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Charbonnier, S.

Publications and source records attributed to Charbonnier, S..

5 recordsLinked to original sources

Stealth CAR-Tregs evade CD3 antibody therapy and skew immune responses toward regulation

Organ transplantation standard of care relies on lifelong immunosuppression, increasing infection and malignancy risks. An emerging approach using Chimeric Antigen Receptor Regulatory T cells (CAR-Tregs) targeting donor antigens, allows the suppression of alloimmune responses while preserving protective immunity. However, transplant recipients harbor a substantial pool of alloreactive memory T-cells, limiting CAR-Tregs tolerance-promoting effect. To address this challenge, our strategy combines selective depletion of activated T-cells, using non-mitogenic CD3 antibody therapy, with HLA-A2-targeted-CAR-Treg therapy. We established that T-cell receptor alpha chain (TRAC) deletion does not impair CAR-Treg antigen-specific activation, expansion, or their transcriptomic, phenotypic, epigenetic, and functional profiles. TRAC-/-CAR-Tregs exhibit robust protection from CD3 antibody depletion in circulation and peripheral tissues, whereas most TRAC+/+CAR-T cells are eliminated. Importantly, TRAC+/+CAR-T cells that escape CD3 antibody mediated depletion exhibit a transcriptomic signature consistent with T-cell exhaustion. Our findings demonstrate that CD3 antibody therapy provides an in vivo survival advantage to TRAC-/-CAR-Tregs, thereby shifting the immune balance toward regulation. This approach might enhance the translational potential of CAR-Treg therapy by reducing the required cell dose needed for clinical efficacy.

immunology↗

Reassessment of body temperature and thermoregulation strategies in Mesozoic marine reptiles

Ichthyosauria, Plesiosauria and Metriorhynchidae were apex predators in Mesozoic oceanic trophic networks. Previous stable oxygen isotope studies suggested that several taxa belonging to these groups were endothermic and for some of them homeothermic organisms. However, these conclusions remain contentious owing to the associated uncertainties regarding the {delta}18O value and oxygen isotope fractionation relative to environmental sea water. Here, we present new hydroxylapatite phosphate {delta}18O values ({delta}18Op) of Ichthyosauria, Plesiosauria and Metriorhynchidae (Middle Jurassic to Early Cretaceous) recovered from mid- to high-paleolatitudes to better constrain their thermophysiology and investigate the presence of regional heterothermies. The intra-skeletal {delta}18Op variability failed to reveal distinct heterothermic patterns within any of the specimens, indicating either intra-body temperature homogeneity or an overriding diagenetic overprint of the original biological {delta}18Op bone record. Body temperature estimates have then been reassessed from new and published {delta}18Op values of well-preserved isolated teeth, recently revised Mesozoic latitudinal {delta}18O oceanic gradient and 18O-enrichment factor of fully aquatic air-breathing vertebrates. Our results confirm that Ichthyosauria were homeothermic endotherms (31{degrees}C to 41{degrees}C), while Plesiosauria were likely poikilothermic endotherms (27{degrees}C to 34{degrees}C). The new body temperature estimates of the Metriorhynchidae (25{degrees}C to 32{degrees}C) closely follow ambient temperatures and point to poikilothermic strategy with no or little endothermic abilities. These results improve our understanding of Mesozoic marine reptile thermoregulation and indicate that due to their limited body temperature variations, the {delta}18Op values from Ichthyosauria fossil remains could be used as valuable archives of Mesozoic oceans {delta}18Osw values that may help improve palaeoenvironmental and palaeoclimatic reconstructions. Non-technical abstractSome marine reptiles from the Mesozoic such as ichthyosaurs, plesiosaurs and metriorhynchids, were capable of reaching elevated body temperatures and for some of them to maintain it few degrees above that of their marine environment, a characteristic similar to that observed in modern cetaceans. Nevertheless, the estimation of their body temperature from the chemical oxygen signature of their fossil remains (bones and teeth) is accompanied by uncertainties associated with the chemical oxygen signature of the surrounding water and the mineralisation processes of the bones and teeth. In this study, new data were collected from four ichthyosaurs, three plesiosaurs and one metriorhynchid in order to gain a deeper understanding of the mechanisms by which these marine reptiles were able to maintain a body temperature higher than that of their environment. The chemical signatures of oxygen in the bones and teeth of the specimens did not exhibit any discernible patterns indicative of specific zones of heat production or loss, as observed in modern marine vertebrates. Concurrently, we reassessed the estimated body temperature of these marine reptiles, thereby corroborating the hypothesis that ichthyosaurs were homeothermic endotherms. Conversely, our novel estimates suggest that plesiosaurs were likely poikilothermic endotherms, whereas metriorhynchids were probably also poikilothermic endotherms but with a limited capacity for heat production. Finally, the narrow range of body temperatures maintained by ichthyosaurs indicates that the oxygen chemical signature of fossilised remains could serve as a valuable marker for reconstructing variations in the oxygen isotope composition of the Mesozoic oceans, paving the way to enhance our understanding of the environment and climate of this period in Earths history.

paleontology↗

CD28 costimulatory domain protects against tonic signaling-induced functional impairment in CAR-Tregs

The use of chimeric antigen receptor (CAR)-engineered regulatory T cells (Tregs) has emerged as a promising strategy to promote immune tolerance in transplantation. However, in conventional T cells (Tconvs), CAR expression is often associated with tonic signaling resulting from ligand-independent baseline activation. Tonic signaling may cause CAR-T cell dysfunction, especially when the CAR structure incorporates the CD28 costimulatory domain (CSD) rather than the 4-1BB CSD. Here, we explored the impact of tonic signaling on human CAR-Tregs according to the type of CSD. Compared to CD28-CAR-Tregs, 4-1BB-CAR-Tregs showed enhanced proliferation and greater activation of MAP kinase and mTOR pathways but exhibited decreased lineage stability and reduced abilities to produce IL-10 and be restimulated through the CAR. Although both CAR-Treg populations were suppressive in vivo, cell tracking with bioluminescence imaging found longer persistence for CD28-CAR-Tregs than for 4-1BB-CAR-Tregs. This study demonstrates that CD28-CAR best preserves Treg function and survival in the context of tonic signaling, in contrast with previous findings for Tconvs. SUMMARYLamarthee et al investigated the impact of chimeric antigen receptor (CAR) tonic signaling on CAR-engineered Tregs according to the incorporated costimulatory domain (either CD28 or 4-1BB). CD28 ameliorated Treg stability, long-term survival and function compared to 4-1BB.

immunology↗

Exceptional Late Devonian arthropods document the origin of decapod crustaceans

With over 15,000 extant species, Decapoda--or ten-legged crustaceans such as crabs, shrimp, lobsters, and relatives-- are among the most speciose and economically important group of crustaceans. Despite of their diversity, anatomical disparity, and remarkable fossil record extending back to the Late Paleozoic, the origins of Decapoda and their phylogenetic relationships with eumalacostracans remains elusive and inconclusive. Molecular dating suggests that decapods originated in the Late Ordovician (~450 Mya), but no reliable fossil crown groups are found until the Late Devonian. Moreover, there is no consensus on which lineages belong to stem groups, obscuring our understanding of the roots of the ten-legged decapod body plans as a whole, and how they relate to other non-decapod crustaceans. We present new, exceptional fossils from the Late Devonian of Czech Republic and Poland that belong to {dagger}Angustidontida, an odd shrimp-looking crustacean with a combination of anatomical features unlike those of any crown eumalacostracan known--extinct or extant. Our phylogenetic analyses, including representatives of all major lineages of crown eumalacostracans plus {dagger}Angustidontida, identify angustidontids as the only known stem-group decapod, and give hints about the transformation series, polarity of change, and evolutionary pathways leading to the modern decapod body plans seen today.

paleontology↗

The oldest freshwater crabs: claws on dinosaur bones

With approximately 1,500 extant species, freshwater crabs (Decapoda: Brachyura) are among the most diverse decapod crustaceans. Nevertheless, their fossil record is extremely limited: only Potamidae, Potamonautidae and Trichodactylidae are reported up to the Eocene of the Neotropics so far. This work documents unusually large decapod claws from the Upper Cretaceous (Campanian) continental deposits of Velaux and vicinity (southern France), in close association with large vertebrate remains. In addition to (1) the systematic assignment of these claws, the study addresses (2) the salinity trends in the deposit environment from its faunal assemblage and the elementary chemical patterns of fossils, and (3) the likely scenario for their auto/allochtony in the Velaux fluvial system. These claws belong to a new taxon, Dinocarcinus velauciensis n. gen. n. sp., referred to as Portunoidea sensu lato, a group of “true” crabs nowadays linked to marine systems. However, the faunal assemblage, the claw taphonomy and the carbonates Y/Ho signatures support their ancient freshwater/terrestrial ecology, making them the oldest reported continental brachyurans and extending the presence of crabs in freshwater environments by 40 Ma. Either as primary or as secondary freshwater crabs, the occurrence of these portunoids in Velaux is an evidence for the independent colonizations of continental environments by multiple brachyuran clades over time, as early as the Campanian.View Full Text

paleontology↗