Transforming Growth Factor β1 Inhibits Fas Ligand Expression and Subsequent Activation-induced Cell Death in T Cells via Downregulation of c-Myc

Activation-induced cell death (AICD) is a process that regulates the size and the duration of the primary immune T cell response. In this report, we investigated the mechanisms involved in the regulation of AICD by transforming growth factor β1 (TGF-β1). We found that TGF-β1 decreased apoptosis of human T cells or T cell hybridomas after activation by anti-CD3. This decrease was associated with inhibition of Fas (Apo-1/CD95) ligand (FasL) expression, whereas Fas signaling was not affected by TGF-β1. In parallel, TGF-β1 inhibited c-Myc expression in T cell hybridomas, and ectopic expression of a chimeric molecule composed of c-Myc and the steroid binding domain of the estrogen receptor (Myc-ER) blocked both the inhibition of FasL and the decrease of AICD induced by TGF-β1, providing that 4-hydroxytamoxifen was present. These results identify one mechanism by which TGF-β1 blocks AICD to allow the clonal expansion of effector T cells and the generation of memory T cells during immune responses

Compromising the Unfolded Protein Response Induces Autophagy-Mediated Cell Death in Multiple Myeloma Cells

OBJECTIVE: To determine whether the Unfolded Protein Response (UPR) sensors (PERK, ATF6 and IRE-1) can be targeted to promote death of Multiple Myeloma (MM) cells. METHODS: We have knocked-down separately each UPR stress sensor in human MM cell lines using RNA interference and followed MM cell death by monitoring the membrane, mitochondrial and nuclear alterations. Involvement of caspases in MM cell death consecutive to UPR sensor knock-down was analyzed by western blotting, measurement of their enzymatic activity using fluorigenic substrates and susceptibility to a pan-caspase inhibitor. Activation of the autophagic process was measured directly by detection of autophagosomes (electronic microscopy), monodansylcadaverine staining, production of the cleaved form of the microtubule-associated protein 1A/1B light chain 3 (LC3) and indirectly by analyzing the impact of pharmacological inhibitors of autophagy such as 3MA and bafilomycin A1. RESULTS: We show that extinction of a single UPR stress sensor (PERK) induces a non-apoptotic form of cell death in MM cells that requires autophagy for its execution. We also show that this cytotoxic autophagic process represses the apoptosis program by reducing the cytosolic release of the apoptogenic factors Smac/DIABLO and cytochrome c. INTERPRETATION: Altogether our findings suggest that autophagy can contribute to execution of death in mammalian cells that are exposed to mild ER stress. They also suggest that the autophagic process can regulate the intrinsic apoptotic pathway by inhibiting production of death effectors by the mitochondria, thus preventing formation of a functional apoptosome. Altogether these findings give credit to the idea that UPR sensors can be envisaged as therapeutic targets for the treatment of MM

L'isomorphisme entre les tours de Lubin-Tate et de Drinfeld

Ce livre contient une démonstration détaillée et complète de l'existence d'un isomorphisme équivariant entre les tours p-adiques de Lubin-Tate et de Drinfeld. Le résultat est établi en égales et inégales caractéristiques. Il y est également donné comme application une démonstration du fait que les cohomologies équivariantes de ces deux tours sont isomorphes, un résultat qui a des applications à l'étude de la correspondance de Langlands locale. Au cours de la preuve des rappels et des compléments sont donnés sur la structure des deux espaces de modules précédents, les groupes formels p-divisib

Bridging the gap between the evolutionary dynamics and the molecular mechanisms of meiosis : a model based exploration of the PRDM9 intra-genomic Red Queen

Molecular dissection of meiotic recombination in mammals, combined with population-genetic and comparative studies, have revealed a complex evolutionary dynamics characterized by short-lived recombination hotspots, whose exact location is determined by the DNA-binding protein PRDM9. To explain these fast evolutionary dynamics, a so-called intra-genomic Red Queen model has been proposed, based on the interplay between two antagonistic forces: biased gene conversion, mediated by double-strand breaks, resulting in hotspot extinction (the hotspot conversion paradox), followed by positive selection favoring mutant PRDM9 alleles recognizing new sequence motifs. Although this model predicts many empirical observations, the exact causes of the positive selection acting on new PRDM9 alleles is still not well understood. In this direction, experiment on mouse hybrids have suggested that, in addition to targeting double strand breaks, PRDM9 has another role during meiosis. Specifically, PRDM9 symmetric binding (simultaneous binding at the same site on both homologues) would facilitate homology search and, as a result, the pairing of the homologues. Although discovered in hybrids, this second function of PRDM9 could also be involved in the evolutionary dynamics observed within populations. To address this point, here, we present a theoretical model of the evolutionary dynamics of meiotic recombination integrating current knowledge about the molecular function of PRDM9. Our modeling work gives important insights into the selective forces driving the turnover of recombination hotspots. Specifically, the reduced symmetrical binding of PRDM9 caused by the loss of high affinity binding sites induces a net positive selection eliciting new PRDM9 alleles recognizing new targets. The model also offers new insights about the influence of the gene dosage of PRDM9, which can paradoxically result in negative selection on new PRDM9 alleles entering the population, driving their eviction and thus reducing standing variation at this locus

La nature du sol et la composition floristique comme facteurs de modulation de la diversité et de la fonctionnalité des communautés microbiennes en prairie permanente

National audienceLa composition floristique, le mode d’exploitation (fauche, pâturage), l’intensité d’exploitation (chargement, fréquence des coupes, fertilisation) et la pérennité de la couverture végétale sont connus comme étant des facteurs déterminants du fonctionnement des prairies permanentes (Gaujour et al. 2012). Ces pratiques de gestion peuvent modifier les stocks de C directement en modulant les entrées de matières organiques (MO) (litière et/ou effluents d’élevage) et indirectement en orientant la composition et le fonctionnement des communautés végétales ce qui pourrait agir sur le temps de résidence et la localisation de la MO (Hassink et Neeteson 1991). Ce projet a pour objectif de caractériser les pools de C organique du sol et les communautés bactériennes sous des prairies permanentes différant selon leur composition floristique et la nature de l’antécédent en termes de couverture de sol (3 habitats : culture, forêt, prairie). L’hypothèse de ce travail est que ces facteurs en modifiant la nature des pools de C du sol (labile vs récalcitrant) ont sélectionné des communautés bactériennes différentes tant du point de vue de la diversité génétique que de leurs traits fonctionnels en lien avec la minéralisation des MO. Pour valider cette hypothèse, des échantillons de sol ont été prélevés en mai 2017 sur 12 parcelles de prairies (4 parcelles par habitat) sur lesquelles des relevés de composition floristique ont été effectués. Les résultats montrent que la composition floristique des 12 parcelles de prairies permanentes échantillonnées se différencie selon la nature de l’antécédent. Des différences de pH et de teneurs en C entre les sols de 3 types de prairies étudiées. Les activités enzymatiques (en lien avec les cycles biogéochimiques) mettent en évidence des différences selon l’antécédent de couverture du sol suggérant des fonctionnalités différentielles liées d’une part au temps de résidence des pools de C et d’autre part à des différences de diversité des communautés microbiennes du sol