Dominant Role of CD80–CD86 Over CD40 and ICOSL in the Massive Polyclonal B Cell Activation Mediated by LATY136F CD4+ T Cells

Coordinated interactions between T and B cells are crucial for inducing physiological B cell responses. Mutant mice in which tyrosine 136 of linker for activation of T cell (LAT) is replaced by a phenylalanine (LatY136F) exhibit a strong CD4+ T cell proliferation in the absence of intended immunization. The resulting effector T cells produce high amounts of TH2 cytokines and are extremely efficient at inducing polyclonal B cell activation. As a consequence, these LatY136F mutant mice showed massive germinal center formations and hypergammaglobulinemia. Here, we analyzed the involvement of different costimulators and their ligands in such T–B interactions both in vitro and in vivo, using blocking antibodies, knockout mice, and adoptive transfer experiments. Surprisingly, we showed in vitro that although B cell activation required contact with T cells, CD40, and inducible T cell costimulator molecule-ligand (ICOSL) signaling were not necessary for this process. These observations were further confirmed in vivo, where none of these molecules were required for the unfolding of the LAT CD4+ T cell expansion and the subsequent polyclonal B cell activation, although, the absence of CD40 led to a reduction of the follicular B cell response. These results indicate that the crucial functions played by CD40 and ICOSL in germinal center formation and isotype switching in physiological humoral responses are partly overcome in LatY136F mice. By comparison, the absence of CD80–CD86 was found to almost completely block the in vitro B cell activation mediated by LatY136F CD4+ T cells. The role of CD80–CD86 in T–B cooperation in vivo remained elusive due to the upstream implication of these costimulatory molecules in the expansion of LatY136F CD4+ T cells. Together, our data suggest that CD80 and CD86 costimulators play a key role in the polyclonal B cell activation mediated by LatY136F CD4+ T cells even though additional costimulatory molecules or cytokines are likely to be required in this process

Parallélisation d'un simulateur d'agents situés

Colloque avec actes et comité de lecture. nationale.National audienceNous avons réalisé un simulateur d'un ensemble de robots, où chaque robot est représenté par un agent, se déplaçant dans un environnement réel, constitué des couloirs du Loria. Ce simulateur repose sur un modèle stochastique d'interaction entre l'agent et son environnement que nous avons proposé. La modélisation de ces phénomènes peut entraîner une complexité importante du modèle et un grand besoin en capacité de calcul pour la simulation. Ceci nous a amené à une implantation parallèle du simulateur, après une étude des problèmes posés, tout en profitant du parallélisme intrinsèque des SMA

An R-based reproducible and user-friendly preprocessing pipeline for CyTOF data

Mass cytometry (CyTOF) has become a method of choice for in-depth characterization of tissue heterogeneity in health and disease, and is currently implemented in multiple clinical trials, where higher quality standards must be met. Currently, preprocessing of raw files is commonly performed in independent standalone tools, which makes it difficult to reproduce. Here, we present an R pipeline based on an updated version of CATALYST that covers all preprocessing steps required for downstream mass cytometry analysis in a fully reproducible way. This new version of CATALYST is based on Bioconductor’s SingleCellExperiment class and fully unit tested. The R-based pipeline includes file concatenation, bead-based normalization, single-cell deconvolution, spillover compensation and live cell gating after debris and doublet removal. Importantly, this pipeline also includes different quality checks to assess machine sensitivity and staining performance while allowing also for batch correction. This pipeline is based on open source R packages and can be easily be adapted to different study designs. It therefore has the potential to significantly facilitate the work of CyTOF users while increasing the quality and reproducibility of data generated with this technology

Monoslope and Multislope MUSCL Methods for unstructured meshes

International audienceWe present new MUSCL techniques associated with cell-centered Finite Volume method on triangular meshes. The first reconstruction consists in calculating a one vectorial slope per control volume by a minimization procedure with respect to a prescribed stability condition. The second technique we propose is based on the computation of three scalar slopes per triangle (one per edges) still respecting some stability condition. The resulting algorithm provides a very simple scheme which is extensible to higher dimensional problems. Numerical approximations have been performed to obtain the convergence order for the advection scalar problem whereas we treat a nonlinear vectorial example, namely the Euler system, to show the capacity of the new MUSCL technique to deal with more complexe situations

TACI, unlike BAFF-R, is solely activated by oligomeric BAFF and APRIL to support survival of activated B cells and plasmablasts.

The cytokine BAFF binds to the receptors TACI, BCMA, and BAFF-R on B cells, whereas APRIL binds to TACI and BCMA only. The signaling properties of soluble trimeric BAFF (BAFF 3-mer) were compared with those of higher-order BAFF oligomers. All forms of BAFF bound BAFF-R and TACI, and elicited BAFF-R-dependent signals in primary B cells. In contrast, signaling through TACI in mature B cells or plasmablasts was only achieved by higher-order BAFF and APRIL oligomers, all of which were also po-tent activators of a multimerization-dependent reporter signaling pathway. These results indicate that, although BAFF-R and TACI can provide B cells with similar signals, only BAFF-R, but not TACI, can respond to soluble BAFF 3-mer, which is the main form of BAFF found in circulation. BAFF 60-mer, an efficient TACI agonist, was also detected in plasma of BAFF transgenic and nontransgenic mice and was more than 100-fold more active than BAFF 3-mer for the activation of multimerization-dependent signals. TACI supported survival of activated B cells and plasmablasts in vitro, providing a rational basis to explain the immunoglobulin deficiency reported in TACI-deficient persons

Single-cell proteomics defines the cellular heterogeneity of localized prostate cancer

Localized prostate cancer exhibits multiple genomic alterations and heterogeneity at the proteomic level. Single-cell technologies capture important cell-to-cell variability responsible for heterogeneity in biomarker expression that may be overlooked when molecular alterations are based on bulk tissue samples. This study aims to identify prognostic biomarkers and describe the heterogeneity of prostate cancer and the associated microenvironment by simultaneously quantifying 36 proteins using single-cell mass cytometry analysis of over 1.6 million cells from 58 men with localized prostate cancer. We perform this task, using a high-dimensional clustering pipeline named Franken to describe subpopulations of immune, stromal, and prostate cells, including changes occurring in tumor tissues and high-grade disease that provide insights into the coordinated progression of prostate cancer. Our results further indicate that men with localized disease already harbor rare subpopulations that typically occur in castration-resistant and metastatic disease

An Immune Atlas of Clear Cell Renal Cell Carcinoma

Immune cells in the tumor microenvironment modulate cancer progression and are attractive therapeutic targets. Macrophages and T cells are key components of the microenvironment, yet their phenotypes and relationships in this ecosystem and to clinical outcomes are ill defined. We used mass cytometry with extensive antibody panels to perform in-depth immune profiling of samples from 73 clear cell renal cell carcinoma (ccRCC) patients and five healthy controls. In 3.5 million measured cells, we identified 17 tumor-associated macrophage phenotypes, 22 T cell phenotypes, and a distinct immune composition correlated with progression-free survival, thereby presenting an in-depth human atlas of the immune tumor microenvironment in this disease. This study revealed potential biomarkers and targets for immunotherapy development and validated tools that can be used for immune profiling of other tumor types.ISSN:0092-8674ISSN:1097-417

Les jeunes et le cyclomoteur

Die jugendlichen und das moped steuerungspraxis Das Moped nimmt einen grossen Platz im «Herzen» und im Leben der jungen Fahrer ein. Die Praxis und die Benutzung dieses technischen Gegenstandes haben jedoch die Aufmerksamkeit der Forscher im Bereich der Human-und Sozialwissenschaften kaum auf sich V. O. gelenkt. Dieser Artikel versucht diese Lücke auszufüllen und richtet dabei seine Aufmerksamkeit auf die Steuerung eines Mopeds. Welche Beziehung unterhält der junge Fahrer mit seinem eigenen Körper, seiner Maschine, der Strasse und seinem Umfeld, wenn er Moped fährt ? Durch die Analyse dieser angewandten Praxis, davon gehen wir aus, kann man die risikoreichen «Verhaltensweisen» besser verstehen und die normative Sprache abbrechen.Young people and the moped : pragmatics of driving The moped occupies an important place in the heart and existence of young users. However, the practice and use of this technical object have not caught much attention from the social and human sciences researchers. This paper aims to fill the gap and focuses on the action of driving or «piloting» a moped. Which kind of relationship does the young user have with his body, the vehicle, the road and his environment when he is riding his moped ? The analysis of this located and equipped practice allows us, according to our hypothesis, to have a better understanding of the at risk «driving» and to break with a normative discourseQuelle relation le jeune utilisateur entretient-il avec son propre corps, sa machine, la route et son environnement lorsqu’il conduit son cyclomoteur ? L’analyse de cette pratique située et appareillée nous permet, de mieux comprendre les «conduites» à risque et de rompre avec un discours normatif.Los jóvenes y el ciclomotor, pragmática del pilotaje El ciclomotor ocupa un lugar importante en el •corazón” y la existencia de los jóvenes utilizadores. Sin embargo la práctica y el uso de este objeto técnico apenas han llamado la atención de los investigadores en Ciencias Humanas y Sociales. Este documento intenta colmar esta laguna enfocando su atención en el acto de conducir o •pilotar” un ciclomotor. ¿ Qué relación mantiene el joven utilizador con su propio cuerpo, su máquina y su entorno, cuando conduce su ciclomotor ? El análisis de esta práctica enmarcada y contrastada nos permite, o así lo suponemos, comprender mejor las •conductas” de riesgo y romper con un discurso normativo.Chevrier Stéphane. Les jeunes et le cyclomoteur. In: Agora débats/jeunesses, 27, 2002. Les jeunes et le risque. pp. 86-97

Événements et sécurité

La ville se reconfigure lors des grands événements (festival, manifestation, match de foot, etc.), les foules sont contenues par le cadre bâti urbain et s’en emparent, les publics vibrent au rythme des attracteurs proposés par les organisateurs ou créés par eux-mêmes. Un climat s’installe, qui doit toujours être unique pour faire événement, qui attire ou qui repousse, qui se prépare, qui va crescendo mais qui doit aussi savoir progressivement descendre pour revenir au calme puis laisser des traces dans les mémoires et dans les médias. Les spécialistes de la sécurité urbaine et du maintien de l’ordre, qu’ils soient publics ou privés, ont appris à anticiper sur ces états toujours instables, à pré-positionner des forces et des moyens opérationnels, mais aussi à réviser leurs plans car des incidents viennent toujours ponctuer ces grands événements urbains. Trois événements (un match de foot, un festival de musique, une manifestation syndicale) ont été suivis grâce à des méthodes d’observation originales et minutieuses permettant de restituer tous les points de vue, sans jamais les totaliser mais en montrant leurs articulations. L’ouvrage permet ainsi de restituer « l’art du bon moment » (le kairos) qui fait l’expertise de ces professionnels du climat urbain et de leurs équipements