector attenuation on T‐cell memory formation following subcutaneous administration. We found that the spread‐deficient virus (ΔgL‐MCMV) was impaired in its ability to induce memory CD8+ T cells reactive to some (M38, IE1) but not all (IE3) viral antigens. Impaired‐memory T‐cell development was associated with a preferential and pronounced loss of polyfunctional (IFN‐γ+ TNF‐α+) T cells and also reduced accumulation of TCF1+ T cells, and was not rescued by increasing the dose of replication‐defective MCMV. Finally, whilst vector attenuation reduced dendritic cell (DC) recruitment to skin‐draining lymph nodes, systematic depletion of multiple DC subsets during acute subcutaneous MCMV infection had a negligible impact on T‐cell memory formation, implying that attenuated responses induced by replication‐deficient vectors were likely not a consequence of impaired initial DC activation. Thus, overall, these data imply that the choice of antigen and/or cloning strategy of exogenous antigen in combination with the route of immunization may influence the ability of attenuated CMV vectors to induce robust functional T‐cell memory. [ABSTRACT FROM AUTHOR]

Summary: The role of antigen‐presenting cells in the skin immune system, in particular Langerhans cells and dendritic cells, has not been well defined. We recently published a study in 'Immunology' where we reported that the loss of langerin‐positive cells in the skin accelerated wound repair in the Lang‐DTR mouse. The study published here by Li, et al. reports delayed wound closure following depletion of CD11c‐positive cells in the CD11c‐DTR mouse. In this commentary, we attribute the differences between these results to several factors that differ between the studies including the depletion of different cell populations; differences in the age and the sex of mice; differences in antibiotic use between the studies; and differences in the location of the biopsies that were taken. Here, we describe the impact of these differences on wound healing and conclude that further standardization of the wound model, and further characterization of the specific cells that are depleted in these mice, is necessary to better understand how antigen‐presenting cells contribute to wound healing. [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]

Summary: Dendritic cells (DCs) are essential for generating T‐cell‐based immune responses through sensing of potential inflammatory and metabolic cues in the local environment. However, there is still limited insight into the processes defining the resultant DC phenotype, including the type of early transcriptional changes in pro‐inflammatory cues towards regulatory or type 2 immune‐based cues induced by a variety of exogenous and endogenous molecules. Here we compared the ability of a selected number of molecules to modulate the pro‐inflammatory phenotype of lipopolysaccharide (LPS) and interferon‐γ (IFN‐γ)‐stimulated human monocyte‐derived DCs towards an anti‐inflammatory or regulatory phenotype, including Ascaris suum body fluid [helminth pseudocoelomic fluid (PCF)], the metabolites succinate and butyrate, and the type 2 cytokines thymic stromal lymphopoietin and interleukin‐25. Our data show that helminth PCF and butyrate treatment suppress the T helper type 1 (Th1)‐inducing pro‐inflammatory DC phenotype through induction of different transcriptional programs in DCs. RNA sequencing indicated that helminth PCF treatment strongly inhibited the Th1 and Th17 polarizing ability of LPS + IFN‐γ‐matured DCs by down‐regulating myeloid differentiation primary response gene 88 (MyD88)‐dependent and MyD88‐independent pathways in Toll‐like receptor 4 signaling. By contrast, butyrate treatment had a strong Th1‐inhibiting action, and transcripts encoding important gut barrier defending factors such as IL18, IL1B and CXCL8 were up‐regulated. Collectively, our results further understanding of how compounds from parasites and gut microbiota‐derived butyrate may exert immunomodulatory effects on the host immune system. [ABSTRACT FROM AUTHOR]

Summary: Dendritic cells (DC) are a class of bone‐marrow‐derived cells arising from lympho‐myeloid haematopoiesis that form an essential interface between the innate sensing of pathogens and the activation of adaptive immunity. This task requires a wide range of mechanisms and responses, which are divided between three major DC subsets: plasmacytoid DC (pDC), myeloid/conventional DC1 (cDC1) and myeloid/conventional DC2 (cDC2). Each DC subset develops under the control of a specific repertoire of transcription factors involving differential levels of IRF8 and IRF4 in collaboration with PU.1, ID2, E2‐2, ZEB2, KLF4, IKZF1 and BATF3. DC haematopoiesis is conserved between mammalian species and is distinct from monocyte development. Although monocytes can differentiate into DC, especially during inflammation, most quiescent tissues contain significant resident populations of DC lineage cells. An extended range of surface markers facilitates the identification of specific DC subsets although it remains difficult to dissociate cDC2 from monocyte‐derived DC in some settings. Recent studies based on an increasing level of resolution of phenotype and gene expression have identified pre‐DC in human blood and heterogeneity among cDC2. These advances facilitate the integration of mouse and human immunology, support efforts to unravel human DC function in vivo and continue to present new translational opportunities to medicine. [ABSTRACT FROM AUTHOR]

Summary: Respiratory syncytial virus (RSV) is the most common cause of hospitalization due to bronchiolitis in infants. Although the mechanisms behind this association are not completely elucidated, they appear to involve an excessive immune response causing lung pathology. Understanding the host response to RSV infection may help in the identification of targets for therapeutic intervention. We infected in‐vitro human monocyte‐derived dendritic cells (DCs) with RSV and analysed various aspects of the cellular response. We found that RSV induces in DCs the expression of CD38, an ectoenzyme that catalyses the synthesis of cyclic ADPR (cADPR). Remarkably, CD38 was under the transcriptional control of RSV‐induced type I interferon (IFN). CD38 and a set of IFN‐stimulated genes (ISGs) were inhibited by the anti‐oxidant N‐acetyl cysteine. When CD38‐generated cADPR was restrained by 8‐Br‐cADPR or kuromanin, a flavonoid known to inhibit CD38 enzymatic activity, RSV‐induced type I/III IFNs and ISGs were markedly reduced. Taken together, these results suggest a key role of CD38 in the regulation of anti‐viral responses. Inhibition of CD38 enzymatic activity may represent an encouraging approach to reduce RSV‐induced hyperinflammation and a novel therapeutic option to treat bronchiolitis. [ABSTRACT FROM AUTHOR]

Dendritic cells (DCs) in mesenteric lymph nodes (MLNs) induce Foxp3+ regulatory T cells to regulate immune responses to beneficial or non-harmful agents in the intestine, such as commensal bacteria and foods. Several studies in MLN DCs have revealed that the CD103+ DC subset highly induces regulatory T cells, and another study has reported that MLN DCs from programmed death ligand 1 (PD-L1) -deficient mice could not induce regulatory T cells. Hence, the present study investigated the expression of these molecules on MLN CD11c+ cells. Four distinct subsets expressing CD103 and/or PD-L1 were identified, namely CD11b+ CD103+ PD-L1High, CD11b− CD103+ PD-L1High, CD11b− CD103+ PD-L1Low and CD11b+ CD103− PD-L1Int. Among them, the CD11b− CD103+ PD-L1High DC subset highly induced Foxp3+ T cells. This subset expressed Aldh1a2 and Itgb8 genes, which are involved in retinoic acid metabolism and transforming growth factor- β (TGF- β) activation, respectively. Exogenous TGF- β supplementation equalized the level of Foxp3+ T-cell induction by the four subsets whereas retinoic acid did not, which suggests that high ability to activate TGF- β is determinant for the high Foxp3+ T-cell induction by CD11b− CD103+ PD-L1High DC subset. Finally, this subset exhibited a migratory DC phenotype and could take up and present orally administered antigens. Collectively, the MLN CD11b− CD103+ PD-L1High DC subset probably takes up luminal antigens in the intestine, migrates to MLNs, and highly induces regulatory T cells through TGF- β activation. [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]

Mycobacterium tuberculosis inhibits optimal T helper type 1 (Th1) responses during infection. However, the precise mechanisms by which virulent M. tuberculosis limits Th1 responses remain unclear. Here, we infected dendritic cells ( DCs) with the virulent M. tuberculosis strain H37Rv or the attenuated strain H37Ra to investigate the phenotypic and functional alterations in DCs and resultant T-cell responses. H37Rv-infected DCs suppressed Th1 responses more strongly than H37Ra-infected DCs. Interestingly, H37Rv, but not H37Ra, impaired DC surface molecule expression ( CD80, CD86 and MHC class II) due to prominent interleukin-10 ( IL-10) production while augmenting the expression of tolerogenic molecules including PD-L1, CD103, Tim-3 and indoleamine 2,3-dioxygenase on DCs in a multiplicity-of-infection (MOI) -dependent manner. These results indicate that virulent M. tuberculosis drives immature DCs toward a tolerogenic phenotype. Notably, the tolerogenic phenotype of H37Rv-infected DCs was blocked in DCs generated from IL-10−/− mice or DCs treated with an IL-10-neutralizing monoclonal antibody, leading to restoration of Th1 polarization. These findings suggest that IL-10 induces a tolerogenic DC phenotype. Interestingly, p38 mitogen-activated protein kinase ( MAPK) activation predominantly mediates IL-10 production; hence, H37Rv tends to induce a tolerogenic DC phenotype through expression of tolerogenic molecules in the p38 MAPK- IL-10 axis. Therefore, suppressing the tolerogenic cascade in DCs is a novel strategy for stimulating optimal protective T-cell responses against M. tuberculosis infection. [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]

Dengue virus ( DENV) infection is an emerging public health hazard threatening inhabitants of the tropics and sub-tropics. Dendritic cells ( DCs) are one of the major targets of DENV and the initiators of the innate immune response against the virus. However, current in vitro research on the DENV- DC interaction is hampered by the low availability of ex vivo DCs and donor variation. In the current study, we attempted to develop a novel in vitro DC model using immature DCs derived from the myeloid leukaemia cell line MUTZ-3 ( IMDCs) to investigate the DENV- DC interaction. The IMDCs morphologically and phenotypically resembled human immature monocyte-derived dendritic cells ( IMMo DCs). However, the permissiveness of IMDCs to DENV2 was lower than that of IMMo DCs. RT- PCR arrays showed that a group of type I interferon ( IFN) -inducible genes, especially IFIT1, IFITM1, and IFI27, were significantly up-regulated in IMMo DCs but not in IMDCs after DENV2 infection. Further investigation revealed that IFIT genes were spontaneously expressed at both transcriptional and protein levels in the naive IMDCs but not in the naive IMMo DCs. It is possible that the poor permissiveness of IMDCs to DENV2 was a result of the high basal levels of IFIT proteins. We conclude that the IMDC model, although less permissive to DENV2, is a useful platform for studying the suppression mechanism of DENV2 and we expand the knowledge of cellular factors that modulate DENV2 infection in the human body. [ABSTRACT FROM AUTHOR]

Macrophages and dendritic cells ( DCs) in murine spleen are essential for the maintenance of immune homeostasis by elimination of blood-borne foreign particles and organisms. It has been reported that splenic DCs, especially CD8 α+ CD103+ DCs, are responsible for tolerance to apoptosis-associated antigens. However, the molecular mechanism by which these DCs maintain immune homeostasis by blood-borne apoptotic cell clearance remains elusive. Here, we found that the CCL22/ CCR4 axis played a critical role in the maintenance of immune homeostasis during apoptotic cell clearance by splenic CD8 α+ CD103+ DCs. The present results revealed that systemic administration of apoptotic cells rapidly induced a large number of CCL22 and CCR4+ regulatory T (Treg) cells in the spleen of C57 BL/6J mice. Further study demonstrated that CD8 α+ CD103+ DCs dominantly produce much higher CCL22 than CD8 α+ CD103− DCs. Moreover, the transient deletion of CD8 α+ CD103+ DCs caused a decrease in CCL22 levels together with CCR4+ Treg cell percentage. Subsequently, the levels of some pro-inflammatory cytokines, such as interleukin-17 and interferon- γ in the spleen with the absence of CD8 α+ CD103+ DCs increased in response to the administration of apoptotic cells. Hence, intravenous injection of apoptotic cells induced a subsequent increase in CCL22 expression and CCR4+ Treg cells, which contribute to the maintenance of immune homeostasis at least partially by splenic CD8 α+ CD103+ DCs. [ABSTRACT FROM AUTHOR]

Paracoccidioidomycosis is a systemic infection prevalent in Latin American countries. Disease develops after inhalation of Paracoccidioides brasiliensis conidia followed by an improper immune activation by the host leucocytes. Dendritic cells ( DCs) are antigen-presenting cells with the unique ability to direct the adaptive immune response by the time of activation of naive T cells. This study was conducted to test whether extracts of P. brasiliensis would induce maturation of DCs. We found that DCs treated with extracts acquired an inflammatory phenotype and upon adoptive transfer conferred protection to infection. Interestingly, interleukin-10 production by CD8+ T cells was ablated following DC transfer. Further analyses showed that lymphocytes from infected mice were high producers of interleukin-10, with CD8+ T cells being the main source. Blockage of cross-presentation to CD8+ T cells by modulated DCs abolished the protective effect of adoptive transfer. Collectively, our data show that adoptive transfer of P. brasiliensis-modulated DCs is an interesting approach for the control of infection in paracoccidioidomycosis. [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 magnitude of the cellular adaptive immune response is critical for the control of Mycobacterium tuberculosis infection in the chronic phase. In addition, the genetic background is equally important for resistance or susceptibility to tuberculosis. In this study, we addressed whether lung populations of dendritic cells, obtained from genetically different hosts, would play a role in the magnitude and function of CD4+ populations generated after M. tuberculosis infection. Thirty days post-infection, C57 BL/6 mice, which generate a stronger interferon- γ ( IFN- γ)-mediated immune response than BALB/c mice, exhibited a higher number and frequency of lung CD11c+ CD11b− CD103+ cells compared with BALB/c mice, which exhibited a high frequency of lung CD11c+ CD11b+ CD103− cells. CD11c+ CD11b− CD103+ cells, purified from lungs of infected C57 BL/6 mice, but not from infected BALB/c mice, induced a higher frequency of IFN- γ-producing or interleukin-17 ( IL-17)-producing CD4+ cells. Moreover, CD4+ cells also arrive at the lung of C57 BL/6 mice faster than in BALB/c mice. This pattern of immune response seems to be associated with higher gene expression for CCL4, CCL19, CCL20 and CCR5 in the lungs of infected C57 BL/6 mice compared with infected BALB/c mice. The results described here show that the magnitude of IFN- γ-producing or IL-17-producing CD4+ cells is dependent on CD11c+ CD11b− CD103+ cells, and this pattern of immune response is directly associated with the host genetic background. Therefore, differences in the genetic background contribute to the identification of immunological biomarkers that can be used to design human assays to predict progression of M. tuberculosis infection. [ABSTRACT FROM AUTHOR]

The autoimmune destruction of pancreatic β-cells is the hallmark of type 1 diabetes (T1D). Failure of anti-CD3 antibodies to provide long-lasting reversal of T1D and the expression of a natural killer (NK) cell ligand on β-cells suggest that NK cells play a role in disease pathogenesis. Indeed, killing of β-cells by NK cells has been shown to occur, mediated by activation of the NK cell activating receptor, NKp46. α1-Antitrypsin (AAT), an anti-inflammatory and immunomodulatory glycoprotein, protects β-cells from injurious immune responses and is currently evaluated as a therapeutic for recent onset T1D. Although isolated T lymphocytes are not inhibited by AAT, dendritic cells (DC) become tolerogenic in its presence and other innate immune cells become less inflammatory. Yet a comprehensive profile of NK cell responses in the presence of AAT has yet to be described. In the present study, we demonstrate that AAT significantly reduces NK cell degranulation against β-cells, albeit in the whole animal and not in isolated NK cell cultures. AAT-treated mice, and not isolated cultured β-cells, exhibited a marked reduction in NKp46 ligand levels on β-cells. In related experiments, AAT-treated DC exhibited reduced inducible DC-expressed interleukin-15 levels and evoked a weaker NK cell response. NK cell depletion in a T1D mouse model resulted in improved β-cell function and survival, similar to the effects observed by AAT treatment alone; nonetheless, the two approaches were non-synergistic. Our data suggest that AAT is a selective immunomodulator that retains pivotal NK cell responses, while diverting their activities away from islet β-cells. [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 article presents a list of key words related to immunology used in the papers published in the August 1987 issue of the periodical "Immunology." Some of the key words are autoantibodies, autoantibody secretion, autoimmune phenomena, B-cell activation, benign monoclonal gammopathy, B lymphocytes, B-lymphoma cells namalwa, bovine alloreactive cytotoxic cells, C1 inhibitor, C3-IgG complexes, cap formation, delayed hypersensitivity, dendritic cells, dendritic cells and macrophages, dengue virus-induced cytotoxic factors, desensitization, endothelial cells, enteropathy, immunological, fibronectin and foot-and-mouth disease virus.

Myeloid dendritic cells ( mDC) are key mediators of innate and adaptive immunity to virus infection, but the impact of HIV infection on the m DC response, particularly early in acute infection, is ill-defined. We studied acute pathogenic simian immunodeficiency virus ( SIV) infection of rhesus macaques to address this question. The m DC in blood and bone marrow were depleted within 12 days of intravenous infection with SIVmac251, associated with a marked proliferative response. In lymph nodes, m DC were apoptotic, activated and proliferating, despite normal m DC numbers, reflecting a regenerative response that compensated for m DC loss. Blood m DC had increased expression of MHC class II, CCR7 and CD40, whereas in lymph nodes these markers were significantly decreased, indicating that acute infection induced maturation of m DC in blood but resulted in accumulation of immature m DC in lymph nodes. Following SIV infection, lymph node m DC had an increased capacity to secrete tumour necrosis factor- α upon engagement with a Toll-like receptor 7/8 ligand that mimics exposure to viral RNA, and this was inversely correlated with MHC class II and CCR7 expression. Lymph node m DC had an increased ability to capture and cleave soluble antigen, confirming their functionally immature state. These data indicate that acute SIV infection results in increased m DC turnover, leading to accumulation in lymph nodes of immature m DC with an increased responsiveness to virus stimulation. [ABSTRACT FROM AUTHOR]

Dendritic cells ( DCs) are professional antigen-presenting cells specifically targeted during Plasmodium infection. Upon infection, DCs show impaired antigen presentation and T-cell activation abilities. In this study, we aimed to evaluate whether cellular extracts obtained from Plasmodium berghei-infected erythrocytes ( Pb X) modulate DCs phenotypically and functionally and the potential therapeutic usage of Pb X-modulated DCs in the control of experimental autoimmune encephalomyelitis ( EAE, the mouse model for human multiple sclerosis). We found that Pb X-treated DCs have impaired maturation and stimulated the generation of regulatory T cells when cultured with naive T lymphocytes in vitro. When adoptively transferred to C57 BL/6 mice the EAE severity was reduced. Disease amelioration correlated with a diminished infiltration of cytokine-producing T cells in the central nervous system as well as the suppression of encephalitogenic T cells. Our study shows that extracts obtained from P. berghei-infected erythrocytes modulate DCs towards an immunosuppressive phenotype. In addition, the adoptive transfer of Pb X-modulated DCs was able to ameliorate EAE development through the suppression of specific cellular immune responses towards neuro-antigens. To our knowledge, this is the first study to present evidence that DCs treated with P. berghei extracts are able to control autoimmune neuroinflammation. [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]

The rapid differentiation of monocytes into macrophages ( MΦ) and dendritic cells is a pivotal aspect of the innate immune response. Differentiation is triggered following recognition of microbial ligands that activate pattern recognition receptors or directly by pro-inflammatory cytokines. We demonstrate that interleukin-1β ( IL-1β) induces the rapid differentiation of monocytes into CD209+ MΦ, similar to activation via Toll-like receptor 2/1, but with distinct phenotypic and functional characteristics. The IL-1β induced MΦ express higher levels of key markers of phagocytosis, including the Fc-receptors CD16 and CD64, as well as CD36, CD163 and CD206. In addition, IL-1β-induced MΦ exert potent phagocytic activity towards inert particles, oxidized low-density lipoprotein and mycobacteria. Furthermore, IL-1β-induced MΦ express higher levels of HLA- DR and effectively present mycobacterial antigens to T cells. Therefore, the ability of IL-1β to induce monocyte differentiation into MΦ with both phagocytosis and antigen-presenting function is a distinct part of the innate immune response in host defence against microbial infection. [ABSTRACT FROM AUTHOR]

The IMi Ds® immunomodulatory compounds lenalidomide and pomalidomide are agents with anti-inflammatory, immunomodulatory and anti-cancer activity. An excellent success rate has been shown for multiple myeloma in phase I/ II clinical trials leading to Food and Drug Administration approval of lenalidomide. One mechanism by which these drugs could enhance anti-tumour immunity may be through enhanced dendritic cell ( DC) function. Thalidomide, a compound structurally related to lenalidomide and pomalidomide, is known to enhance DC function, and we have investigated whether its analogues, pomalidomide and lenalidomide, also have functional effects on DCs. We used mouse bone marrow-derived DCs treated with 5 or 10 μ m pomalidomide, or lenalidomide from day 1 of culture. Treatment with IMi D® immunomodulatory compounds increased expression of Class I ( H2- Kb), CD86, and pomalidomide also increased Class II (I- Ab) expression in bone marrow-derived DCs, as measured by flow cytometry. Fluorescent bead uptake was increased by up to 45% when DCs were treated with 5 or 10 μ m pomalidomide or lenalidomide compared with non-treated DCs. Antigen presentation assays using DCs primed with ovalbumin, and syngeneic T cells from transgenic OTI and OTII mice (containing MHC restricted, ovalbumin-specific, T cells) showed that both pomalidomide and lenalidomide effectively increased CD8+ T-cell cross-priming (by up to 47%) and that pomalidomide alone was effective in increasing CD4+ T-cell priming (by 30%). Our observations suggest that pomalidomide and lenalidomide enhance tumour antigen uptake by DCs with an increased efficacy of antigen presentation, indicating a possible use of these drugs in DC vaccine therapies. [ABSTRACT FROM AUTHOR]

The precise function of tissue factor ( TF) expressed by dendritic cells ( DC) is uncertain. As well as initiating thrombin generation it can signal through protease-activated receptor 2 ( PAR-2) when complexed with factor VIIa. We investigated the expression and function of TF on mouse bone marrow ( BM) -derived DC; 20% of BM-derived DC expressed TF, which did not vary after incubation with lipopolysaccharide ( LPS) or dexamethasone ( DEX). However, the pro-coagulant activity of DEX-treated DC in recalcified plasma was 30-fold less than LPS-treated DC. In antigen-specific and allogeneic T-cell culture experiments, the TF on DEX-treated DC provided a signal through PAR-2, which contributed to the reduced ability of these cells to stimulate CD4+ T-cell proliferation and cytokine production. In vivo, an inhibitory anti- TF antibody and a PAR-2 antagonist enhanced antigen-specific priming in two models where antigen was given without adjuvant, with an effect approximately 50% that seen with LPS, suggesting that a similar mechanism was operational physiologically. These data suggest a novel TF and PAR-2-dependent mechanism on DEX- DC in vitro and unprimed DC in vivo that contributes to the low immunogenicity of these cells. Targeting this pathway has the potential to influence antigen-specific CD4+ T-cell activation. [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]

Summary It is well established that the generation of a high-affinity long-lived antibody response requires the presence of T cells, specifically CD4+ T cells. These CD4+ T cells support the generation of a germinal centre (GC) response where somatic hypermutation and affinity maturation take place leading to the generation of memory B cells and plasma cells, which provide long-lasting protection. Greater insight into the nature of the CD4+ T cells involved in this process was provided by two studies in 2000 that described CD4+ T cells residing in the B cell follicle that expressed CXCR5. As a result these cells were named follicular B helper T cells, now more commonly known as T follicular helper (Tfh) cells. Since then there has been enormous growth in our understanding of these cells, now considered a distinct T helper (Th) cell lineage that can arise from naive CD4+ T cells following activation. This review summarizes some of the most recent work that has characterized Tfh cells and the pathways that lead to their generation. [ABSTRACT FROM AUTHOR]

Mannose-binding lectin (MBL) is a serum lectin that plays a significant role in innate host defence. Individuals with mutations in exon 1 of the MBL2 gene have reduced MBL ligand binding and complement activation function and increased incidence of infection. We proposed that, during infection, MBL deficiency may impact on dendritic cell (DC) function. We analysed the blood myeloid DC (MDC) surface phenotype, inflammatory cytokine production and antigen-presenting capacity in MBL-deficient (MBL-D) individuals and MBL-sufficient (MBL-S) individuals using whole blood culture supplemented with zymosan (Zy) or MBL-opsonized zymosan (MBL-Zy) as a model of infection. Zy-stimulated MDCs from MBL-D individuals had significantly increased production of interleukin (IL)-6 and tumour necrosis factor (TNF)-α. Stimulation with MBL-Zy significantly decreased IL-6 production by MDCs from MBL-D, but had no effect on TNF-α production. MDCs from both MBL-S and MBL-D individuals up-regulated expression of the activation molecule CD83, and down-regulated expression of homing (CXCR4), adhesion (CD62L, CD49d) and costimulatory (CD40, CD86) molecules in response to Zy and MBL-Zy. MDC from both MBL-D and MBL-S individuals induced proliferation of allogeneic (allo) T cells following Zy or MBL-Zy stimulation; however, MBL-D individuals demonstrated a reduced capacity to induce effector allo-T cells. These data indicate that MBL deficiency is associated with unique functional characteristics of pathogen-stimulated blood MDCs manifested by increased production of IL-6, combined with a poor capacity to induce effector allo-T-cell responses. In MBL-D individuals, these functional features of blood MDCs may influence their ability to mount an immune response. [ABSTRACT FROM AUTHOR]

Invariant NKT (iNKT) cells are a distinctive subtype of CD1d-restricted T cells involved in regulating autoimmunity and capable of producing various T helper type 1 (Th1), Th2 and Th17 cytokines. Activation of iNKT cells by their exogenous ligand α-galactosylceramide (α-GalCer) exerts therapeutic effects in autoimmune diseases such as rheumatoid arthritis (RA). However, the pathophysiological role of iNKT cells in RA, in the absence of exogenous stimulation, is incompletely understood. We investigated the potential pathophysiological effects of iNKT cells in mice with collagen-induced arthritis (CIA), a model of RA. We found that iNKT cells underwent activation only in the early phases of the disease (6 days post-induction). In the liver, but not the spleen or lymph nodes, this early activation led to the release of interleukins -4, -17A and -10 and of interferon-γ; and an increased CD69 expression. Importantly, clinical and histological signs of arthritis were improved by the functional blockade of iNKT cells by a monoclonal antibody to CD1d at the early phase of the disease. This improvement was associated on day 6 post-induction with decreased expression of co-stimulatory molecules (CD80, CD86, CD40) on splenic dendritic cells and macrophages, whereas regulatory T-cell suppressive effects and proportions were not modified. Taken in concert, these findings suggest that iNKT cells are activated early in the course of CIA and contribute to the pathogenesis of arthritis. Therefore, iNKT-cell activation may be a valid treatment target in RA. [ABSTRACT FROM AUTHOR]

Several tools have proved useful in the study of invariant natural killer T (iNKT) cells, including CD1d-deficient mice, Jα281-deficient mice, synthetic lipid antigens and antigen-loaded CD1d tetramers. However, the generation and examination of long-term primary murine iNKT cell lines in vitro has been challenging. Here, we show the rapid generation of iNKT cell lines from splenic iNKT cells of Vα14 T-cell receptor (TCR) transgenic (Tg) mice. These purified iNKT cells were stimulated by bone marrow-derived dendritic cells (BMDCs) loaded with α-galactosylceramide (αGalCer) and cultured with interleukin (IL)-2 and IL-7. iNKT cells proliferated dramatically, and the cell number exhibited a 100-fold increase within 2 weeks and a 105-fold increase in 8 weeks after repeated stimulation with αGalCer. The iNKT cell lines consisted of iNKT cells expressing Vβ chains including Vβ8.1/8.2, Vβ14, Vβ10, Vβ6 and Vβ7, and responded to stimulation with αGalCer presented both by BMDCs and by plate-bound CD1d. In addition, the iNKT cell lines produced interferon (IFN)-γ when activated by lipopolysaccharide (LPS) or CpG oligodeoxynucleotide (ODN)-stimulated BMDCs. Further, we show that iNKT cell lines produced cytokines in response to microbial antigens. In summary, high-yield iNKT cell lines were generated very rapidly and robustly expanded, and these iNKT cells responded to both TCR and cytokine stimulation in vitro. Given the desire to study primary iNKT cells for many purposes, these iNKT cell lines should provide an important tool for the study of iNKT cell subsets, antigen and TCR specificity, activation, inactivation and effector functions. [ABSTRACT FROM AUTHOR]

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+ CD25hi CD27hi 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. [ABSTRACT FROM AUTHOR]

Antigen uptake by dendritic cells is essential for the induction of antigen-specific T-cell responses. Here, we investigate the ability of dendritic cells from different mouse strains to endocytose antigens. The uptake of different fluorescently labelled soluble antigens by bone marrow-derived dendritic cells from BALB/c, C57BL/6 and C3H/HeN mice was analysed by flow cytometry. Using transferrin as a specific marker for clathrin-mediated endocytosis, we observed no significant differences of transferrin uptake by dendritic cells from BALB/c, C57BL/6 and C3H/HeN mice. Similar results were obtained by analysing macropinocytosis with lucifer yellow. In contrast, analysing the uptake of ovalbumin, which is predominantly mediated by clathrin-mediated endocytosis via the macrophage mannose receptor, we found that dendritic cells from C3H/HeN mice take up three- to fivefold more ovalbumin than dendritic cells from BALB/c or C57BL/6 mice. Blocking the uptake of ovalbumin via the macrophage mannose receptor by using mannan led to a comparable uptake of ovalbumin by dendritic cells from all three mouse strains. Consistently, dendritic cells from C3H/HeN mice displayed significantly increased expression of the macrophage mannose receptor compared to dendritic cells from BALB/c or C57BL/6 mice. In conclusion, receptors involved in antigen uptake such as the macrophage mannose receptor may be differentially expressed and may explain variations of T-cell responses after vaccination in different individuals. [ABSTRACT FROM AUTHOR]