Thymus‐derived regulatory T cells restrain pro‐inflammatory Th1 responses by downregulating CD

The severity and intensity of autoimmune disease in Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) patients and in scurfy mice emphasizes the critical role played by thymus-derived regulatory T cells (tTregs) in maintaining peripheral immune tolerance. However, although tTregs are critical to prevent lethal autoimmunity and excessive inflammatory responses, their suppressive mechanism remains elusive. Here we demonstrate that tTregs selectively inhibit CD27/CD70-dependent Th1 priming, while leaving the IL-12-dependent pathway unaffected. Immunized mice depleted of tTregs showed an increased response of IFN-γ-secreting CD4+ T cells that was strictly reliant on a functional CD27/CD70 pathway. In vitro studies revealed that tTregs downregulate CD70 from the plasma membrane of dendritic cells (DCs) in a CD27-dependent manner. CD70 downregulation required contact between Tregs and DCs and resulted in endocytosis of CD27 and CD70 into the DC. These findings reveal a novel mechanism by which tTregs can maintain tolerance or prevent excessive, proinflammatory Th1 responsesin pressSCOPUS: ar.jFLWINinfo:eu-repo/semantics/publishe

Etude de la matière dense et tiède à l'aide de diagnostics X - Applications aux intérieurs planétaires

With the recent discovery of many exoplanets, modelling the interior of these celestial bodies is becoming a fascinating scientific challenge. In this context, it is crucial to accurately know the equations of state and the macroscopic and microscopic physical properties of their constituent materials in the Warm Dense Matter regime (WDM). Moreover, planetary models rely almost exclusively on physical properties obtained using first principles simulations based on density functional theory (DFT) predictions. It is thus of paramount importance to validate the basic underlying mechanisms occurring for key planetary constituents (metallization, dissociation, structural modifications, phase transitions, etc…) as pressure and temperature both increase. In this thesis, we were interested in two materials that can be mainly found in the Earth-like planets: silica, or SiO2, as a model compound of the silicates that constitute the major part of their mantles, and iron, which is found in abundance in their cores. These two materials were compressed and brought to the WDM regime by using strong shock created by laser pulses during various experiments performed on the LULI2000, JLF, GEKKO XII and LCLS laser facilities. In order to penetrate this dense matter and to have access to its both ionic and electronic structures, we have probed silica and iron with X-ray diagnostics, such as time-resolved X-ray Absorption Near Edge Structure (XANES) and time-resolved X-ray diffraction. In parallel with these experiments, we performed quantum molecular dynamics simulations based on DFT at conditions representative of the region investigated experimentally so as to extract the interesting physical processes and comprehend the limits of the implemented models. In particular, these works allowed us to highlight the metallization processes of silica in temperature and the structural changes of its liquid in density, as well as to more constrain the melting curve of iron at very high pressures.La découverte récente d’un grand nombre d’exoplanètes et en particulier de super-Terres fascine, entrainant avec elle des interrogations toutes aussi nombreuses. Comment modéliser la dynamique de ces objets célestes ? Comment interpréter leurs relations masse/volume ? Qu’en est-il de leur champ magnétique ? Pour aborder ces questions, il est primordial de connaître précisément les équations d’état et les propriétés physiques, autant macroscopiques que microscopiques, des matériaux qui les composent et qui sont soumis à des conditions extrêmes relevant du domaine de la matière dense et tiède (WDM). En outre, les propriétés physiques de ces matériaux, sur lesquels reposent presque exclusivement les modèles planétaires, sont obtenues grâce à des calculs de premier principe basés sur la théorie de la fonctionnelle de la densité (DFT). Il est par conséquent crucial de valider les processus fondamentaux intrinsèques à ces matériaux lorsque leur pression et leur température augmentent afin de confirmer et/ou corriger ces modèles : modifications de leur structure ionique et électronique, métallisation, dissociation, changements de phase, etc. Les travaux réalisés au cours de cette thèse se sont concentrés sur deux matériaux que l’on retrouve principalement dans les planètes de type tellurique : la silice, ou SiO2, comme composé modèle des silicates constituant essentiellement leur manteau, et le fer, élément présent en abondance en leur cœur. Ces matériaux ont été portés dans le régime de la WDM à l’aide de chocs créés par laser au cours de différentes campagnes expérimentales réalisées sur les grandes installations laser LULI2000, JLF (LLNL-USA), GEKKO XII (Japon) et LCLS (Stanford-USA). Afin de pénétrer et sonder cette matière dense et de collecter des renseignements précieux tant sur sa structure ionique qu’électronique, des diagnostics principalement basés sur l'emploi de rayonnement X - à savoir spectroscopie d'absorption près du flanc K (XANES) et diffraction résolues temporellement – ont été utilisés. Parallèlement à ces expériences, des calculs de dynamique moléculaire ab initio basés sur la théorie de la DFT ont été réalisés dans les mêmes conditions que celles atteintes expérimentalement afin d'en extraire les processus physiques intéressants et d'appréhender les limites de la modélisation mise en œuvre. L’ensemble de ces travaux a notamment permis de comprendre le mécanisme de fermeture du gap lors du processus de métallisation de la silice en température et les changements de structure de son liquide en densité, ainsi que de contraindre davantage la courbe de fusion du fer aux très hautes pressions

Spatio-temporal characterization of attosecond pulses from plasma mirrors

International audienceReaching light intensities above 1025 W cm−2 and up to the Schwinger limit of order 1029 W cm−2 would enable the testing of fundamental predictions of quantum electrodynamics. A promising—yet challenging—approach to achieve such extreme fields consists in reflecting a high-power femtosecond laser pulse off a curved relativistic mirror. This enhances the intensity of the reflected beam by simultaneously compressing it in time down to the attosecond range, and focusing it to submicrometre focal spots. Here we show that such curved relativistic mirrors can be produced when an ultra-intense laser pulse ionizes a solid target and creates a dense plasma that specularly reflects the incident light. This is evidenced by measuring the temporal and spatial effects induced on the reflected beam by this so-called plasma mirror. The all-optical measurement technique demonstrated here will be instrumental for the use of relativistic plasma mirrors with the upcoming generation of petawatt lasers that recently reached intensities of 5 × 1022 W cm−2, and therefore constitutes a viable experimental path to the Schwinger limit

Sub-laser-cycle control of relativistic plasma mirrors

We present measurements of high-order harmonics and relativistic electrons emitted into the vacuum from a plasma mirror driven by temporally-shaped ultra-intense laser waveforms, produced by collinearly combining the main laser field with its second harmonic. We experimentally show how these observables are influenced by the phase delay between these two frequencies at the attosecond timescale, and relate these observations to the underlying physics through an advanced analysis of 1D/2D Particle-In-Cell simulations. These results demonstrate that sub-cycle shaping of the driving laser field provides fine control on the properties of the relativistic electron bunches responsible for harmonic and particle emission from plasma mirrors

Liquid properties in the Fe-FeS system under moderate pressure: Tool box to model small planetary cores

International audienc

Human Mesenchymal Stem Cell Failure to Adapt to Glucose Shortage and Rapidly Use Intracellular Energy Reserves Through Glycolysis Explains Poor Cell Survival After Implantation

International audienc

Understanding and leveraging cell metabolism to enhance mesenchymal stem cell transplantation survival in tissue engineering and regenerative medicine applications

International audienceIn tissue engineering and regenerative medicine, stem cell-specifically, mesenchymal stromal/stem cells (MSCs)-therapies have fallen short of their initial promise and hype. The observed marginal, to no benefit, success in several applications has been attributed primarily to poor cell survival and engraftment at transplantation sites. MSCs have a metabolism that is flexible enough to enable them to fulfill their various cellular functions and remarkably sensitive to different cellular and environmental cues. At the transplantation sites, MSCs experience hostile environments devoid or, at the very least, severely depleted of oxygen and nutrients. The impact of this particular setting on MSC metabolism ultimately affects their survival and function. In order to develop the next generation of cell-delivery materials and methods, scientists must have a better understanding of the metabolic switches MSCs experience upon transplantation. By designing treatment strategies with cell metabolism in mind, scientists may improve survival and the overall therapeutic potential of MSCs. Here, we provide a comprehensive review of plausible metabolic switches in response to implantation and of the various strategies currently used to leverage MSC metabolism to improve stem cell-based therapeutics. Significance statement: Lack of success of stem cell-based therapies has been largely attributed to the massive cell death observed post-transplantation, which is caused by the metabolic shock these cells experience as they transition from in vitro to a hostile, injured site in vivo. The metabolism in mesenchymal stem cells (MSCs), specifically, is highly sensitive to cellular and environmental cues. In order to improve cell survival rate posttransplantation, it is important that scientists understand, and take into account, the needs and demands of MSC metabolism as they design the next generation of MSC-based therapies

Thymus-derived regulatory T cells restrain pro-inflammatory Th1 responses by downregulating CD70 on dendritic cells

The severity and intensity of autoimmune disease in Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) patients and in scurfy mice emphasizes the critical role played by thymus-derived regulatory T cells (tTregs) in maintaining peripheral immune tolerance. However, although tTregs are critical to prevent lethal autoimmunity and excessive inflammatory responses, their suppressive mechanism remains elusive. Here we demonstrate that tTregs selectively inhibit CD27/CD70-dependent Th1 priming, while leaving the IL-12-dependent pathway unaffected. Immunized mice depleted of tTregs showed an increased response of IFN-γ-secreting CD4+ T cells that was strictly reliant on a functional CD27/CD70 pathway. In vitro studies revealed that tTregs downregulate CD70 from the plasma membrane of dendritic cells (DCs) in a CD27-dependent manner. CD70 downregulation required contact between Tregs and DCs and resulted in endocytosis of CD27 and CD70 into the DC. These findings reveal a novel mechanism by which tTregs can maintain tolerance or prevent excessive, proinflammatory Th1 responsesin pressSCOPUS: ar.jFLWINinfo:eu-repo/semantics/publishe

Enzyme-controlled, nutritive hydrogel for mesenchymal stromal cell survival and paracrine functions

International audienceAbstract Culture-adapted human mesenchymal stromal cells (hMSCs) are appealing candidates for regenerative medicine applications. However, these cells implanted in lesions as single cells or tissue constructs encounter an ischemic microenvironment responsible for their massive death post-transplantation, a major roadblock to successful clinical therapies. We hereby propose a paradigm shift for enhancing hMSC survival by designing, developing, and testing an enzyme-controlled, nutritive hydrogel with an inbuilt glucose delivery system for the first time. This hydrogel, composed of fibrin, starch (a polymer of glucose), and amyloglucosidase (AMG, an enzyme that hydrolyze glucose from starch), provides physiological glucose levels to fuel hMSCs via glycolysis. hMSCs loaded in these hydrogels and exposed to near anoxia (0.1% pO 2 ) in vitro exhibited improved cell viability and angioinductive functions for up to 14 days. Most importantly, these nutritive hydrogels promoted hMSC viability and paracrine functions when implanted ectopically. Our findings suggest that local glucose delivery via the proposed nutritive hydrogel can be an efficient approach to improve hMSC-based therapeutic efficacy

Dynamic X-ray diffraction observation of shocked solid iron up to 170 GPa

International audienceInvestigation of the iron phase diagram under high pressure and temperature is crucial for the determination of the composition of the cores of rocky planets and for better understanding the generation of planetary magnetic fields. Here we present X-ray diffraction results from laser-driven shock-compressed single-crystal and polycrystalline iron, indicating the presence of solid hexagonal close-packed iron up to pressure of at least 170 GPa along the principal Hugoniot, corresponding to a temperature of 4,150 K. This is confirmed by the agreement between the pressure obtained from the measurement of the iron volume in the sample and the inferred shock strength from velocimetry deductions. Results presented in this study are of the first importance regarding pure Fe phase diagram probed under dynamic compression and can be applied to study conditions that are relevant to Earth and super-Earth cores