The regulation of IL-10 expression

Interleukin (IL)-10 is an important immunoregulatory cytokine and an understanding of how IL-10 expression is controlled is critical in the design of immune intervention strategies. IL-10 is produced by almost all cell types within the innate (including macrophages, monocytes, dendritic cells (DCs), mast cells, neutrophils, eosinophils and natural killer cells) and adaptive (including CD4(+) T cells, CD8(+) T cells and B cells) immune systems. The mechanisms of IL-10 regulation operate at several stages including chromatin remodelling at the Il10 locus, transcriptional regulation of Il10 expression and post-transcriptional regulation of Il10 mRNA. In addition, whereas some aspects of Il10 gene regulation are conserved between different immune cell types, several are cell type- or stimulus-specific. Here, we outline the complexity of IL-10 production by discussing what is known about its regulation in macrophages, monocytes, DCs and CD4(+) T helper cells

The Cholesterol biosynthesis pathway regulates IL-10 expression in human Th1 cells

The mechanisms controlling CD4+ T cell switching from an effector to an anti-inflammatory (IL-10+) phenotype play an important role in the persistence of chronic inflammatory diseases. Here, we identify the cholesterol biosynthesis pathway as a key regulator of this process. Pathway analysis of cultured cytokine-producing human T cells reveals a significant association between IL-10 and cholesterol metabolism gene expression. Inhibition of the cholesterol biosynthesis pathway with atorvastatin or 25-hydroxycholesterol during switching from IFNγ+ to IL-10+ shows a specific block in immune resolution, defined as a significant decrease in IL-10 expression. Mechanistically, the master transcriptional regulator of IL10 in T cells, c-Maf, is significantly decreased by physiological levels of 25-hydroxycholesterol. Strikingly, progression to rheumatoid arthritis is associated with altered expression of cholesterol biosynthesis genes in synovial biopsies of predisposed individuals. Our data reveal a link between sterol metabolism and the regulation of the anti-inflammatory response in human CD4+ T cells

On the charge transport mechanisms in Ge-rich GeSbTe alloys

International audienceGe-rich GeSbTe (GST) alloys are attracting Phase Change Materials for future memories as their higher crystallization temperature offers an extended range of applications. We have studied the electrical characteristics of PCM cells using such alloys as active layers. We show by impedance spectroscopy that the cells in the RESET (amorphous) state are not only resistive but also exhibit a capacitive component. Although trap-assisted conduction models are apparently able to describe the I(V) and I(T) characteristics of the devices in this state, their physical background is thus questionable. Alternatively, we show that granular models, describing electrical transport through conductive grains separated by insulating interfaces, are also able to simulate these characteristics, while fed by physically sound fitting parameters. Moreover, we show that the SET (crystalline) state is not simply ohmic but that its characteristics, as conductive as a metal but reacting as an insulator to temperature, resemble to those found in a semiconductor doped with a very low ionization energy defect. Finally, all these characteristics can be understood by considering that the electrical properties of cells made of Ge-rich GST layers are not those characteristic of some defective and homogeneous material but instead result from strong chemical heterogeneities found both in the amorphous and crystalline states of these Ge-rich alloys

Material and electrical characterization of TMS-based silicidation of the Cu-dielectric barrier interface for electromigration improvement of 65 nm interconnects

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Material and electrical characterization of TMS-based silicidation of the Cu-dielectric barrier interface for electromigration improvement of 65 nm interconnects

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Integration of gas cluster process for copper interconnects reliability improvement and process impact evaluation on BEOL dielectric materials

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Enhanced thermal confinement in phase-change memory targeting current reduction

International audienceIn this work, we present the extensive electrical characterization of 4kb Phase-Change Memory (PCM) arrays based on "Wall" structure and Ge-rich GeSbTe (GST) material, integrating a SiC dielectric with low thermal conductivity surrounding the heater element for enhanced cell thermal efficiency. We investigate the effects of the introduction of such dielectrics on the electrical performances of the device and we provide a promising path to achieve energy-efficient PCM cells supporting our results by electro-thermal TCAD simulations

New techniques to characterize properties of advanced dielectric barriers for sub-65 nm technology node

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Complement receptor CD46 co-stimulates optimal human CD8+ T cell effector function via fatty acid metabolism

The induction of human CD4+ Th1 cells requires autocrine stimulation of the complement receptor CD46 in direct crosstalk with a CD4+ T cell-intrinsic NLRP3 inflammasome. However, it is unclear whether human cytotoxic CD8+ T cell (CTL) responses also rely on an intrinsic complement-inflammasome axis. Here we show, using CTLs from patients with CD46 deficiency or with constitutively-active NLRP3, that CD46 delivers co-stimulatory signals for optimal CTL activity by augmenting nutrient-influx and fatty acid synthesis. Surprisingly, although CTLs express NLRP3, a canonical NLRP3 inflammasome is not required for normal human CTL activity, as CTLs from patients with hyperactive NLRP3 activity function normally. These findings establish autocrine complement and CD46 activity as integral components of normal human CTL biology, and, since CD46 is only present in humans, emphasize the divergent roles of innate immune sensors between mice and men