A spatially-organized multicellular innate immune response in lymph nodes limits systemic pathogen spread

The lymphatic network that transports interstitial fluid and antigens to lymph nodes constitutes a conduit system that can be hijacked by invading pathogens to achieve systemic spread unless dissemination is blocked in the lymph node itself. Here, we show that a network of diverse lymphoid cells (natural killer cells, γδ T cells, natural killer T cells, and innate-like CD8+ T cells) are spatially prepositioned close to lymphatic sinus-lining sentinel macrophages where they can rapidly and efficiently receive inflammasome-generated IL-18 and additional cytokine signals from the pathogen-sensing phagocytes. This leads to rapid IFNγ secretion by the strategically positioned innate lymphocytes, fostering antimicrobial resistance in the macrophage population. Interference with this innate immune response loop allows systemic spread of lymph-borne bacteria. These findings extend our understanding of the functional significance of cellular positioning and local intercellular communication within lymph nodes while emphasizing the role of these organs as highly active locations of innate host defense

Tuning of antigen sensitivity by T cell receptor-dependent negative feedback controls T cell effector function inflammed tissues

Activated T cells must mediate effector responses sufficient to clear pathogens while avoiding excessive tissue damage. Here we have combined dynamic intravital microscopy with ex vivo assessments of T cell cytokine responses to generate a detailed spatiotemporal picture of CD4+ T cell effector regulation in the skin. In response to antigen, effector T cells arrested transiently on antigen presenting cells, briefly producing cytokine and then resuming migration. Antigen recognition led to PD-1 upregulation of the programmed death-1 (PD-1) glycoprotein by T cells and blocking its canonical ligand, programmed death-ligand 1 (PD-L1), lengthened the duration of migration arrest and cytokine production, showing that PD-1 interaction with PD-L1 is a major negative feedback regulator of antigen responsiveness. We speculate that the immune system employs a mechanism involving T cell recruitment, transient activation, and rapid desensitization, allowing the T cell response to rapidly adjust to changes in antigen presentation and minimize collateral injury to the host

Neutrophil swarms require LTB4 and integrins at sites of cell death in vivo

Neutrophil recruitment from blood to extravascular sites of sterile or infectious tissue damage is a hallmark of early innate immune responses, and the molecular events leading to cell exit from the bloodstream have been well defined1,2. Once outside the vessel, individual neutrophils often show extremely coordinated chemotaxis and cluster formation reminiscent of the swarming behaviour of insects3,4,5,6,7,8,9,10,11. The molecular players that direct this response at the single-cell and population levels within the complexity of an inflamed tissue are unknown. Using two-photon intravital microscopy in mouse models of sterile injury and infection, we show a critical role for intercellular signal relay among neutrophils mediated by the lipid leukotriene B4, which acutely amplifies local cell death signals to enhance the radius of highly directed interstitial neutrophil recruitment. Integrin receptors are dispensable for long-distance migration12, but have a previously unappreciated role in maintaining dense cellular clusters when congregating neutrophils rearrange the collagenous fibre network of the dermis to form a collagen-free zone at the wound centre. In this newly formed environment, integrins, in concert with neutrophil-derived leukotriene B4 and other chemoattractants, promote local neutrophil interaction while forming a tight wound seal. This wound seal has borders that cease to grow in kinetic concert with late recruitment of monocytes and macrophages at the edge of the displaced collagen fibres. Together, these data provide an initial molecular map of the factors that contribute to neutrophil swarming in the extravascular space of a damaged tissue. They reveal how local events are propagated over large-range distances, and how auto-signalling produces coordinated, self-organized neutrophil-swarming behaviour that isolates the wound or infectious site from surrounding viable tissue

Media violence and the self: the impact of personalized gaming characters in aggressive video games on aggressive behavior

A recent development in video games is that players can design and personalize their own in-game characters. It was predicted that this innovation could lead to elevations in the intensity of the psychological effects of video games. The present study confirmed this hypothesis, revealing that participants who played an aggressive video game using their own, personalized character exhibited higher levels of aggressive behavior than participants who played an aggressive game with a non-personalized character. The aggressive behavior levels of the own-character players also exceeded those of individuals who played a non-aggressive game, regardless of whether or not they used a personalized character. Process analyses revealed that participants playing a violent video game with a personalized game character experienced more arousal and self-activation than they did when playing with an impersonal, default game character, which in turn increased aggressive responses

Immunization with HIV Gag targeted to dendritic cells followed by recombinant New York vaccinia virus induces robust T-cell immunity in nonhuman primates

Protein vaccines, if rendered immunogenic, would facilitate vaccine development against HIV and other pathogens. We compared in nonhuman primates (NHPs) immune responses to HIV Gag p24 within 3G9 antibody to DEC205 ( DEC-HIV Gag p24 ), an uptake receptor on dendritic cells, to nontargeted protein, with or without poly ICLC, a synthetic double stranded RNA, as adjuvant. Priming s.c. with 60 ?g of both HIV Gag p24 vaccines elicited potent CD4+ T cells secreting IL-2, IFN-γ, and TNF-α, which also proliferated. The responses increased with each of three immunizations and recognized multiple Gag peptides. DEC-HIV Gag p24 showed better cross-priming for CD8+ T cells, whereas the avidity of anti-Gag antibodies was ∼10-fold higher with nontargeted Gag 24 protein. For both protein vaccines, poly ICLC was essential for T- and B-cell immunity. To determine whether adaptive responses could be further enhanced, animals were boosted with New York vaccinia virus (NYVAC)-HIV Gag/Pol/Nef. Gag-specific CD4+ and CD8+ T-cell responses increased markedly after priming with both protein vaccines and poly ICLC. These data reveal qualitative differences in antibody and T-cell responses to DEC-HIV Gag p24 and Gag p24 protein and show that prime boost with protein and adjuvant followed by NYVAC elicits potent cellular immunity

Selective exposure and decision framing: The impact of gain and loss framing on confirmatory information search after decisions

When people make decisions, they often prefer to receive information that supports rather than conflicts with their decision. To date, this effect has mainly been investigated in the context of decisions about gains, whereas decisions about losses have received less attention. Based on Prospect Theory, we expected information search to be differently affected by whether people previously have decided about gains or losses. Three studies have revealed that selectivity of information search is stronger after gain-framed rather than after loss-framed decision problems. An investigation of the underlying psychological processes revealed that gain decisions are made with increased subjective decision certainty (i.e. they are easier and less effortful to make), which in turn systematically increases confirmatory information search

Uncovering metabolic pathways relevant to phenotypic traits of microbial genomes

A new machine learning-based method is presented here for the identification of metabolic pathways related to specific phenotypes in multiple microbial genomes

metaP-Server: A Web-Based Metabolomics Data Analysis Tool

Metabolomics is an emerging field that is based on the quantitative measurement of as many small organic molecules occurring in a biological sample as possible. Due to recent technical advances, metabolomics can now be used widely as an analytical high-throughput technology in drug testing and epidemiological metabolome and genome wide association studies. Analogous to chip-based gene expression analyses, the enormous amount of data produced by modern kit-based metabolomics experiments poses new challenges regarding their biological interpretation in the context of various sample phenotypes. We developed metaP-server to facilitate data interpretation. metaP-server provides automated and standardized data analysis for quantitative metabolomics data, covering the following steps from data acquisition to biological interpretation: (i) data quality checks, (ii) estimation of reproducibility and batch effects, (iii) hypothesis tests for multiple categorical phenotypes, (iv) correlation tests for metric phenotypes, (v) optionally including all possible pairs of metabolite concentration ratios, (vi) principal component analysis (PCA), and (vii) mapping of metabolites onto colored KEGG pathway maps. Graphical output is clickable and cross-linked to sample and metabolite identifiers. Interactive coloring of PCA and bar plots by phenotype facilitates on-line data exploration. For users of commercial metabolomics kits, cross-references to the HMDB, LipidMaps, KEGG, PubChem, and CAS databases are provided. metaP-server is freely accessible at http://metabolomics.helmholtz-muenchen.de/metap2/

Activation of Peroxisome Proliferator-Activated Receptor-Gamma by Glitazones Reduces the Expression and Release of Monocyte Chemoattractant Protein-1 in Human Mesothelial Cells

Human peritoneal mesothelial cells (MC) play an important role in inflammatory processes of the peritoneal cavity by producing various cytokines and chemokines, such as monocyte chemoattractant protein-1 (MCP-1). The present study was designed to assess the effect of the peroxisome proliferator-activated receptor-gamma- (PPARγ-) activator rosiglitazone on the mesothelial MCP-1 expression and release. Primary cultures of MC were obtained from omental tissue. MCP-1 antigen concentrations were measured in the cell supernatant by ELISA and MCP-1 mRNA levels by real-time polymerase chain reaction. The presence of PPARγ on MC was assayed in a Western Blot analysis. MC constitutively express PPARγ. Activation of this receptor via rosiglitazone (0,1–10 μmol/L) resulted in significantly reduced amounts of mesothelial MCP-1 release as well as MCP-1 mRNA. The use of the PPARγ inhibitor GW-9662 could completely prevent the rosiglitazone effects. Rosiglitazone was also effective in reducing TNFα-induced enhanced secretion of MCP-1. Our findings indicate that glitazones are effective in reducing constitutive and TNFα-stimulated mesothelial MCP-1 mRNA expression and release

The Racing-Game Effect: Why Do Video Racing Games Increase Risk-Taking Inclinations?

The present studies investigated why video racing games increase players’ risk-taking inclinations. Four studies reveal that playing video racing games increases risk taking in a subsequent simulated road traffic situation, as well as risk-promoting cognitions and emotions, blood pressure,sensation seeking, and attitudes toward reckless driving. Study 1 ruled out the role of experimental demand in creating such effects. Studies 2 and 3 showed that the effect of playing video racing games on risk taking was partially mediated by changes in selfperceptions as a reckless driver. These effects were evident only when the individual played racing games that reward traffic violations rather than racing games that do not reward traffic violations (Study 3) and when the individual was an active player of such games rather than a passive observer (Study 4). In sum, the results underline the potential negative impact of racing games on traffic safety