In order to evaluate the electron microprobe (EMP) method for chemical dating of monazite, we chemically analyzed selected suites of monazite grains that were previously dated by standard U/Pb isotopic methods at three laboratories each equipped with a sensitive high resolution ion microprobe (SHRIMP). Representing diverse igneous and metamorphic lithologies, these grains yielded conventional isotopic ages ranging in age from Neoarchean to Devonian. Chemical dating was performed at Virginia Tech using a Cameca SX-50 EMP in which the analytical routines and settings were specifically optimized for monazite geochronology, including correction of analytical peaks for all major spectral interferences and correction of peak intensities for local background emission. Placement of cross-grain analytical traverses was based on backscattered electron (BSE) images together with wavelength-dispersive (WD) generated X-ray maps for Y, Th, U, and Ca, which revealed the internal compositional complexity of each grain. Shorter EMP traverses were selected adjacent to each SHRIMP pit in order to provide the best possible comparison of ages obtained by the two dating methods. Synthesis protocol for key elemental measurements (Y, Th, U, and Pb) was developed utilizing the 1Ï elemental errors associated with individual analyses, providing an objective approach for data synthesis. Analytical dates were either accepted or excluded based on analytical and spatial justifications. Isotopic dating techniques utilize three independent age calculations, provided the sample is old enough to have accumulated sufficient 207Pb (i.e., ≥~1000 Ma). Similarly, the chemical dating method can utilize two independent age calculations (i.e., Th/Pb and U/Pb) and a U-Th-Pbtotal centroid age in Th/Pb vs. U/Pb space, verified independently against the calculated Th* or U* CHIME ages. Across the entire 2,200 m.y. age range represented by the sample set, the chemical ages calculated from the EMP data chemical ages are internally consistent (within 2Ï error) with the previously measured SHRIMP isotopic ages, except in one case where bulk mixing of discrete age domains within an ablation pit led to an isotopically discordant apparent age. Overall, this study illustrates that EMP chemical dating (1) represents both an accurate and precise primary method for dating monazite from igneous and polymetamorphic terrains; (2) provides superior spatial resolution for obtaining meaningful ages from small and/or irregular domains of discrete age that may be irresolvable or misinterpreted by other dating techniques that sample larger volumes; and (3) illuminates the geological meaning of isotopically discordant monazite ages obtained using conventional methods with lower spatial resolution (e.g., SHRIMP). / Ph. D.

Dans cette thèse, je reconstitue la dynamique de la circulation méridienne de retournement de l’Atlantique (AMOC) au cours des changements climatiques rapides de la dernière période glaciaire. Je trouve ainsi que le ralentissement de la cellule supérieure de l’AMOC commence 1420 ± 250 (1σ) années avant le déplacement vers le sud de l’ITCZ associé au « Heinrich Stadial » 2 et 690 ± 180 (1σ) années avant celui associé au « Heinrich Stadial » 4. Mes résultats confirment donc qu’un ralentissement de l’AMOC pourrait être à l’origine des migrations de l’ITCZ associées aux « Heinrich Stadials » et fournissent une première estimation précise du décalage temporel entre ces deux variables climatiques. Sur la base de ces résultats, je propose un mécanisme expliquant les différences entre les « Heinrich Stadials » et les « Dansgaard-Oeschger Stadials ».Je montre que deux cellules de circulation étaient probablement actives dans l’océan Atlantique pendant les périodes chaudes au Groenland (« interstadials ») : une cellule supérieure initiée par l’écoulement au-dessus de 2500 m d’une masse d’eau en provenance du nord et se dirigeant vers le sud, et une cellule inférieure initiée par l’écoulement au-dessous de 4000 m d’une masse d’eau en provenance du sud et se dirigeant vers le nord. Le taux de renouvellement de la masse d’eau profonde de la cellule supérieure était probablement plus faible que celle de la masse d’eau actuellement formée dans les hautes latitudes de l’océan Atlantique Nord. Au début des « Heinrich Stadials », la structure de l’AMOC a significativement changé et des eaux en provenance du sud ont probablement dominé l’océan Atlantique en-dessous de 1300 m de profondeur. / In this thesis, I reconstruct the dynamic of the Atlantic Meridional Overturning Circulation (AMOC) during fast climate changes of the last glacial period. I find that the AMOC upper circulation cell started to slowdown 1420 ± 250 (1σ) and 690 ± 180 (1σ) years before the southward shifts of the Inter Tropical Convergence Zone associated with Heinrich Stadial 2 and Heinrich Stadial 4, respectively. I therefore confirm that an AMOC slowdown could be at the origin of the ITCZ shifts that occured during Heinrich Stadials and provide the first precise estimate of the phasing between these two climate variables. Based on these results I propose a mechanism explaining the difference between Heinrich and Dansgaard-Oeschger stadials.Using modeling results, I show that the Atlantic Ocean circulation during periods of higher Greenland temperatures (interstadials) was markedly different from that of the Holocene. Two overturning cells were likely active in the Atlantic Ocean: an upper overturning circulation cell initiated by northern-sourced deep water flowing southward above ~2500 m depth at the equator, and a lower overturning circulation cell initiated by southern sourced deep water flowing northward below ~4000 m depth at the equator. The overturning rate of the upper overturning cell was likely lower than that of present-day North Atlantic Deep Water. At the onset of Heinrich Stadials, the structure of the AMOC significantly changed, and southern-sourced deep-waters likely dominated the equatorial Atlantic Ocean below 1300 m depth.

La datation des carbonates est un enjeu important en géosciences car ces minéraux sont présents dans tous les grands cycles superficiels terrestres. Actuellement, l’âge de formation des cristaux de calcite de failles peut être déterminé par la méthode de déséquilibre U-Th ou par la méthode U-Pb. La potentialité de la méthode (U-Th-Sm)/He a été envisagée à partir des premiers résultats de diffusion de l’hélium dans les carbonates (Copeland et al. 2007) qui montrent que l’hélium est rétentif à basse température, inférieure à 70°C. Le développement de cette méthode nécessite une identification des propriétés cristallochimiques et du comportement de la calcite afin de discuter la validité des âges obtenus. Une zone de déformation au contact d’une faille normale du fossé d’effondrement de Gondrecourt à Augeville (Est du bassin de Paris) et des cristaux de calcite géodique des argilites de Tournemire (Aveyron) ont été étudiés. Une étude pétrographique et géochimique (analyse des isotopes stables δ18O et δ13C et des éléments mineurs et traces) a permis d’identifier les phases de remplissage de la zone de déformation d’Augeville. Sur les phases de remplissages une étude cristallographique par DRX (diffraction des rayons X) et ATG (analyse thermogravimétrique) a permis d’identifier les propriétés mécaniques de la calcite à différentes températures. Des expériences de diffusion de l’hélium ont été conduites selon un protocole différent de celui de Copeland et al. (2007) : temps de chauffage inférieur à 12 heures au lieu de paliers de chauffage de plusieurs heures à semaines. Des datations (U-Th-Sm)/He ont été réalisées sur toutes les phases de remplissage de la zone de déformation ainsi que sur les cristaux géodiques de Tournemire. Les résultats pour Gondrecourt mettent en évidence une zone de déformation à remplissage calcitique pluriphasée qui marque chaque étape de l’évolution tectonique de la zone. Il s’agit majoritairement de remplissages de brèches hydrauliques à brèches chaotiques avec, pour finir, la mise en place de filons. Sur ces minéralisations les résultats cristallochimiques montrent que lorsqu’ils sont soumis à une température croissante, de température ambiante à 400°C, ou sur le long terme à 200°C, il y a un accroissement du nombre de microfissures qui aboutit à la formation de clivage. L’évolution cristallochimique sous l’effet de la température présente des modifications structurales pour chacune des phases étudiées. Les expériences de diffusion dépendent de ces microfissures et de cette évolution microstructurale. Ces résultats mettent en évidence les mécanismes de diffusion de l’hélium dans la calcite à travers de multiples domaines de diffusion différents de la taille du grain. Ces domaines de diffusion dépendent de l’état microstructural de l’échantillon. Les résultats de datation (U-Th-Sm)/He présentent une large dispersion de 0,1 Ma à 35 Ma pour la zone de déformation de Gondrecourt et de 0,4 Ma à 20 Ma pour les cristaux géodiques de Tournemire. La variation des âges est en partie liée à la position des cristaux de calcite dans la succession paragénétique qui entraine un continuum de fracturation qui génère de multiples domaines de diffusion dans les cristaux de calcite. / Carbonate dating is a major issue in geosciences due to their widespread terrestrial environments presence . Precipitation ages determination are actually provide by U-Th disequilibrium series for young <1 Ma carbonates crystal and/or U-Pb method for older samples. In addition, Copeland et al. (2007) have proposed the development of (U-Th-Sm)/He dating method based on retentive helium behavior at surface temperature, conclusion issue of their first diffusion coefficients determined on carbonates samples. In this thesis work, the intention was to get an identification of crystallo-chemical properties and behavior of helium in calcite to date samples by (U-Th-Sm)/He and finally discuss the validity of this method. Deformation zones in contact to the normal fault of the Gondrecourt trench close to Augeville (eastern side of Basin of Paris) and calcite crystals geodic Tournemire argillites (Aveyron) were studied. Petrographic and geochemical couples studies (analysis of stable isotopes δ18O and δ13C and minor and trace elements) have allow the filling phases identification of the Augeville deformation zone. Based on the filling phases results, a crystallographic study by XRD (X-ray diffraction) and TGA (Thermogravimetric analysis) have been performed to identify the mechanical properties of calcite at different temperatures. Then, diffusion experiments on natural helium were conducted using a protocol differing than Copeland et al. (2007): heating time less than 12 hours instead of heating stages from hours to weeks. (U-Th-Sm)/He analyses were performed on all filling phases of the deformation zone and on the crystal geodes of Tournemire. Results for Gondrecourt samples show a deformation zone that marks several calcitic fillings corresponding to each stage of the tectonic evolution of the area. Calcite filling mainly corresponds to breccia and/or vein fillings which have precipitated approximatively in the same time. Crystallochemical results of these samples, show an increased number of microcracks leading to the formation of cleavage when samples are subjected to temperature increasing, from room temperature to 400 °C, or several days the long term at 200 °C. The crystallochemical evolution under the effect of temperature exhibits structural modifications for each studied phase. Diffusion experiments depend on these microcracks abundance and the microstructural evolution. These results emphasize the mechanisms of helium diffusion in calcite across multiple diffusion domains at different grain size. These multiple diffusion domains are linked to microstructural state of the sample. The results of dating (U-Th-Sm)/He ages show a wide dispersion of 0.1 to 35 Ma for the deformation zone Gondrecourt and from 0.4 to 20 Ma for Tournemire crystal geodes. Ages variation are partly related to the calcite crystals position in the paragenetic sequence. When a mineral undergoes deformations it becomes less retentive.

Pesquisas versando sobre a distribuição de radionuclídeos naturais na Antártica são raras e desta forma, há grande interesse em se conhecer sua ocorrência e os fatores envolvidos com sua mobilização, transferência e acúmulo neste ambiente extremamente frágil. Os radionuclídeos naturais têm sido intensamente utilizados como traçadores no meio ambiente oceânico, auxiliando na compreensão de processos como afundamento, remoção e ressuspensão de partículas, mistura de massas dágua e circulação oceânica. O 234Th (t½ = 24,1 dias) é um radionuclídeo partículo-reativo produzido continuamente na água do mar pelo decaimento radioativo de seu precursor solúvel e de caráter conservativo com a salinidade 238U (t½ = 4,5 109 anos). Como apresenta meiavida relativamente curta, o 234Th é apropriado para quantificar processos que ocorrem em escala de tempo de dias a semanas. O desequilíbrio 234Th/ 238U nas águas superficiais do oceano tem sido utilizado para determinar o fluxo de carbono orgânico que afunda via material particulado. O fluxo de partículas produtivas biologicamente para além da zona eufótica no Oceano Austral tem destaque especial devido à sua importância no controle das concentrações de CO2 na atmosfera. Os radionuclídeos 210Pb (t½ = 22,3 anos) e 210Po (t½ = 138 dias) também são partículo-reativos. O desequilíbrio 210Po/ 210Pb tem sido utilizado para estimar os fluxos de partículas exportadas no oceano em uma escala de tempo de várias semanas. Os isótopos de Ra de meias-vidas longas, 226Ra (t½ = 1.600 anos) e 228Ra (t½ = 5,75 anos) são solúveis na água do mar exibem propriedades únicas que os tornam bons traçadores de massas dágua. Este trabalho teve por objetivos estudar as distribuições dos radionuclídeos naturais 238U, 234Th, 226Ra, 228Ra, 210Pb e 210Po no Estreito de Bransfield, durante duas campanhas realizadas no Verão Austral de 2011 (OPERANTAR XXIX e XXX). / Research on the distribution of natural radionuclides in Antartica is rare and thus, there is great interest in to know their occurrence and factors related to its mobilization, transference and accumulation in this extremely fragile environment. Natural radionuclides have been used intensively as tracers in the ocean, helping to better understand processes as sinking and particle ressuspention, water masses mixture and oceanic circulation. 234Th (t½ = 24.1 days) is a particle-reactive radionuclide produced continuously in seawater by the decay of its soluble precursor conservative with salinity 238U (t½ = 4.5 109 years). Since 234Th presents relatively short half-life, it is used to quantify processes that occur in temporal scale varying from days to weeks. The disequilibrium 234Th/ 238U in the surface ocean has been applied to estimate carbon fluxes exported via sinking material. The flux of particles biologically productive out of the euphotic zone in the Southern Ocean has special attention due to its importance in the control of CO2 atmospheric concentrations. The radionuclides 210Pb (t½ = 22.3 years) and 210Po (t½ = 138 days) are also particle-reactive. The disequilibrium 210Po/ 210Pb has been used to estimate fluxes of particles exported in the ocean in the time scale of weeks. The long-lived Ra isotopes, 226Ra (t½ = 1,600 years) and 228Ra (t½ = 5.75 years) are soluble in seawater, presenting unique properties that make them excellent tracers of water masses. This research work had the aim to study the distributions of natural radionuclides 238U, 234Th, 226Ra, 228Ra, 210Pb and 210Po in the Bransfield Strait during 2 samplings carried out in the 2011 Austral Summer (OPERANTAR XXIX and XXX).

Pesquisas versando sobre a distribuição de radionuclídeos naturais na Antártica são raras e desta forma, há grande interesse em se conhecer sua ocorrência e os fatores envolvidos com sua mobilização, transferência e acúmulo neste ambiente extremamente frágil. Os radionuclídeos naturais têm sido intensamente utilizados como traçadores no meio ambiente oceânico, auxiliando na compreensão de processos como afundamento, remoção e ressuspensão de partículas, mistura de massas dágua e circulação oceânica. O 234Th (t½ = 24,1 dias) é um radionuclídeo partículo-reativo produzido continuamente na água do mar pelo decaimento radioativo de seu precursor solúvel e de caráter conservativo com a salinidade 238U (t½ = 4,5 109 anos). Como apresenta meiavida relativamente curta, o 234Th é apropriado para quantificar processos que ocorrem em escala de tempo de dias a semanas. O desequilíbrio 234Th/ 238U nas águas superficiais do oceano tem sido utilizado para determinar o fluxo de carbono orgânico que afunda via material particulado. O fluxo de partículas produtivas biologicamente para além da zona eufótica no Oceano Austral tem destaque especial devido à sua importância no controle das concentrações de CO2 na atmosfera. Os radionuclídeos 210Pb (t½ = 22,3 anos) e 210Po (t½ = 138 dias) também são partículo-reativos. O desequilíbrio 210Po/ 210Pb tem sido utilizado para estimar os fluxos de partículas exportadas no oceano em uma escala de tempo de várias semanas. Os isótopos de Ra de meias-vidas longas, 226Ra (t½ = 1.600 anos) e 228Ra (t½ = 5,75 anos) são solúveis na água do mar exibem propriedades únicas que os tornam bons traçadores de massas dágua. Este trabalho teve por objetivos estudar as distribuições dos radionuclídeos naturais 238U, 234Th, 226Ra, 228Ra, 210Pb e 210Po no Estreito de Bransfield, durante duas campanhas realizadas no Verão Austral de 2011 (OPERANTAR XXIX e XXX). / Research on the distribution of natural radionuclides in Antartica is rare and thus, there is great interest in to know their occurrence and factors related to its mobilization, transference and accumulation in this extremely fragile environment. Natural radionuclides have been used intensively as tracers in the ocean, helping to better understand processes as sinking and particle ressuspention, water masses mixture and oceanic circulation. 234Th (t½ = 24.1 days) is a particle-reactive radionuclide produced continuously in seawater by the decay of its soluble precursor conservative with salinity 238U (t½ = 4.5 109 years). Since 234Th presents relatively short half-life, it is used to quantify processes that occur in temporal scale varying from days to weeks. The disequilibrium 234Th/ 238U in the surface ocean has been applied to estimate carbon fluxes exported via sinking material. The flux of particles biologically productive out of the euphotic zone in the Southern Ocean has special attention due to its importance in the control of CO2 atmospheric concentrations. The radionuclides 210Pb (t½ = 22.3 years) and 210Po (t½ = 138 days) are also particle-reactive. The disequilibrium 210Po/ 210Pb has been used to estimate fluxes of particles exported in the ocean in the time scale of weeks. The long-lived Ra isotopes, 226Ra (t½ = 1,600 years) and 228Ra (t½ = 5.75 years) are soluble in seawater, presenting unique properties that make them excellent tracers of water masses. This research work had the aim to study the distributions of natural radionuclides 238U, 234Th, 226Ra, 228Ra, 210Pb and 210Po in the Bransfield Strait during 2 samplings carried out in the 2011 Austral Summer (OPERANTAR XXIX and XXX).

The redox-sensitive geochemical behavior of uranium permits the use of Th/U ratios as a geochemical proxy for the oxidation state of the atmosphere and oceans during sedimentary processes. Due to the effects of post-depositional uranium mobility on Th/U ratios during events involving oxygenated fluids, direct measurements of Th/U ratios are often misleading, but the whole rock Pb isotope composition may be used to determine a sample¡¦s apparent time-integrated Th/U ratio (ƒÛa) and the timing associated with the onset of the U-Th-Pb geochemistry. Rare earth element (REE) concentrations were determined by isotope dilution mass spectrometry to evaluate the influence of multiple provenance components and potential mobility of Th, U, and Pb during post-depositional processes on the Th/U ratio. The Pb isotope compositions and REE concentrations were determined for six Paleoproterozoic sedimentary sequences, which were the focus of previous studies involving the timing of the rise of atmospheric oxygen. The Mount McRae Shale, Huronian Supergroup, and Zaonezhskaya Formation have been interpreted as experiencing post-depositional alteration (perhaps associated with orogenic events) due to Pb-Pb ages that are younger than the likely depositional age and observed fractionation of REE in chondrite normalized REE patterns and interelement REE ratios (e.g. La/Nd, La/Yb, Eu/Eu*). Similar geochemical proxies have been interpreted as sedimentary geochemical features of the Timeball Hill Formation, Hotazel Formation, and Sengoma Argillite Formation. This study of Paleoproterozoic sedimentary units constrains the onset of U-Th decoupling, most likely due to the onset of oxidative weathering conditions, began by 2.32 Ga, the latest.

Disertacijoje nagrinėjami Lietuvos bajorijos mediniai gyvenamieji pastatai, darbe vadinami ponų namais. Darbo t i k s l a s – išaiškinti ir pateikti Lietuvos bajorų namų medinės architektūros raidą nuo Valakų reformos iki 1861 Valstiečių reformos. Darbe tirti esami bei neišlikę (žinomi dėka šaltinių) mediniai bajorijos namai, nustatyti vyravę pastatų tipai, priežastys, lėmusios tipų kaitą, atskleidžiami architektūros ypatumai, ponų namo santykis su etnine ir profesionaliąja architektūra. Tyrimai parodė, kad skirtingų bajorijos sluoksnių ponų namų architektūros raida vyko skirtingai. Stambių ir vidutinių bajorų namų raida buvo intensyvi, ją ypač veikė stilinės architektūros pokyčiai. Smulkių bajorų namai kito mažai, statyboje laikytasi etninių tradicijų. Pagal stambių ir vidutinių bajorų XVI a. vidurio– XIX a. vidurio pastatų planines ir tūrines –erdvines struktūras ir formas, išskirti trys architektūrinės raidos etapai: ankstyvasis- formavimosi (iki XVII a. vidurio), „barokinis“ (XVII a. vidurio – XVIII a. septinto dešimtmečio); „klasicistinis“ (XVIII a. pabaigos – XIX a. vidurio). Pirmajame etape iš esmės pakito gyvenamosios erdvės sankloda ir namo įvaizdis: vietoje kelių skirtingų funkcijų namų, skirtų bajoro šeimai ir jo svečiams (gyvenamojo, pokylių namo, ir kt.) susiformavo vienas daugiafunkcinis, parterinis, simetriškos kompozicijos ponų namas. Antrajame ir trečiajame etapuose daugiafunkcinis ponų namas buvo tobulinamas pagal etiketo (gyvenimo būdo) ir vyravusių... [toliau žr. visą tekstą] / Doctoral thesis Evolution of wooden architecture of manor houses in Lithuania (from the middle of 16th century till the middle of 19th century) explore and present an evolution of the wooden architecture of manor houses since the middle of the 16th century till the middle of the 19th century. The thesis investigates the existing and not existing (known from the sources) wooden residential buildings of Lithuanian nobility, identifies their dominant types and reasons, which influenced the change of architecture, and reveals the singularities of the architecture and the relation of a manor’s house with ethnic and professional architecture. The research has shown that the architectural evolution of the manor house owned by nobility of different rank was developing differently. The development of great and middle-class nobility’s manor house was intense, especially influenced by the changes in style architecture. The small noblemen‘s houses were changing a little, their construction followed the ethnic traditions. According to the layout and shape of structures and forms of the buildings set on the manors of great and middle-class nobility, three stages of their architectural evolution were singled out: the period of early formation (till the middle of the 17th century), “baroque” period (from the middle of the 17th century till the seventh decade of the 18th century) and the “classicism” period (from the end of 18th century till the end of the 19th century). The doctoral thesis... [to full text]

Les mastocytes sont des cellules immunitaires présentes dans tous les tissus de l'organisme. Ils ont été depuis longtemps associés aux réponses allergiques, mais ces cellules sont aussi des acteurs majeurs de la réponse inflammatoire. La dégranulation des mastocytes, ou exocytose des granules sécrétoires, est un mécanisme d'action important de ces cellules. Au laboratoire, nous avons mis au point une méthode innovante qui nous permet de suivre en temps réel la dynamique de cette dégranulation. Cette méthode repose sur l'utilisation de l'avidine couplé à un fluorochrome qui se lie spécifiquement à la matrice des granules. Nous avons recherché les modalités de la dégranulation lorsque les mastocytes sont activés par un ligand cellulaire comme des cellules cibles recouvertes d'anticorps. Nous avons pu mettre en évidence, de façon surprenante, que les mastocytes dégranulent de manière polarisée contre une cellule cible opsonisée avec des anticorps de type IgE ou IgG en mettant en place un nouveau mécanisme que nous avons nommé ADDS (Antibody Dependent Degranulatory Synapse). L'ADDS est caractérisée par une signalisation du récepteur RFc et une dépolymérisation du cytosquelette cortical d'actine locales. De plus, cette synapse peut aussi avoir lieu lorsque le mastocyte est au contact d'un parasite opsonisé comme Toxoplasma Gondii, et induit la mort du parasite et la libération de cytokines et chimiokines pro-inflammatoires. Nous avons ensuite analysé la dynamique de la dégranulation à l'échelle " single cell " et sa régulation par des facteurs inflammatoires. Grâce à une approche de " cell barcoding " et de cytométrie en flux en temps réel, nous avons pu mettre en évidence que la dégranulation induite par l'agrégation des RFc?I était contrôlée par deux mécanismes : un premier qui règle le nombre de mastocytes qui dégranulent et un second qui régule l'intensité de la dégranulation. L'interleukine 33 peut finement potentialiser ces deux mécanismes en augmentant le pourcentage de mastocytes qui dégranulent et l'intensité de la dégranulation. L'IL-33 induit ainsi l'émergence de cellules hautement inflammatoires. Dans un second axe de recherche, nous avons étudié quel pouvait être l'impact des prostaglandines dans le dialogue entre mastocytes et lymphocytes T CD4+ Helper (TH). Nos résultats indiquent un rôle insoupçonné de la prostaglandine D2 et la prostaglandine E2 comme des acteurs importants pour la production d'interleukine 17 par les LTH. En conclusion, mon travail de thèse nous a permis de révéler l'existence de la synapse dégranulatoire des mastocytes, de nouveaux mécanismes contrôlant la dégranulation et d'identifier les mastocytes comme une source importante de prostaglandines impliquées dans la polarisation des LTH. / Mast cells are tissue-resident immune cells particularly enriched in regions exposed to the external environment. They have been associated, for a long time, with allergic disorders but these cells are also major effectors of inflammatory response. The degranulation process, or granule exocytosis, is one of the main effector functions of mast cells and it has been implicated in various biological processes. In our laboratory, we have developed a new method to monitor live mast cell degranulatory response. This approach is based on fluorescent avidin that binds selectively mast cell granule matrix. Thanks to this method, we have investigated the degranulatory response following mast cell activation by cell bound antigens. We have shown that mast cells can undergo polarized degranulation toward IgE- or IgG-opsonized cells in a new mechanism we named ADDS (Antibody Dependent Degranulatory Synapse). The ADDS is characterized by a local signaling of FcR receptors and cortical actin depolymerisation. Moreover, this synapse takes place when mast cells are triggered by opsonized parasite Toxoplasma Gondii. It leads to the death of the parasite and the release of pro-inflammatory cytokines and chemokines. We next analyzed the mast cell degranulatory response dynamics at the single cell level and its regulation by alarmin IL-33. Using cutting-edge "cell barcoding" approach and live flow cytometry, we showed that Fc?RI mediated degranulatory response is controlled by two mechanisms: a first one that sets the frequency of degranulated mast cells and a second one that regulates the magnitude of the degranulation. The IL-33 fine tunes these two mechanisms by augmenting both the frequency of degranulated mast cells and the extent of individual mast cell degranulation. Our results indicate that interleukin 33 induces the emergence of high inflammatory mast cells. In a second axis of research, we analysed the influence of prostaglandins during the cooperation between mast cells and CD4+ T helper cells. Our results indicate that prostaglandin D2 and E2 produced by mast cells are important inducers of interleukin 17 by CD4+ T helper cells. Taken together, my thesis work revealed that mast cells can form degranulatory synapses, new mechanisms that control the degranulatory response and identified mast cells as a source of pro-IL-17 prostaglandins during their cooperation with CD4+ T helper cells.

Les antibiotiques (ATB) inhibent l'efficacité anti-tumorale du blocage de PD1, mais les mécanismes sous-jacents à leurs effets immunosuppresseurs demeurent inconnus. Nous montrons ici que les ATB favorisent l'accumulation des cellules T FoxP3+ et RORct+ a4b7hi dans les ganglions lymphatiques et les lésions tumorales. Les ATB induisent la perte de l'adressine MadCAM-1 iléale provoquant la recirculation des lymphocytes T régulateurs et TH17 α4β7hi de l’iléon vers le microenvironnement tumoral (TME). Cette migration a été visualisée grâce à 2 méthodes, la première consiste en l’ injection directe de carboxyfluoresceine succinimidyl ester (CFSE) dans les ganglions lymphatiques mésentériques des souris porteuses de tumeurs, l’autre utilise des souris transgéniques Kaede contenant une protéine flurorescente photoconvertible. Les hétérodimères d'adressine MAdCAM-1 et d'intégrine α4β7 sont indispensables pour l'efficacité anti-tumorale et dans l'immuno-surveillance induite par les anticorps anti-PD1. L’utilisation de modèles knock-out de MadCAM-1 ou d’ anticorps bloquant son ligand α4β7, compromettent l’efficacité anticancéreuse du blocage du PD1 ceci en mobilisant les cellules entérotropes α4β7hi Treg et TH17 vers le TME et inversement, en réduisant le retour du Treg du TME vers l'intestin. L’inhibition de la voie MadCAM-1 au niveau iléal réduit simultanément les lymphocytes CCR5+ effecteurs et mémoires dans le tissu tumoral. Ces résultats démontrent l’existence d’un lien mécanistique entre la dysbiose intestinale et l'efficacité du traitement anti- tumoral, l’importance de l'axe intestin-tumeur dans l’ immunosurveillance du cancer et ouvre des perspectives d’application clinique pour cibler la voie MAdCAM-1 α4β7+ . / Antibiotics (ATB) inhibit the anticancer efficacy of PD1 blockade but the mechanisms underlying their immunosuppressive effects remains unknown. Here we show that ATB promote the accumulation of enterotropic, ileum egressing FoxP3+ and RORct+ α4β7 hi T cells into tumor draining lymph nodes and tumor lesions. ATB induce the loss of ileal MadCAM-1 adressin provoking the recirculation of α4β7 hi ileal Treg and TH17 cells to the tumor microenvironment (TME), as visualized using direct injection of carboxyfluorescein succinimidyl ester in mesenteric lymph nodes of tumor bearers as well as Kaede transgenic mice harboring a photoconvertible flurorescent protein. MAdCAM-1 addressin and α4β7 integrin heterodimers are indispensable for the anticancer efficacy and the immuno-surveillanc elicited by anti-PD1 antibodies. Gene defects in MadCAM-1 as well as antibodies blocking its ligand α4β7, severely compromise the anticancer effects of PD1 blockade by mobilizing enterotropic α4β7hi Treg and TH17 cells towards the TME and conversely reducing Treg homing from the TME to the gut, concomitantly reducing CCR5+ effector memory tumor infiltrating lymphocytes. These findings demonstrate a mechanistic link between gut dysbiosis and tumor treatment efficacy and unveil the potential clinical relevance of the MAdCAM-1 α4β7+ and the gut-tumor axis in cancer immunosurveillance.

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