Mayday - integrative analytics for expression data

Battke, Florian; Symons, Stephan; Nieselt, Kay

doi:10.1186/1471-2105-11-121

Cited by 104 publications

(100 citation statements)

References 30 publications

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“…3B), suggesting that MR-mediated T-cell impairment shares mechanisms operative in T-cell tolerance. Next, we applied a combined approach to identify and prioritize candidate effector molecules responsible for MR-mediated T-cell impairment as defined by differential expression at least at one time point (first criterion), being part of the tolerance gene set (second criterion), and being part of a set of genes (n = 45) that were previously associated with T-cell anergy or tolerance (third criterion) (11)(12)(13)(14)(15)(16)(17)(18)(19)(20). For genes within the intersection of these three gene groups, a sum rank was determined based on most significant differential expression (Fig.…”

Section: Resultsmentioning

confidence: 99%

Mannose receptor induces T-cell tolerance via inhibition of CD45 and up-regulation of CTLA-4

Schuette

Embgenbroich

Ulas

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The mannose receptor (MR) is an endocytic receptor involved in serum homeostasis and antigen presentation. Here, we identify the MR as a direct regulator of CD8 + T-cell activity. We demonstrate that MR expression on dendritic cells (DCs) impaired T-cell cytotoxicity in vitro and in vivo. This regulatory effect of the MR was mediated by a direct interaction with CD45 on the T cell, inhibiting its phosphatase activity, which resulted in up-regulation of cytotoxic T-lymphocyte-associated Protein 4 (CTLA-4) and the induction of T-cell tolerance. Inhibition of CD45 prevented expression of B-cell lymphoma 6 (Bcl-6), a transcriptional inhibitor that directly bound the CTLA-4 promoter and regulated its activity. These data demonstrate that endocytic receptors expressed on DCs contribute to the regulation of T-cell functionality.T he mannose receptor (MR) is an endocytic receptor belonging to the C-type lectin family and is expressed by distinct populations of dendritic cells (DCs), macrophages, and endothelial cells (1). It consists of an N-terminal cysteine-rich domain (CR), a fibronectin type II (FN II) domain, eight C-type lectinlike domains (CTLDs), a transmembrane region, and a short intracellular region. The CTLDs of the MR can bind to glycoconjugates terminated in mannose, fucose, or glucose. Despite the presence of eight CTLDs, only CTLD4 is responsible for carbohydrate binding. Additionally, the MR can bind to sulfated carbohydrates via its CR and to collagen via its FN II domain (1).In a previous study, we demonstrated that antigens internalized by the MR are processed specifically for cross-presentation (2). The correlation between the MR and cross-presentation offered the possibility that antigens targeted toward the MR could induce potent cytotoxic T-cell responses. Because the induction of a strong cytotoxic T-cell response against tumor-specific antigens is a crucial process in many tumor vaccination strategies, antigen targeting toward the MR seemed to be a promising approach. However, in in vivo tumor models, antigen targeting toward the MR did not result in a strong cytotoxic T-cell response but, instead, led to the induction of antigen-specific T-cell tolerance (3, 4). Therefore, we analyzed whether the MR has a regulatory effect on the induction of immune responses by means distinct from antigen uptake and presentation, and we investigated a direct influence of the MR on T-cell activation. We could demonstrate that the presence of the MR on the antigen-presenting cell (APC) directly impairs the cytotoxic activity of T cells in vitro and in vivo. We showed that this effect was due to a direct interaction of the MR with CD45 on the T-cell surface. This interaction inhibited CD45 activity and resulted in the up-regulation of the inhibitory molecule cytotoxic T-lymphocyte-associated Protein 4 (CTLA-4), which was responsible for the impaired cytotoxic activity of the T cells. ResultsThe Presence of the MR on DCs Reduces Cytotoxic Activity of CD8 + T Cells. To investigate whether the MR influences T-cell ...

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Section: Resultsmentioning

confidence: 99%

Mannose receptor induces T-cell tolerance via inhibition of CD45 and up-regulation of CTLA-4

Schuette

Embgenbroich

Ulas

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…RNA was isolated as described above, labeled using the Illumina TotalPrep RNA amplification kit (Ambion, Austin, TX) and hybridized to Ref12v3 Arrays. Data were quantile normalized and analyzed using Genome studio and Mayday software [21].…”

Section: Microarray Analysismentioning

confidence: 99%

Pretreatment with Interferon-γ Enhances the Therapeutic Activity of Mesenchymal Stromal Cells in Animal Models of Colitis

et al. 2011

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Mesenchymal stromal cells (MSCs) are currently under investigation for the treatment of inflammatory disorders, including Crohn's disease. MSCs are pluripotent cells with immunosuppressive properties. Recent data suggest that resting MSCs do not have significant immunomodulatory activity, but that the immunosuppressive function of MSCs has to be elicited by interferon-c (IFN-c). In this article, we assessed the effects of IFN-c prestimulation of MSCs (IMSCs) on their immunosuppressive properties in vitro and in vivo. To this end, we pretreated MSCs with IFN-c and assessed their therapeutic effects in dextran sodium sulfate (DSS)-and trinitrobenzene sulfonate (TNBS)-induced colitis in mice. We found that mice treated with IMSCs (but not MSCs) showed a significantly attenuated development of DSS-induced colitis. Furthermore, IMSCs alleviated symptoms of TNBS-induced colitis. IMSCtreated mice displayed an increase in body weight, lower colitis scores, and better survival rates compared with untreated mice. In addition, serum amyloid A protein levels and local proinflammatory cytokine levels in colonic tissues were significantly suppressed after administration of IMSC. We also observed that IMSCs showed greater migration potential than unstimulated MSCs to sites within the inflamed intestine. In conclusion, we show that prestimulation of MSCs with IFN-c enhances their capacity to inhibit Th1 inflammatory responses, resulting in diminished mucosal damage in experimental colitis. These data demonstrate that IFN-c activation of MSCs increases their immunosuppresive capacities and importantly, their therapeutic efficacy in vivo. STEM CELLS 2011;

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“…To correct for systematic bias at high-end fluorescence intensity measurements, the highest 2% of processed signals in the green channel were further normalized according to an intensity-dependent, nonlinear strategy, to optimize fitting to their respective counterparts in the red channel. Heat maps were created using the program Mayday (23).…”

Section: Microarray Experimentsmentioning

confidence: 99%

Identification of Two Forms of TNF Tolerance in Human Monocytes: Differential Inhibition of NF-κB/AP-1– and PP1-Associated Signaling

Günther

Vogt

Hampel

et al. 2014

The Journal of Immunology

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The molecular basis of TNF tolerance is poorly understood. In human monocytes we detected two forms of TNF refractoriness, as follows: absolute tolerance was selective, dose dependently affecting a small group of powerful effector molecules; induction tolerance represented a more general phenomenon. Preincubation with a high TNF dose induces both absolute and induction tolerance, whereas low-dose preincubation predominantly mediates absolute tolerance. In cells preincubated with the high TNF dose, we observed blockade of IκBα phosphorylation/proteolysis and nuclear p65 translocation. More prominent in cells preincubated with the high dose, reduced basal IκBα levels were found, accompanied by increased IκBα degradation, suggesting an increased IκBα turnover. In addition, a nuclear elevation of p50 was detected in tolerant cells, which was more visible following high-dose preincubation. TNF-induced phosphorylation of p65-Ser536, p38, and c-jun was inhibited, and basal inhibitory p65-Ser468 phosphorylation was increased in tolerant cells. TNF tolerance induced by the low preincubation dose is mediated by glycogen synthesis kinase-3, whereas high-dose preincubation-mediated tolerance is regulated by A20/glycogen synthesis kinase-3 and protein phosphatase 1–dependent mechanisms. To our knowledge, we present the first genome-wide analysis of TNF tolerance in monocytic cells, which differentially inhibits NF-κB/AP-1–associated signaling and shifts the kinase/phosphatase balance. These forms of refractoriness may provide a cellular paradigm for resolution of inflammation and may be involved in immune paralysis.

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Mayday - integrative analytics for expression data

Cited by 104 publications

References 30 publications

Mannose receptor induces T-cell tolerance via inhibition of CD45 and up-regulation of CTLA-4

Mannose receptor induces T-cell tolerance via inhibition of CD45 and up-regulation of CTLA-4

Pretreatment with Interferon-γ Enhances the Therapeutic Activity of Mesenchymal Stromal Cells in Animal Models of Colitis

Identification of Two Forms of TNF Tolerance in Human Monocytes: Differential Inhibition of NF-κB/AP-1– and PP1-Associated Signaling

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