CD9+ Regulatory B Cells Induce T Cell Apoptosis via IL-10 and Are Reduced in Severe Asthmatic Patients

CD9 was recently identified as a marker of murine IL-10-competent regulatory B cells. Functional impairments or defects in CD9+ IL-10-secreting regulatory B cells are associated with enhanced asthma-like inflammation and airway hyperresponsiveness. In mouse models, all asthma-related features can be abrogated by CD9+ B cell adoptive transfer. We aimed herein to decipher the profiles, features, and molecular mechanisms of the regulatory properties of CD9+ B cells in human and mouse. The profile of CD9+ B cells was analyzed using blood from severe asthmatic patients and normal and asthmatic mice by flow cytometry. The regulatory effects of mouse CD9+ B cells on effector T cell death, cell cycle arrest, apoptosis, and mitochondrial depolarization were determined using yellow dye, propidium iodide, Annexin V, and JC-1 staining. MAPK phosphorylation was analyzed by western blotting. Patients with severe asthma and asthmatic mice both harbored less CD19+CD9+ B cells, although these cells displayed no defect in their capacity to induce T cell apoptosis. Molecular mechanisms of regulation of CD9+ B cells characterized in mouse showed that they induced effector T cell cycle arrest in sub G0/G1, leading to apoptosis in an IL-10-dependent manner. This process occurred through MAPK phosphorylation and activation of both the intrinsic and extrinsic pathways. This study characterizes the molecular mechanisms underlying the regulation of CD9+ B cells to induce effector T cell apoptosis in mice and humans via IL-10 secretion. Defects in CD9+ B cells in blood from patients with severe asthma reveal new insights into the lack of regulation of inflammation in these patients

C5aR2 Regulates STING-Mediated Interferon Beta Production in Human Macrophages

The complement system mediates diverse regulatory immunological functions. C5aR2, an enigmatic receptor for anaphylatoxin C5a, has been shown to modulate PRR-dependent pro-inflammatory cytokine secretion in human macrophages. However, the specific downstream targets and underlying molecular mechanisms are less clear. In this study, CRISPR-Cas9 was used to generate macrophage models lacking C5aR2, which were used to probe the role of C5aR2 in the context of PRR stimulation. cGAS and STING-induced IFN-β secretion was significantly increased in C5aR2 KO THP-1 cells and C5aR2-edited primary human monocyte-derived macrophages, and STING and IRF3 expression were increased, albeit not significantly, in C5aR2 KO cell lines implicating C5aR2 as a regulator of the IFN-β response to cGAS-STING pathway activation. Transcriptomic analysis by RNAseq revealed that nucleic acid sensing and antiviral signalling pathways were significantly up-regulated in C5aR2 KO THP-1 cells. Altogether, these data suggest a link between C5aR2 and nucleic acid sensing in human macrophages. With further characterisation, this relationship may yield therapeutic options in interferon-related pathologies

C5aR2 regulates STING-mediated interferon beta production in human macrophages

The complement system mediates diverse regulatory immunological functions. C5aR2, an enigmatic receptor for anaphylatoxin C5a, has been shown to modulate PRR-dependent pro-inflammatory cytokine secretion in human macrophages. However, the specific downstream targets and underlying molecular mechanisms are less clear. In this study, CRISPR-Cas9 was used to generate macrophage models lacking C5aR2, which were used to probe the role of C5aR2 in the context of PRR stimulation. cGAS and STING-induced IFN-β secretion was significantly increased in C5aR2 KO THP-1 cells and C5aR2-edited primary human monocyte-derived macrophages, and STING and IRF3 expression were increased, albeit not significantly, in C5aR2 KO cell lines implicating C5aR2 as a regulator of the IFN-β response to cGAS-STING pathway activation. Transcriptomic analysis by RNAseq revealed that nucleic acid sensing and antiviral signalling pathways were significantly up-regulated in C5aR2 KO THP-1 cells. Altogether, these data suggest a link between C5aR2 and nucleic acid sensing in human macrophages. With further characterisation, this relationship may yield therapeutic options in interferon-related pathologies

The neutron and its role in cosmology and particle physics

Experiments with cold and ultracold neutrons have reached a level of precision such that problems far beyond the scale of the present Standard Model of particle physics become accessible to experimental investigation. Due to the close links between particle physics and cosmology, these studies also permit a deep look into the very first instances of our universe. First addressed in this article, both in theory and experiment, is the problem of baryogenesis ... The question how baryogenesis could have happened is open to experimental tests, and it turns out that this problem can be curbed by the very stringent limits on an electric dipole moment of the neutron, a quantity that also has deep implications for particle physics. Then we discuss the recent spectacular observation of neutron quantization in the earth's gravitational field and of resonance transitions between such gravitational energy states. These measurements, together with new evaluations of neutron scattering data, set new constraints on deviations from Newton's gravitational law at the picometer scale. Such deviations are predicted in modern theories with extra-dimensions that propose unification of the Planck scale with the scale of the Standard Model ... Another main topic is the weak-interaction parameters in various fields of physics and astrophysics that must all be derived from measured neutron decay data. Up to now, about 10 different neutron decay observables have been measured, much more than needed in the electroweak Standard Model. This allows various precise tests for new physics beyond the Standard Model, competing with or surpassing similar tests at high-energy. The review ends with a discussion of neutron and nuclear data required in the synthesis of the elements during the "first three minutes" and later on in stellar nucleosynthesis.Comment: 91 pages, 30 figures, accepted by Reviews of Modern Physic

Study of lymphocyte regulation in lung and kidney transplantation

La transplantation s’accompagne aujourd’hui systematiquement de traitements immunosuppresseurs qui inhibent la reponse alloimmune dirigee contre le greffon afin d’eviter son rejet. Cependant, ces traitements lourds ont de nombreux effets deleteres et ne permettent pas de controler efficacement la survenue du rejet chronique a long terme. L’objectif de ce travail de these, base sur deux situations cliniques distinctes, s’inscrit dans deux axes prioritaires de la recherche en transplantation : (1) identifier des marqueurs predictifs de la perte de fonction des greffons pulmonaires et (2) decrypter les mecanismes de l’acceptation des greffons renaux dans une situation de tolerance operationnelle. Tout d’abord, nous avons etudie les mecanismes de l’acceptation du greffon, chez des patients transplantes renaux presentant un greffon fonctionnel en l’absence de traitement immunosuppresseur. Nous avons identifie chez ces patients une proportion plus importante de lymphocytes T regulateurs memoires circulants, ayant la capacite de degrader l’ATP extracellulaire et favoriser un etat protolerogenique. Ce mecanisme, defaillant chez les patients stables sous traitement, pourrait participer au maintien d’un greffon renal fonctionnel chez les patients tolerants non traites. Dans un second temps, nous nous sommes interesses, chez des patients transplantes pulmonaire, a la prediction de la survenue du rejet chronique. Nous avons mis en evidence un profil lymphocytaire T regulateur modifie chez les patients qui developperont un rejet chronique a long-terme. Le suivi de ce biomarqueur pourrait permettre une meilleure identification des patients a risque de rejet.Transplantation is nowadays systematically associated with the administration of immunosuppressive treatments inhibiting the allo-immune response toward the graft to prevent the rejection by the recipient's immune system. However, these heavy treatments have several deleterious effects and are not able to control longterm chronic rejection development. Thus, the objective of this PhD work, based on two distinct clinical situations, is part of two priority axes of transplant research: (1) identify early predictive markers of long-term lung allograft dysfunction and (2) decipher the mechanisms involved in the acceptance of kidney allograft in operational tolerance. We first investigated the mechanisms of graft acceptance in kidney transplanted patients with a functional graft in the absence of immunosuppressive therapy. We identified in these patients a greater proportion of circulating memory regulatory T lymphocytes, with an increased ability to degrade extracellular ATP, a pro-inflammatory mediator, and favour a protolerogenic environment. Thus, this mechanism, not efficient in stable patients under treatments, could participate in the inhibition of the allo-immune response leading to maintaining a functional kidney graft in the absence of immunosuppression. In a second time, we interested in the prediction of chronic rejection occurrence in lung transplanted patients. We report that the early posttransplant regulatory T lymphocyte profile is modified in patients who will develop chronic rejection in the 3 years. Thus, monitoring this predictive biomarker could allow a better identification of patients at risk of rejection

Wireline Tractor System with User Programmable Behaviors for Semi-Autonomous Restriction Navigation

Abstract A semi-autonomous wireline tractor solution for casedhole applications enabling navigation through complex restrictions with minimal operator interaction in absence of digital telemetry is presented. The robotic conveyance technology provides a foundation for applications where programming of tractoring behaviors is available to field personnel as a part of the job design. Digital telemetry may not be available for wireline tractor tools. A conveyance system with programmable behaviors allows downhole navigation when conventional telemetry is nonexistent or has prohibitively low bandwidth or a protocol conflict, which is relevant in configurations with third-party tools. The presented control technology utilizes downhole on-board measurements with tracking and decoding of head voltage waveforms where electrical power is supplied by the surface system. Voltage is set by an operator to fall into one of several predefined bands representing specific tool commands that trigger a set of robotic sequences. The logging cable can be freed to carry a high-frequency communication signal to payload tools while powering both the tractor and its payload. Although the tractor does not have feedback through its telemetry data, tractor operational condition can be derived from the variations of electrical current measured at surface. A head voltage stabilization system along with a load calibration method compensates voltage fluctuations due to load changes and losses in the logging cable. An advanced signal-processing algorithm implemented in downhole embedded software quantizes denoised voltage and reliably maps it to operational bands, effectively eliminating transient processes resulting from high-power jobs. The voltage estimation technique supports a finite set of commands to be interpreted by the downhole tools and to activate control logic implemented as scripted state machines with a core based on the deterministic finite automaton concept. Behaviors scripted and parametrized by an operator in custom metalanguage use a dictionary of actions and conditions provided by the embedded software that runs the tools. Controllers may be designed and put into action by nonprogrammers to solve restriction navigation needs for a known well completion. The availability of design and simulation software aids job planning. Multiple tractor configurations with individually controlled arms were successfully tested at locations in the USA and Eurasia, with and without third-party tools with their own telemetry. Reliable restriction navigation using preprogrammed behaviors controlled by voltage levels has been demonstrated. The design opens development opportunities for other semi-autonomous downhole applications. Run-time pattern recognition of electrical current in the software enables further automation of the surface power system to drive the downhole navigation, detect and respond to anomalies, and reliably manipulate voltage transitions. The presented technology removes the compatibility barrier between different telemetry systems and elevates flexibility of systems lacking telemetry while preserving their usability and robustness.</jats:p

CD9+ Regulatory B Cells Induce T Cell Apoptosis via IL-10 and Are Reduced in Severe Asthmatic Patients

International audienceCD9 was recently identified as a marker of murine IL-10-competent regulatory B cells. Functional impairments or defects in CD9 + IL-10-secreting regulatory B cells are associated with enhanced asthma-like inflammation and airway hyperresponsiveness. In mouse models, all asthma-related features can be abrogated by CD9 + B cell adoptive transfer. We aimed herein to decipher the profiles, features, and molecular mechanisms of the regulatory properties of CD9 + B cells in human and mouse. The profile of CD9 + B cells was analyzed using blood from severe asthmatic patients and normal and asthmatic mice by flow cytometry. The regulatory effects of mouse CD9 + B cells on effector T cell death, cell cycle arrest, apoptosis, and mitochondrial depolarization were determined using yellow dye, propidium iodide, Annexin V, and JC-1 staining. MAPK phosphorylation was analyzed by western blotting. Patients with severe asthma and asthmatic mice both harbored less CD19 + CD9 + B cells, although these cells displayed no defect in their capacity to induce T cell apoptosis. Molecular mechanisms of regulation of CD9 + B cells characterized in mouse showed that they induced effector T cell cycle arrest in sub G0/G1, leading to apoptosis in an IL-10-dependent manner. This process occurred through MAPK phosphorylation and activation of both the intrinsic and extrinsic pathways. This study characterizes the molecular mechanisms underlying the regulation of CD9 + B cells to induce effector T cell apoptosis in mice and humans via IL-10 secretion. Defects in CD9 + B cells in blood from patients with severe asthma reveal new insights into the lack of regulation of inflammation in these patients

High circulating CD4+CD25[hi]FOXP3+ T cell subpopulation early after lung transplantation is associated with development of BOS

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Increased degradation of ATP is driven by memory~regulatory T cells in kidney transplantation tolerance

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