B7-H4 Treatment of T Cells Inhibits ERK, JNK, p38, and AKT Activation

B7-H4 is a newly identified B7 homolog that plays an important role in maintaining T-cell homeostasis by inhibiting T-cell proliferation and lymphokine-secretion. In this study, we investigated the signal transduction pathways inhibited by B7-H4 engagement in mouse T cells. We found that treatment of CD3+ T cells with a B7-H4.Ig fusion protein inhibits anti-CD3 elicited T-cell receptor (TCR)/CD28 signaling events, including phosphorylation of the MAP kinases, ERK, p38, and JNK. B7-H4.Ig treatment also inhibited the phosphorylation of AKT kinase and impaired its kinase activity as assessed by the phosphorylation of its endogenous substrate GSK-3. Expression of IL-2 is also reduced by B7-H4. In contrast, the phosphorylation state of the TCR proximal tyrosine kinases ZAP70 and lymphocyte-specific protein tyrosine kinase (LCK) are not affected by B7-H4 ligation. These results indicate that B7-H4 inhibits T-cell proliferation and IL-2 production through interfering with activation of ERK, JNK, and AKT, but not of ZAP70 or LCK

Coxiella burnetii employs the Dot/Icm type IV secretion system to modulate host NF-KB/RelA activation

Coxiella burnetii is the causative agent of Q fever and an obligate intracellular pathogen in nature that survives and grows in a parasitophorous vacuole (PV) within eukaryotic host cells. C. burnetii promotes intracellular survival by subverting apoptotic and pro-inflammatory signaling pathways that are typically regulated by nuclear transcription factor-κB (NF-κB). We and others have demonstrated that C. burnetii NMII proteins inhibit expression of pro-inflammatory cytokines and induce expression of anti-apoptotic genes during infection. Here, we demonstrate that C. burnetii promotes intracellular survival by modulating NF-κB subunit p65 (RelA) phosphorylation, and thus activation, in a Type Four B Secretion System (T4BSS)-dependent manner. Immunoblot analysis of RelA phosphorylated at serine-536 demonstrated that C. burnetii increases NF-κB activation via the canonical pathway. However, RelA phosphorylation levels were even higher in infected cells where bacterial protein or mRNA synthesis was inhibited. Importantly, we demonstrate that inhibition of RelA phosphorylation impairs PV formation and C. burnetii growth. We found that a T4BSS-defective mutant (CbΔdotA) elicited phosphorylated RelA levels similar to those of wild type C. burnetii infection treated with Chloramphenicol. Moreover, cells infected with CbΔdotA or wild type C. burnetii treated with Chloramphenicol showed similar levels of GFP-RelA nuclear localization, and significantly increased localization compared to wild type C. burnetii infection. These data indicate that without de novo protein synthesis and a functional T4BSS, C. burnetii is unable to modulate NF-κB activation, which is crucial for optimal intracellular growth.Peer reviewedMicrobiology and Molecular Genetic

Fièvre Q (étude des réponses de l'hôte)

L'infection humaine à Coxiella burnetii, une bactérie qui infecte exclusivement les cellules myéloïdes, peut se traduire par des manifestations cliniques connues sous le nom de fièvre Q aiguë. La fièvre Q peut se chroniciser sous forme essentiellement d'endocardites chez les patients atteints d'une valvulopathie et/ou immunodéprimés. Nous avons étudié différents aspects de la réponse de l'hôte à C. burnetii. Notre première hypothèse était que le LPS de C. burnetii est impliqué dans certaines des réponses de l'hôte. En utilisant des souris génétiquement invalidées pour TLR4, le récepteur du LPS, nous avons montré que le LPS contrôle des événements précoces tels que la phagocytose des bactéries par les macrophages, la réorganisation du cytosquelette d'actine qui l'accompagne et la production des cytokines impliquées dans la formation des granulomes. La réponse des lymphocytes T nécessite un double signal transmis par le TCR et des molécules de costimulation dont la plus importante est CD28. L'utilisation de souris génétiquement invalidées pour CD28 a permis de montrer que CD28 inhibe la réponse immune impliquée dans la clairance de C. burnetii via probablement la production d'IL-10. La fièvre Q aiguë se caractérise par une réponse immune protectrice alors que la fièvre Q chronique se caractérise par un défaut de réponse immune dont pourrait rendre compte la dérégulation du réseau de cytokines. Nous avons effectué un suivi de patients atteints de différentes présentations cliniques de fièvre Q aiguë et dosé des cytokines telles que le TNF et l'IL-10. La fièvre Q aiguë est associée à une surproduction de cytokines et la survenue d'une endocardite chez les patients valvulopathes est associée à des taux élevés et persistants de TNF, qui pourraient ainsi servir de marqueur d'évolution chronique de la fièvre Q. Nous avons enfin montré que les monocytes des patients atteints de fièvre Q chronique évolutive présentent un défaut de maturation phagosomale et une moindre capacité à éliminer C. burnetii que les monocytes de patients convalescents ou guéris. L'IL-10 produite en excès chez ces malades est responsable de ce double défautThe human infection by Coxiella burnetii, a bacterium that exclusively lives in myeloid cells, may manifest as acute Q fever. Q fever may become chronic in patients with valvulopathy and immunodepressed patients; its major presentation is endocarditis. We have studied different aspects of the host response to C. burnetii infection. We hypothetized that C. burnetii LPS is involved in some host responses. By using mice genetically deficient in TLR4, the LPS receptor, we showed that LPS controlled early events such as C. burnetii uptake by macrophages, reorganization of actin cytoskeleton and production of cytokines involved in granuloma formation. The T cell response neads signalling through TCR and costimulation molecules such as CD28. Using CD28 knock-out mice showed that CD28 inhibited the immune response involved in the clearance of C. burnetii likely through IL-10 production. Acute Q fever is characterized by a protective immune response whereas chronic Q fever is characterized by a defective immune response including dysregulated cytokine network. The following-up of patients with different clinical presentations of acute Q fever and the production of cytokines such as TNF and IL-10 by monocytes were performed. The acute Q fever was associated with increased cytokine production, and the occurrence of endocarditis in patients with valvulopathy was associated with increased and persistent amounts of TNF, which may be markers of chronic evolution of Q fever. Finally, we showed that monocytes from patients with evolutive chronic Q fever had defective phagosomal maturation and a lesser ability to eliminate C. burnetii than monocytes from convalescent patients and cured patients. Both events were related to IL-10 over-productionAIX-MARSEILLE2-BU Méd/Odontol. (130552103) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF

Dielectric Properties of Hexagonal Perovskite Ceramics Prepared by Different Routes

International audienceIn this work, four different methods, i.e. solid state reaction, citrate sol–gel process, Pechini and microwave are employed to synthesize Ba4YMn3O11.5±δ ceramics. The phase structure of the powders can be well indexed as a 12R hexagonal perovskite crystallizing in space group . The density and morphology (average grain size) of sintered samples vary with the synthesis processes. The dielectric permittivity and loss tangent of the samples have been measured in the frequency range 1 kHz–1 MHz. The results show that they are very sensitive to the synthesis process. The best properties are obtained for the sample synthetized by citrate process. This compound has a high dielectric permittivity (), which is almost frequency independent over the 100 Hz–100 kHz range from room temperature to 150 °C. This has been attributed to the IBLC mechanism. By impedance spectroscopy analysis, all the compounds were found to be electrically heterogeneous, exhibiting semiconducting grains and insulating grain boundaries. Finally, we show that the IBLC model is well adapted to the materials obtained by the modified citrate synthesis route, but not to the ones from the other routes

Atypical response of spondyloarthritis to biologics revealing Whipple's disease: a case-report

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Cu-Doping Effect on Dielectric Properties of Organic Gel Synthesized Ba4YMn3-xCuxO11.5±δ

International audienceCopper doped-Ba4YMn3ÀxCuxO11.5 7 δ samples were synthesized by an organic gel assisted citrate process. X-ray diffraction of compositions with x \textonequarter0.002, 0.005, 0.01, 0.02 and 0.04 does not reveal any change of hexagonal perovskite structure on doping. The effects of Cu-doping on the microstructure and dielectric properties were investigated. Cu doping modifies the electrical properties at the level of the impedance characteristics of both grain and grain boundary and to understand these different behaviours, we have carried out high-resolution transmission electron microscopy analysis

Capacitance Scaling of Grain Boundaries with Colossal Permittivity of CaCu3Ti4O12-Based Materials

International audienceSamples of copper-deficient CaCu3Ti4O12 (CCTO) compared to the nominal composition, all synthesized via organic gel-assisted citrate process, show huge change of grain boundaries capacitance as deduced from a fit of an RC element model to the impedance spectroscopic data. The grain boundary capacitance is found to scale with the permittivity measured at 1 kHz weighted by the size of the grains. This result is found consistent with the internal barrier layer capacitance (IBLC) model

Leading Role of Grain Boundaries in Colossal Permittivity of Doped and Undoped CCTO

International audienceThe role of grain boundaries in the colossal permittivity \epsilon of doped and undoped calcium copper titanate, CaCu3Ti4O12 (CCTO), is illustrated by a first correlation \textendash over four orders of magnitude \textendash between \epsilon and the capacity of grain boundaries, not that of grains, deduced from the analysis of impedance measurements. The DC resistance of the CCTO sample which is essential to make efficient capacitors for technological applications, as well as the loss factor tan(δ), are found to be correlated with the resistance of the grain boundaries rather than that of the grains. The correlation extends over almost seven orders of magnitude. These findings, consistent with the internal barrier layer capacitance (IBLC) model, indicate the leading role of grain boundaries in the origin of the capacitance of CCTO samples