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• MR1, a non-polymorphic ubiquitous antigen presenting molecule presents small metabolites to T cells. • MR1T cells recognize small drugs and microbial metabolites presented by MR1. • MR1T cells also recognize self-metabolites accumulating in tumor cells. • MR1T cells are multi-functional and express polyclonal TCR heterodimers. MR1 is an MHC class I-like molecule with unique structural and biological features that make it an important member among the molecules involved in antigen presentation to T cells. Distinctive features include ubiquitous expression of the MR1 gene and its monomorphism. Another relevant property is that the MR1 protein appears at very low levels on the plasma membrane and its surface expression is regulated by antigen binding. Finally, the nature of presented antigens differs from those that bind other presenting molecules and includes small metabolites of microbial and self-origin, small drugs and tumor-associated antigens. This opinion paper describes in detail some of those features and discusses recent literature in the field. [ABSTRACT FROM AUTHOR]

In this paper, the experimental activity was carried out on five pulverized coals with different particle sizes taken from the industrial demonstration plant of SE-Gasifier Pulverized Coal Gasification in Nanjing, China. Flow properties of pulverized coal including powder cohesion, angle of internal friction and tensile strength were determined by the rotational shear cell accessory of Freeman FT4 Powder Rheometer. These pulverized coal samples were further discharged from a bench-scale discharge system and an industrial device in the SE gasification industrial plant. The effects of mean particle size, fine contents and hopper pressure on the flow properties and the discharge of pulverized coal were discussed. The tensile strength was used to correlate with the feeding characteristics of pulverized coal and proved to be an effective indicator to describe the powder feeding performance. A combination of a continuum approach and a particle–particle approach was therefore built to predict the tensile strength. The model, considered the elastic deformation, was further modified by taking into account the effect of particle size distribution. The predicted tensile strengths were compared with those obtained from the Mohr-Coulomb approach, giving errors mostly below ±25%. It was therefore considered as a valuable way to provide reference for the evaluation of feeding characteristics of pulverized coal for entrained-flow gasification. Unlabelled Image • Pulverized coal was taken from the industrial demonstration plant. • Flow properties and discharge behaviors of pulverized coal were determined. • Tensile strength was correlate with powder feeding performance. • A modified model was built to predict tensile strength. [ABSTRACT FROM AUTHOR]

Presentation of exogenous antigens loaded on major histocompatibility complex class I molecules by antigen presenting cells, termed cross-presentation, is essential for the induction of CD8+ T cells and is performed mainly by specialized dendritic cell subsets. Research into this field has described two main mechanisms of cross-presentation, the cytosolic pathway and the vacuolar pathway. As the first step in cross-presentation, surface receptors relating to cross-presentation are required in the recognition and uptake of Ags, which include C-type lectin receptors, immunoglobulin γ Fc region receptor, chemokine receptor, scavenger receptor etc. After uptake by the cells, there are also many molecules that enable Ags to participate in cross-presentation pathways. By this approach, exogenous Ags can induce CD8+ T cells into cytotoxic T lymphocytes, which is of great significance to induce antitumor and antiviral immune responses, and the molecular mechanism would facilitate the development of related adjuvants. However, the detailed mechanisms of cross-presentation still remain unknown. In this paper, some latest researches, including two major pathways, DC surface receptors and application prospects are summarized. [ABSTRACT FROM AUTHOR]

Dendritic cells (DCs) are highly specialized antigen-presenting cells (APCs) able to induce both specific immunity and immune tolerance. Using information gathered from the tissue where they reside, DCs adjust their functional activity to ensure that protective immunity is favoured while unwanted or exaggerated immune responses are prevented. The remarkable ability of these cells to induce, enhance and orient the immune response, while at the same time maintaining self-tolerance, makes them key players in the immune system. Despite the fact that the role of Ca 2+ has been clearly established in human DC functions, the link between ion homeostasis, mainly Ca 2+ , and DC functions is not fully understood. After all, a growing number of works clearly show the role of SOCE and associated channels in the maturation step, and those of K + channels in migration. This review highlights the key papers published over the past few years and summarizes prospects for the near future. [ABSTRACT FROM AUTHOR]

Oligomannose-coated liposomes (OMLs), containing entrapped antigens, serve as effective antigen delivery vehicles and as a novel adjuvant to induce antigen-specific cellular immune responses. However, in vitro activation of antigen-presenting cells (APCs) by OMLs has not yet been demonstrated. In this paper, we found that OMLs can deliver the antigens and the stimulatory signals into inflammatory monocytes in vitro , leading to differentiation of the cells to mature APCs. When OMLs were co-cultured with peripheral blood mononuclear cells from C57BL/6 mice in the presence of mouse serum, OMLs were preferentially incorporated into both Ly6C high monocytes and Ly6C low monocytes, which are referred to as murine inflammatory and resident monocytes, respectively. The expression of CD11c, CD80, CD86, CCR7, and MHC class II on the Ly6C high monocytes was significantly enhanced during the 24 h after OML uptake, whereas upregulation of these molecules on the Ly6C low monocytes was limited. In addition, the antigenic peptide of OVA encased in OMLs was presented on MHC class I of only Ly6C high monocytes. Furthermore, OVA-encasing OML-ingesting monocytes can activate CD8 + T cells from OT-1 mice, suggesting that antigens encapsulated in OMLs were cross-presented in inflammatory monocytes. Adoptive transfer of the monocytes that engulf OVA-encasing OMLs led to induction of an antigen-specific Th1 immune response in mice. Taken together, mature APCs can be generated from inflammatory monocytes in peripheral blood by ex vivo treatment of the cells with OMLs without any additional stimuli. [ABSTRACT FROM AUTHOR]

Malignant glioma is the most lethal of a wide array of CNS neoplasms. Its onset and progression are markedly associated with profound immunosupression and paralysis of T-cell survival and proliferation. Myriad immunotherapeutic strategies are presently used to target such T-cell anomalies in glioma. Our recent work has highlighted use of the novel glycopeptide, the CD2 ligand, T11 target structure (T11TS) as an immunotherapeutic agent against experimentally induced glioma in rats. We have shown that T11TS causes multi-target modulation of key components of the T-cell – antigen presenting cell (APC) immunological synapse. This consequently triggers T-cell activation so as to reverse glioma-induced changes to physiological levels. T11TS administration also causes CD2 upregulation. Earlier we also found T11TS to cause enhanced proliferation of both CD4+ and CD8+ T-cells in glioma conditions. These findings led us to believe that downstream CD2-stimulated “alternative pathway” of calcineurin–NFAT could be a possible target for modulation by T11TS. In the present paper we thus show that immunotherapy with T11TS induces a multi-targeted approach towards activation of this “alternative pathway” of T-cell signaling providing an immunotherapeutic advantage against glioma. We show here that T11TS immunotherapy causes positive modulations of the CD2 pathway-associated proteins, viz., p59fyn, protein kinase C-θ (PKC-θ), calcineurin and nuclear factor for activation of T-cells (NFAT) and hint that this may accord greater survival and proliferation advantage to T-cells of the glioma-bearing animals for augmented defence against glioma. These findings help open a molecular immunotherapeutic door – one which is directed towards clinical studies for glioma-immunotherapy using T11TS. [ABSTRACT FROM AUTHOR]

Summary The mononuclear phagocytic system (MPS), comprised of monocytes, macrophages, and dendritic cells, is essential in tissue homeostasis and in determining the balance of the immune response through its role in antigen presentation. It has been identified as a therapeutic target in infectious disease, cancer, autoimmune disease and transplant rejection. Here, we review the current understanding of the immunophenotype and function of the MPS in normal human liver. Using well-defined selection criteria, a search of MEDLINE and EMBASE databases identified 76 appropriate studies. The majority (n = 67) described Kupffer cells (KCs), although the definition of KC differs between sources, and little data were available regarding their function. Only 10 papers looked at liver dendritic cells (DCs), and largely confirmed the presence of the major dendritic cell subsets identified in human blood. Monocytes were thoroughly characterized in four studies that utilized flow cytometry and fluorescent microscopy and highlighted their prominent role in liver homeostasis and displayed subtle differences from circulating monocytes. There was some limited evidence that liver DCs are tolerogenic but neither liver dendritic cell subsets nor macrophages have been thoroughly characterized, using either multi-colour flow cytometry or multi-parameter fluorescence microscopy. The lobular distribution of different subsets of liver MPS cells was also poorly described, and the ability to distinguish between passenger leukocytes and tissue resident cells remains limited. It was apparent that further research, using modern immunological techniques, is now required to accurately characterize the cells of the MPS in human liver. [ABSTRACT FROM AUTHOR]

Abstract: The CD40L/CD40 signalling pathway is critically involved in the final stage of the maturation of DCs. This paper reports the identification and functional characterization of CD40L and CD40 from Atlantic salmon (Salmo salar). Salmon CD40L is a type II membrane-bound protein with a TNF homology domain in its extracellular C-terminal region, while CD40 is a type I membrane-bound receptor with a sequence pattern of four cysteine-rich domains in its extracellular N-terminal region. The salmon CD40L and CD40 were widely expressed, particularly in immune tissues, and while CD40L expression was induced by in vitro stimulation of HKLs with PHA and ConA, CpG increased CD40 expression. A CD40L construct was overexpressed in the CHSE-214 cell line and co-cultivation of the CD40L-CHSE transfectants with HKL induced a rapid and long-lasting upregulation of important costimulatory molecules like CD40, CD83, B7-H1 and the cytokines IL-12p40, IL-10, IL-1β and IFNs, which all are involved in T-helper cell responses. Furthermore, the CD40L transfected cells increased the percentage of HKLs expressing surface MHCIIβ but unlike other APC maturation stimuli, like CpG, they did not reduce the capacity to internalise antigen. Our results provide the first evidence for the existence of a functional CD40L mediated costimulatory pathway in Atlantic salmon. [Copyright &y& Elsevier]

Abstract: Establishment of a leukemia plasmacytoid dendritic cell line (PMDC05) and intra-lineage transformation from pDCs to mDCs in PMDC05 has been reported. In this paper, we show the applicability of PMDC05 for cellular immunotherapy. By stimulation with LPS, PMDC05 showed enhancement in expression of antigen presentation-associated surface molecules and production of cytokines (IL-12p70 and TNF-α). The antigen presenting ability was markedly increased in PMDC05 stimulated with LPS. By co-culturing of CD8+ T cells with LPS-stimulated and WT1/CMVpp65 peptide-pulsed PMDC05, WT1/CMVpp65 tetramer+ cytotoxic T lymphocytes were efficiently generated. These findings reveal the applicability of PMDC05 in cellular immunotherapy for tumor and severe viral infections. [Copyright &y& Elsevier]

Abstract: Dendritic cells (DCs) are bone marrow-derived professional antigen presenting cells. Due to their role as potent inducers of immune responses, these cells are widely used as adjuvant in experimental clinical settings for cancer immune therapy. We have developed a DC-based vaccine using autologous blood monocytes loaded with allogeneic tumor cell lysate rich in cancer/testis antigens. This vaccine has at present been tested for activity in three phase II clinical trials including two cohorts of patients with advanced colorectal cancer (CRC) and one cohort of patients with advanced non-small-cell-lung-cancer (NSCLC). In the present paper we retrospectively compare the maturation profile based on surface marker expression on DCs generated from the three patient cohorts and between cancer patient cohorts and a cohort of healthy donors. Vaccines were generated under cGMP conditions and phenotypic profiles of DC were analyzed by flow cytometry and the obtained data were used as a basis to set guideline values for our quality control of GMP produced DC vaccines. Each vaccine batch was analyzed for the expression of the surface maturation and differentiation molecules CD14, CD1a, CD83, CD86, MHC class II and CCR7, and the optimal expression pattern is considered as CD14low, CD1a, CD83high, CD86high, MHC class IIhigh and CCR7high. In accordance with data from other studies including other types of cancer patients, especially breast cancer patients, we found that the maturation status of the DC batches depends on cancer type and correlates with clinical status of cancer patients included. [Copyright &y& Elsevier]

Two recent papers published in Immunity and Cell Host & Microbe underline the great importance of B cells and of antibodies (Abs) in orchestrating crucial T helper cell type 2 (Th2) protective immune responses to gastrointestinal nematodes. The findings in animal models now raise major questions as to how B cells and Abs carry out these functions in humans. Here we discuss recent technological advances in humanizing animal models at the level of both Abs and their Fc-receptors, that might provide some answers. [Copyright &y& Elsevier]

Abstract: Antigen presenting molecules play an important role in both innate and adoptive immune responses by priming and activating T cells. Among them, CD1 molecules have been identified to present both exogenous and endogenous lipid antigens to CD1-restricted T cells. The involvement of CD1-restricted T cells in autoimmune diseases and in defense against infectious diseases, however, remains largely unknown. Identifying novel antigenic lipids that bind to CD1 molecules and understanding the role of CD1-restricted T cells should lead to the successful development of vaccines, because the lipids can be used as antigens and also as adjuvants. In this paper, we have constructed functional recombinant human CD1 dimeric proteins and established a competitive ELISA assay to measure the lipid binding to CD1 molecules using the CD1 dimers. By using the competitive ELISA assay, we were able to show that the lipid extracts from murine malaria parasites can actually be loaded onto CD1 molecules. In addition, we have demonstrated that artificial antigen-presenting cells, which consist of magnetic beads coated with CD1d dimer and anti-CD28 antibody, stimulated and expanded human invariant NKT cells as efficiently as autologous immature DCs. A set of the tools presented in the current study should be valuable for screening various CD1 molecule-binding lipid antigens and for isolating CD1-restricted T cells. [Copyright &y& Elsevier]

[Display omitted] • Liposomes self-assembled from lipids are excellent targeted transport carrier materials. • Lipids have the role of immune stimulation, which can stimulate the effect of innate immunity. • Liposomes combined with targeted transport and immunostimulatory effects have great advantages in cancer vaccines. Cancer is still a major threat for human life, and the cancer immunotherapy can be more optimized to prolong life. However, the effect of immunotherapy is not encouraging. In order to achieve outstanding immune effect, it is necessary to strengthen antigens uptake of antigen presenting cells. Adjuvants were added to vaccines to achieve this purpose, which could be divided into two types: as an immunostimulatory molecule, the innate immunities of the body were triggered; or as a delivery carrier, and antigens were cross-delivery through the "cytoplasmic pathway" and released at a specific location. This paper reviewed the relevant research status of tumor vaccine immune adjuvants in recent years. Among the review, the function, combination strategies and derivatives of lipid A were discussed in detail. In addition, some suggestions on the existing problems and research direction of lipids as tumor vaccine adjuvants were put forward. [ABSTRACT FROM AUTHOR]

Abstract: RANDAM-2, a type-I transmembrane antigen constitutively expressed on the neuronal cell lineage during mouse neurogenesis, shows the highest expression level between embryonic day 8.5 (E8.5) and E10.5. As the period well overlaps with the proliferating stages of neural stem cells (NSCs), it is conceivable that NSCs are efficiently separable based on the expression level of RANDAM-2. In this paper, we show that NSCs can be efficiently enriched as RANDAM-2high+ cells by fluorescence-activated cell sorting. Many cells in the RANDAM-2high+ cells had the characteristics of the self-renewal capability and potential for multilineage differentiation into neural cells. In contrast, almost all of the RANDAM-2low+/− cells exhibited not only the extremely low self-renewability but the differentiation capability restricted to neurons. These two subpopulations also differed from each other in terms of the expression level of molecules associated with neural differentiation. These findings demonstrate that RANDAM-2 can be regarded as a useful marker for enrichment of NSCs. [Copyright &y& Elsevier]

Many factors influence the choice of methods used to develop antibody to infectious agents. In this paper, we review the current status of the main technologies used to produce monoclonal antibodies (mAbs) from the B cells of antigen-sensitized animals. While companies are adopting advanced high-throughput methods, the major technologies used by veterinary and medical research laboratories are classical hybridoma fusion and recombinant library selection techniques. These methods have inherent advantages and limitations but have many common aspects when using immunized rodents. Laboratories with expertise in both methods of antibody development have a distinct advantage in their ability to advance mAb technology. New and re-emerging infectious threats in today's world emphasize the need for quality immunoreagents and the need to maintain expertise in mAb development. We provide examples of some common applications for mAb reagents used to identify pathogens such as the SARS-coronavirus (SARS-CoV), Bacillus anthracis, and foot-and-mouth disease (FMD) virus. We also outline a framework for investigators to make rational decisions concerning which method to use to develop mAbs based upon characteristics of the pathogen under study and the intended downstream application. Lastly, we provide parameters for the immunisation of mice and a classification system which describes the expected outcome for mAb development strategies when using classes of immunogens to generate mAbs with desired activities. [ABSTRACT FROM AUTHOR]

Dendritic cells (DCs) are recognized as the sole professional antigen-presenting cells capable of priming naive T cells of the helper and cytotoxic phenotypes. This property is presently exploited with success in vaccinal strategies against pathogens or tumor cells that otherwise escape immune recognition, but the repeated infusions of ex vivo expanded and sensitized DCs are usually required to achieve protection. In this paper, we demonstrate that liposomal antigens can efficiently relay and propagate the action of DCs, inducing a strong long-term response against their associated antigen. Their effect is mainly achieved by improving the ex vivo loading of DCs and by efficiently channeling the activation stimulus into the induction of effector function. This is demonstrated by the sustained immunoglobulin production as well as by the sustained lymphoproliferation and the increased cytokine secretion that can be achieved upon restimulation of DC-primed immune cells with limited amount of liposomal antigenic material. Being well-tolerated and easily prepared, liposomal antigens could therefore be expected to significantly contribute to the efficiency and to a more general utilization of the highly promising but rather cumbersome DC-based immunotherapies. [ABSTRACT FROM AUTHOR]

The molecular mechanisms whereby PPARγ inhibits inflammatory gene expression in macrophages are poorly understood. In a recent Nature paper, provide a new model for trans-repression in which ligand-dependent SUMOylation of PPARγ results in its recruitment to the promoters of inflammatory genes where it inhibits transcription by preventing clearance of corepressor complexes. [Copyright &y& Elsevier]

This article recognizes the work done by Paul Langerhans in the field of investigative dermatology. At the age of 21 Paul published two papers, which described a short project in which he had stained human skin by the gold chloride method invented by his teacher, Cohnheim, and discovered the perplexing nonpiginentary dendritic cells which now carry his name. His second discovery, much better known to medical science, was that of the "islet" cells of the pancreas. During the summer of 1867 and then, after a gap of about a year, from the autumn of 1868, Paul pursued studies for his doctorate in medicine at the Berlin Pathological Institute, during winch time he developed a close friendship with Rudolf Virchow.