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1. Intrinsic factors and CD1d1 but not CD1d2 expression levels control invariant natural killer T cell subset differentiation

Author

Amable, Ludivine, Ferreira Martins, Luis Antonio, Pierre, Remi, Do Cruseiro, Marcio, Chabab, Ghita, Sergé, Arnauld, Kergaravat, Camille, Delord, Marc, Viret, Christophe, Jaubert, Jean, Liu, Chaohong, Karray, Saoussen, Marie, Julien C., Irla, Magali, Georgiev, Hristo, Clave, Emmanuel, Toubert, Antoine, Lucas, Bruno, Klibi, Jihene, and Benlagha, Kamel

Published
2023
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5. Supplementary methods from JAM-C Identifies Src Family Kinase-Activated Leukemia-Initiating Cells and Predicts Poor Prognosis in Acute Myeloid Leukemia

Author

De Grandis, Maria, primary, Bardin, Florence, primary, Fauriat, Cyril, primary, Zemmour, Christophe, primary, El-Kaoutari, Abdessamad, primary, Sergé, Arnauld, primary, Granjeaud, Samuel, primary, Pouyet, Laurent, primary, Montersino, Camille, primary, Chretien, Anne-Sophie, primary, Mozziconacci, Marie-Joelle, primary, Castellano, Remy, primary, Bidaut, Ghislain, primary, Boher, Jean-Marie, primary, Collette, Yves, primary, Mancini, Stéphane J.C., primary, Vey, Norbert, primary, and Aurrand-Lions, Michel, primary

Published
2023
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6. Supplementary Tables from JAM-C Identifies Src Family Kinase-Activated Leukemia-Initiating Cells and Predicts Poor Prognosis in Acute Myeloid Leukemia

Author

De Grandis, Maria, primary, Bardin, Florence, primary, Fauriat, Cyril, primary, Zemmour, Christophe, primary, El-Kaoutari, Abdessamad, primary, Sergé, Arnauld, primary, Granjeaud, Samuel, primary, Pouyet, Laurent, primary, Montersino, Camille, primary, Chretien, Anne-Sophie, primary, Mozziconacci, Marie-Joelle, primary, Castellano, Remy, primary, Bidaut, Ghislain, primary, Boher, Jean-Marie, primary, Collette, Yves, primary, Mancini, Stéphane J.C., primary, Vey, Norbert, primary, and Aurrand-Lions, Michel, primary

Published
2023
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7. Supplementary Figures from JAM-C Identifies Src Family Kinase-Activated Leukemia-Initiating Cells and Predicts Poor Prognosis in Acute Myeloid Leukemia

Author

De Grandis, Maria, primary, Bardin, Florence, primary, Fauriat, Cyril, primary, Zemmour, Christophe, primary, El-Kaoutari, Abdessamad, primary, Sergé, Arnauld, primary, Granjeaud, Samuel, primary, Pouyet, Laurent, primary, Montersino, Camille, primary, Chretien, Anne-Sophie, primary, Mozziconacci, Marie-Joelle, primary, Castellano, Remy, primary, Bidaut, Ghislain, primary, Boher, Jean-Marie, primary, Collette, Yves, primary, Mancini, Stéphane J.C., primary, Vey, Norbert, primary, and Aurrand-Lions, Michel, primary

Published
2023
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10. Kommunales Projektmanagement leicht gemacht : Ein Leitfaden für die Umsetzung erfolgreicher öffentlicher Projekte

Author

Serge Arnauld and Serge Arnauld

Abstract

In einer Welt, in der die Anforderungen an kommunale Projekte ständig wachsen, ist ein effektives Projektmanagement unerlässlich, um die Bedürfnisse der Bürger zu erfüllen und gleichzeitig die Ressourcen effizient zu nutzen. Dieses Buch bietet einen umfassenden Leitfaden, der speziell für Projektmanager in Kommunen und öffentlichen Einrichtungen entwickelt wurde. Serge Arnauld, ein erfahrener Experte im Bereich des öffentlichen Projektmanagements, vermittelt praxisnahes Wissen und bewährte Strategien, um kommunale Projekte erfolgreich zu planen, umzusetzen und abzuschließen. Von der ersten Bedarfsanalyse über die Stakeholder-Einbindung bis hin zur Qualitätssicherung und dem erfolgreichen Abschluss – dieser Leitfaden deckt alle wesentlichen Schritte ab. Mit verständlichen Erklärungen, anschaulichen Fallbeispielen und klaren Handlungsempfehlungen wird dieses Buch zu einem unverzichtbaren Werkzeug für alle, die sich der Herausforderung stellen, öffentliche Projekte in ihrer Gemeinde oder Stadt effektiv zu managen. Lernen Sie, wie Sie typische Stolpersteine vermeiden, Bürgerbeteiligung erfolgreich integrieren und Ihre Projekte termingerecht und budgetkonform abschließen können. Kommunales Projektmanagement leicht gemacht ist der ideale Begleiter für Projektmanager, Verwaltungsmitarbeiter und Entscheidungsträger, die sich auf dem Weg zu einem erfolgreichen Projektmanagement im öffentlichen Sektor weiterentwickeln möchten.

Published
2024

11. Recirculating Foxp3+ regulatory T cells are restimulated in the thymus under Aire control.

Author

Charaix, Jonathan, Borelli, Alexia, Santamaria, Jérémy C., Chasson, Lionel, Giraud, Matthieu, Sergé, Arnauld, and Irla, Magali

Abstract

Thymically-derived Foxp3+ regulatory T cells (Treg) critically control immunological tolerance. These cells are generated in the medulla through high affinity interactions with medullary thymic epithelial cells (mTEC) expressing the Autoimmune regulator (Aire). Recent advances have revealed that thymic Treg contain not only developing but also recirculating cells from the periphery. Although Aire is implicated in the generation of Foxp3+ Treg, its role in the biology of recirculating Treg remains elusive. Here, we show that Aire regulates the suppressive signature of recirculating Treg independently of the remodeling of the medullary 3D organization throughout life where Treg reside. Accordingly, the adoptive transfer of peripheral Foxp3+ Treg in AireKO recipients led to an impaired suppressive signature upon their entry into the thymus. Furthermore, recirculating Treg from AireKO mice failed to attenuate the severity of multiorgan autoimmunity, demonstrating that their suppressive function is altered. Using bone marrow chimeras, we reveal that mTEC-specific expression of Aire controls the suppressive signature of recirculating Treg. Finally, mature mTEC lacking Aire were inefficient in stimulating peripheral Treg both in polyclonal and antigen-specific co-culture assays. Overall, this study demonstrates that Aire confers to mTEC the ability to restimulate recirculating Treg, unravelling a novel function for this master regulator in Treg biology. [ABSTRACT FROM AUTHOR]

Published
2022
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15. Nidogen-1 Contributes to the Interaction Network Involved in Pro-B Cell Retention in the Peri-sinusoidal Hematopoietic Stem Cell Niche

Author

Balzano, Marielle, De Grandis, Maria, Vu Manh, Thien-Phong, Chasson, Lionel, Bardin, Florence, Farina, Anne, Sergé, Arnauld, Bidaut, Ghislain, Charbord, Pierre, Hérault, Léonard, Bailly, Anne-Laure, Cartier-Michaud, Amandine, Boned, Annie, Dalod, Marc, Duprez, Estelle, Genever, Paul, Coles, Mark, Bajenoff, Marc, Xerri, Luc, Aurrand-Lions, Michel, Schiff, Claudine, Mancini, Stéphane, Mancini, Stéphane J.C., Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre d'Immunologie de Marseille - Luminy (CIML), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Génétique, immunothérapie, chimie et cancer (GICC), UMR 6239 CNRS [2008-2011] (GICC UMR 6239 CNRS), Université de Tours-Centre National de la Recherche Scientifique (CNRS), Informatique, Biologie Intégrative et Systèmes Complexes (IBISC), Université d'Évry-Val-d'Essonne (UEVE), University of York [York, UK], Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), Département de Biopathologie, Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Laboratoire des images et des signaux (LIS), Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique de Grenoble (INPG)-Université Joseph Fourier - Grenoble 1 (UJF), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Mi-mAbs (C/O CIML), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Laboratoire de Biologie du Développement [Paris] (LBD), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Biologie Paris Seine (IBPS), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Aix Marseille Université (AMU), Groupe innovation et ciblage cellulaire (GICC), EA 7501 [2018-...] (GICC EA 7501), Université de Tours, University of Oxford [Oxford], Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Biologie du Développement [IBPS] (LBD), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CCSD, Accord Elsevier, and ANR-17-CE14-0019,OSTEOVALYMPH,Autocrinie et paracrinie de l'axe de signalisation CXCL12/CXCR4-CXCR7 dans la niche ostéo-vasculaire: impact sur la spécification et l'engagement lymphoïde des cellules souches hématopoïétiques(2017)

Subjects
[SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, bone marrow, interaction network, [SDV]Life Sciences [q-bio], [SDV.CAN]Life Sciences [q-bio]/Cancer, Mice, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], B cell development, Animals, Stem Cell Niche, lcsh:QH301-705.5, ComputingMilieux_MISCELLANEOUS, Mice, Knockout, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Membrane Glycoproteins, Interleukin-7, Precursor Cells, B-Lymphoid, stromal cell niche, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Hematopoietic Stem Cells, [SDV] Life Sciences [q-bio], [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, lcsh:Biology (General), hematopoietic stem cell, Stromal Cells, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Summary: In the bone marrow, CXCL12 and IL-7 are essential for B cell differentiation, whereas hematopoietic stem cell (HSC) maintenance requires SCF and CXCL12. Peri-sinusoidal stromal (PSS) cells are the main source of IL-7, but their characterization as a pro-B cell niche remains limited. Here, we characterize pro-B cell supporting stromal cells and decipher the interaction network allowing pro-B cell retention. Preferential contacts are found between pro-B cells and PSS cells, which homogeneously express HSC and B cell niche genes. Furthermore, pro-B cells are frequently located in the vicinity of HSCs in the same niche. Using an interactome bioinformatics pipeline, we identify Nidogen-1 as essential for pro-B cell retention in the peri-sinusoidal niche as confirmed in Nidogen-1−/− mice. Finally, human pro-B cells and hematopoietic progenitors are observed close to similar IL-7+ stromal cells. Thus, a multispecific niche exists in mouse and human supporting both early progenitors and committed hematopoietic lineages. : Balzano et al. show that bone marrow peri-sinusoidal stromal cells, which form the hematopoietic stem cell niche, also express B cell niche genes including IL-7 and Nidogen-1. Loss of Nidogen-1 expression specifically affects access of pro-B cells to IL-7, resulting in impaired expansion and differentiation of early B cells. Keywords: B cell development, hematopoietic stem cell, stromal cell niche, interaction network, bone marrow

Published
2019

16. Genetic, structural, and chemical insights into the dual function of GRASP55 in germ cell Golgi remodeling and JAM-C polarized localization during spermatogenesis

Author

Cartier-Michaud, Amandine, Bailly, Anne-Laure, Betzi, Stéphane, Shi, Xiaoli, Lissitzky, Jean-Claude, Zarubica, Ana, Sergé, Arnauld, ROCHE, Philippe, Lugari, Adrien, HAMON, Véronique, Bardin, Florence, Derviaux, Carine, Lembo, Frédérique, Audebert, Stéphane, Marchetto, Sylvie, Durand, Bénédicte, Borg, Jean-Paul, Shi, Ning, Morelli, Xavier, Aurrand-Lions, Michel, Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), ANR-11-IDEX-0001,Amidex,INITIATIVE D'EXCELLENCE AIX MARSEILLE UNIVERSITE(2011), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)

Subjects
Male, Physiology, [SDV]Life Sciences [q-bio], Golgi Apparatus, Mice, Animal Cells, Reproductive Physiology, Spermatocytes, Medicine and Health Sciences, Cell Cycle and Cell Division, Testes, Cells, Cultured, Staining, Chromosome Biology, Intracellular Signaling Peptides and Proteins, Specimen preparation and treatment, Spermatids, humanities, Protein Transport, Meiosis, Seminiferous tubules, Cell Processes, cardiovascular system, Cellular Types, Anatomy, Cellular Structures and Organelles, Genital Anatomy, Protein Binding, Research Article, endocrine system, lcsh:QH426-470, education, Immunoglobulins, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Germ cells, Acrosomes, Animals, Spermatogenesis, Binding Sites, fungi, Reproductive System, DAPI staining, Membrane Proteins, Biology and Life Sciences, Cell Biology, Spermatogonia, Sperm, Mice, Inbred C57BL, Research and analysis methods, lcsh:Genetics, Nuclear staining, Carrier Proteins, Cell Adhesion Molecules
Abstract

Spermatogenesis is a dynamic process that is regulated by adhesive interactions between germ and Sertoli cells. Germ cells express the Junctional Adhesion Molecule-C (JAM-C, encoded by Jam3), which localizes to germ/Sertoli cell contacts. JAM-C is involved in germ cell polarity and acrosome formation. Using a proteomic approach, we demonstrated that JAM-C interacted with the Golgi reassembly stacking protein of 55 kDa (GRASP55, encoded by Gorasp2) in developing germ cells. Generation and study of Gorasp2-/- mice revealed that knock-out mice suffered from spermatogenesis defects. Acrosome formation and polarized localization of JAM-C in spermatids were altered in Gorasp2-/- mice. In addition, Golgi morphology of spermatocytes was disturbed in Gorasp2-/- mice. Crystal structures of GRASP55 in complex with JAM-C or JAM-B revealed that GRASP55 interacted via PDZ-mediated interactions with JAMs and induced a conformational change in GRASP55 with respect of its free conformation. An in silico pharmacophore approach identified a chemical compound called Graspin that inhibited PDZ-mediated interactions of GRASP55 with JAMs. Treatment of mice with Graspin hampered the polarized localization of JAM-C in spermatids, induced the premature release of spermatids and affected the Golgi morphology of meiotic spermatocytes., Author summary Spermatogenesis defects are a common cause of male sterility. Spermatogenesis occurs in the seminiferous tubules of the testes and involves adhesive interactions between developing germ cells and Sertoli cells. Knock-out mouse models identified several adhesion molecules that are critically involved in spermatogenesis. We previously demonstrated that the Junctional Adhesion Molecule-C (JAM-C) plays a crucial role in establishing spermatids polarity. The latter involves rearrangements of the Golgi apparatus in spermatids which contribute to acrosome formation. The present study demonstrated that the C-terminal cytosolic region of JAM-C interacted with the Golgi reassembly stacking protein of 55 kDa (GRASP55) encoded by Gorasp2 and that spermatogenesis was impaired in Gorasp2-deficient mice. We developed an inhibitor of GRASP55 interaction with JAM-C and demonstrated that treatment of wild-type mice with the inhibitory compound induced germ cell loss. Therefore, the male infertility-associated pathway identified in this study is important not only from a genetic point of view, but also as a potential target for male contraception.

Published
2017

20. JAM-C Identifies Src Family Kinase-Activated Leukemia-Initiating Cells and Predicts Poor Prognosis in Acute Myeloid Leukemia

Author

De Grandis, Maria, primary, Bardin, Florence, additional, Fauriat, Cyril, additional, Zemmour, Christophe, additional, El-Kaoutari, Abdessamad, additional, Sergé, Arnauld, additional, Granjeaud, Samuel, additional, Pouyet, Laurent, additional, Montersino, Camille, additional, Chretien, Anne-Sophie, additional, Mozziconacci, Marie-Joelle, additional, Castellano, Remy, additional, Bidaut, Ghislain, additional, Boher, Jean-Marie, additional, Collette, Yves, additional, Mancini, Stéphane J.C., additional, Vey, Norbert, additional, and Aurrand-Lions, Michel, additional

Published
2017
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21. Mouvements cellulaires et moléculaires

Author

Sergé, Arnauld, Irla, Magali, Sergé, Arnauld, Aix Marseille Université (AMU), Adhésion et Inflammation (LAI), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre d'Immunologie de Marseille - Luminy (CIML), and Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
[SDV] Life Sciences [q-bio], [SDV]Life Sciences [q-bio], ComputingMilieux_MISCELLANEOUS
Abstract

International audience

Published
2013

22. Cancer-associated fibroblast-derived annexin A6+ extracellular vesicles support pancreatic cancer aggressiveness

Author

Leca, Julie, primary, Martinez, Sébastien, additional, Lac, Sophie, additional, Nigri, Jérémy, additional, Secq, Véronique, additional, Rubis, Marion, additional, Bressy, Christian, additional, Sergé, Arnauld, additional, Lavaut, Marie-Noelle, additional, Dusetti, Nelson, additional, Loncle, Céline, additional, Roques, Julie, additional, Pietrasz, Daniel, additional, Bousquet, Corinne, additional, Garcia, Stéphane, additional, Granjeaud, Samuel, additional, Ouaissi, Mehdi, additional, Bachet, Jean Baptiste, additional, Brun, Christine, additional, Iovanna, Juan L., additional, Zimmermann, Pascale, additional, Vasseur, Sophie, additional, and Tomasini, Richard, additional

Published
2016
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27. Multiple-target tracing (MTT) algorithm probes molecular dynamics at cell surface

Author

Bertaux Nicolas, Marguet Didier, Sergé Arnauld, Rigneault Hervé, and Aix Marseille Université (AMU)

Subjects
Surface (mathematics), Chemistry, [SDV]Life Sciences [q-bio], Cell, Tracing, Multiple target, Cell biology, Molecular dynamics, medicine.anatomical_structure, medicine, General Earth and Planetary Sciences, Biological system, ComputingMilieux_MISCELLANEOUS, General Environmental Science
Abstract

International audience

Published
2008

28. Barcoding T Cell Calcium Response Diversity with Methods for Automated and Accurate Analysis of Cell Signals (MAAACS)

Author

Salles, Audrey, primary, Billaudeau, Cyrille, additional, Sergé, Arnauld, additional, Bernard, Anne-Marie, additional, Phélipot, Marie-Claire, additional, Bertaux, Nicolas, additional, Fallet, Mathieu, additional, Grenot, Pierre, additional, Marguet, Didier, additional, He, Hai-Tao, additional, and Hamon, Yannick, additional

Published
2013
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39. Antigen Recognition by Autoreactive CD4+ Thymocytes Drives Homeostasis of the Thymic Medulla.

Author

Irla, Magali, Guerri, Lucia, Guenot, Jeanne, Sergé, Arnauld, Lantz, Olivier, Liston, Adrian, Imhof, Beat A., Palmer, Ed, and Reith, Walter

Subjects
IMMUNOGLOBULINS, HOMEOSTASIS, T cell receptors, EPITHELIAL cells, THYMOCYTES, MEDICAL research
Abstract

The thymic medulla is dedicated for purging the T-cell receptor (TCR) repertoire of self-reactive specificities. Medullary thymic epithelial cells (mTECs) play a pivotal role in this process because they express numerous peripheral tissue-restricted self-antigens. Although it is well known that medulla formation depends on the development of single-positive (SP) thymocytes, the mechanisms underlying this requirement are incompletely understood. We demonstrate here that conventional SP CD4+ thymocytes bearing autoreactive TCRs drive a homeostatic process that fine-tunes medullary plasticity in adult mice by governing the expansion and patterning of the medulla. This process exhibits strict dependence on TCR-reactivity with self-antigens expressed by mTECs, as well as engagement of the CD28-CD80/CD86 costimulatory axis. These interactions induce the expression of lymphotoxin a in autoreactive CD4+ thymocytes and RANK in mTECs. Lymphotoxin in turn drives mTEC development in synergy with RANKL and CD40L. Our results show that Ag-dependent interactions between autoreactive CD4+ thymocytes and mTECs fine-tune homeostasis of the medulla by completing the signaling axes implicated in mTEC expansion and medullary organization. [ABSTRACT FROM AUTHOR]

Published
2012
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40. GRASP55 Is Dispensable for Normal Hematopoiesis but Necessary for Myc-Dependent Leukemic Growth

Author

Amandine Cartier-Michaud, Anne-Laure Bailly, Michel Aurrand-Lions, Marielle Balzano, Armelle Goubard, Florence Bardin, Maria De Grandis, Julien M. P. Grenier, Stéphane J. C. Mancini, Arnauld Sergé, Jean-Claude Lissitzky, Centre de Recherche en Cancérologie de Marseille (CRCM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Etablissement Français du Sang Provence-Alpes Côte-d'Azur et Corse (EFS), Sergé, Arnauld, and Bidaut, Ghislain

Subjects
[SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, [SDV.IMM] Life Sciences [q-bio]/Immunology, Carcinogenesis, Cell Survival, [SDV]Life Sciences [q-bio], Immunology, Golgi Apparatus, [SDV.CAN]Life Sciences [q-bio]/Cancer, Apoptosis, Biology, Proto-Oncogene Proteins c-myc, 03 medical and health sciences, Mice, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, medicine, Autophagy, Immunology and Allergy, Animals, ComputingMilieux_MISCELLANEOUS, Mice, Knockout, Gene knockdown, Leukemia, Hematopoietic stem cell differentiation, Golgi Matrix Proteins, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Transport protein, Cell biology, Hematopoiesis, Tumor Burden, [SDV] Life Sciences [q-bio], Mice, Inbred C57BL, Haematopoiesis, Protein Transport, medicine.anatomical_structure, Knockout mouse, [SDV.IMM]Life Sciences [q-bio]/Immunology, Bone marrow, 030215 immunology, Homing (hematopoietic)
Abstract

Grasp55 is a ubiquitous Golgi stacking protein involved in autophagy, protein trafficking, and glucose deprivation sensing. The function of Grasp55 in protein trafficking has been attributed to its PDZ-mediated interaction with the C-terminal PDZ-binding motifs of protein cargos. We have recently shown that such an interaction occurs between Grasp55 and the adhesion molecule Jam-C, which plays a central role in stemness maintenance of hematopoietic and spermatogenic cells. Accordingly, we have found that Grasp55-deficient mice suffer from spermatogenesis defects similar to Jam-C knockout mice. However, whether Grasp55 is involved in the maintenance of immunohematopoietic homeostasis through regulation of protein transport and Jam-C expression remains unknown. In this study, we show that Grasp55 deficiency does not affect hematopoietic stem cell differentiation, engraftment, or mobilization, which are known to depend on expression of Grasp55-dependent protein cargos. In contrast, using an Myc-dependent leukemic model addicted to autophagy, we show that knockdown of Grasp55 in leukemic cells reduces spleen and bone marrow tumor burden upon i.v. leukemic engraftment. This is not due to reduced homing of Grasp55-deficient cells to these organs but to increased spontaneous apoptosis of Grasp55-deficient leukemic cells correlated with increased sensitivity of the cells to glucose deprivation. These results show that Grasp55 plays a role in Myc-transformed hematopoietic cells but not in normal hematopoietic cells in vivo.

Published
2019

41. Differential Requirement for CCR4 and CCR7 during the Development of Innate and Adaptive αβT Cells in the Adult Thymus

Author

Graham Anderson, Arnauld Sergé, William E. Jenkinson, Andrea J. White, Jennifer E. Cowan, Magali Irla, Peter J. L. Lane, Sonia M. Parnell, Nicholas I. McCarthy, Andrea Bacon, Eric J. Jenkinson, Sergé, Arnauld, Medical Research Council Centre for Immune Regulation, Institute for Biomedical Research, University of Birmingham, Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre d'Immunologie de Marseille - Luminy (CIML), and Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Receptors, CCR7, Receptors, CCR4, Regulatory T cell, Cellular differentiation, T cell, Receptors, Antigen, T-Cell, alpha-beta, [SDV]Life Sciences [q-bio], Immunology, Thymus Gland, Biology, Adaptive Immunity, T-Lymphocytes, Regulatory, Clonal deletion, Mice, T-Lymphocyte Subsets, medicine, Immunology and Allergy, Animals, Cell Lineage, ComputingMilieux_MISCELLANEOUS, Mice, Knockout, Immune System Development, FOXP3, Cell Differentiation, Epithelial Cells, Natural killer T cell, Immunity, Innate, Cell biology, Mice, Inbred C57BL, [SDV] Life Sciences [q-bio], Thymocyte, medicine.anatomical_structure, Thymocyte migration, Biomarkers
Abstract

αβT cell development depends upon serial migration of thymocyte precursors through cortical and medullary microenvironments, enabling specialized stromal cells to provide important signals at specific stages of their development. Although conventional αβT cells are subject to clonal deletion in the medulla, entry into the thymus medulla also fosters αβT cell differentiation. For example, during postnatal periods, the medulla is involved in the intrathymic generation of multiple αβT cell lineages, notably the induction of Foxp3+ regulatory T cell development and the completion of invariant NKT cell development. Although migration of conventional αβT cells to the medulla is mediated by the chemokine receptor CCR7, how other T cell subsets gain access to medullary areas during their normal development is not clear. In this study, we show that combining a panel of thymocyte maturation markers with cell surface analysis of CCR7 and CCR4 identifies distinct stages in the development of multiple αβT cell lineages in the thymus. Although Aire regulates expression of the CCR4 ligands CCL17 and CCL22, we show that CCR4 is dispensable for thymocyte migration and development in the adult thymus, demonstrating defective T cell development in Aire−/− mice is not because of a loss of CCR4-mediated migration. Moreover, we reveal that CCR7 controls the development of invariant NKT cells by enabling their access to IL-15 trans-presentation in the thymic medulla and influences the balance of early and late intrathymic stages of Foxp3+ regulatory T cell development. Collectively, our data identify novel roles for CCR7 during intrathymic T cell development, highlighting its importance in enabling multiple αβT cell lineages to access the thymic medulla.

Published
2014

42. Antigen Recognition By Autoreactive Cd4+ Thymocytes Drives Homeostasis Of The Thymic Medulla

Author

Beat A. Imhof, Lucia Guerri, Jeanne Guenot, Adrian Liston, Ed Palmer, Olivier Lantz, Arnauld Sergé, Walter Reith, Magali Irla, Sergé, Arnauld, Université de Genève = University of Geneva (UNIGE), Immunité et cancer (U932), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), and University Hospital Basel [Basel]

Subjects
Male, Anatomy and Physiology, [SDV]Life Sciences [q-bio], Immunofluorescence, CD40 Ligand/metabolism, Gene Expression, lcsh:Medicine, Autoimmunity, Adaptive Immunity, ddc:616.07, Autoantigens, Tissue Culture Techniques, Mice, 0302 clinical medicine, Immune Physiology, Homeostasis, Lymphoid Organs, lcsh:Science, Lymphotoxin-alpha, Antigens, CD40/metabolism, Mice, Knockout, 0303 health sciences, Thymocytes, Multidisciplinary, Receptor Activator of Nuclear Factor-kappa B, hemic and immune systems, Cell biology, Thymocytes/immunology/metabolism/physiology, [SDV] Life Sciences [q-bio], CD4 Antigens, Cytokines, Medicine, Female, Lymphotoxin-alpha/genetics/metabolism, Epithelial Cells/metabolism/physiology, Central tolerance, Signal transduction, Research Article, Signal Transduction, Lymphotoxin alpha, Thymus Gland/cytology/growth & development/immunology, CD40 Ligand, Immunology, Antigens, CD4/metabolism, chemical and pharmacologic phenomena, Thymus Gland, Biology, Lymphotoxin beta Receptor/metabolism, 03 medical and health sciences, Lymphotoxin beta Receptor, Autoantigens/immunology, Immune Tolerance, Animals, CD40 Antigens, Medulla, Body Patterning, Cell Proliferation, 030304 developmental biology, CD86, T-cell receptor, lcsh:R, Immunity, Epithelial Cells, Mice, Inbred C57BL, Lymphotoxin, Immune System, Immunologic Techniques, Clinical Immunology, lcsh:Q, Receptor Activator of Nuclear Factor-kappa B/metabolism, Lymphotoxin beta receptor, 030215 immunology
Abstract

International audience; The thymic medulla is dedicated for purging the T-cell receptor (TCR) repertoire of self-reactive specificities. Medullary thymic epithelial cells (mTECs) play a pivotal role in this process because they express numerous peripheral tissue-restricted self-antigens. Although it is well known that medulla formation depends on the development of single-positive (SP) thymocytes, the mechanisms underlying this requirement are incompletely understood. We demonstrate here that conventional SP CD4⁺ thymocytes bearing autoreactive TCRs drive a homeostatic process that fine-tunes medullary plasticity in adult mice by governing the expansion and patterning of the medulla. This process exhibits strict dependence on TCR-reactivity with self-antigens expressed by mTECs, as well as engagement of the CD28-CD80/CD86 costimulatory axis. These interactions induce the expression of lymphotoxin α in autoreactive CD4⁺ thymocytes and RANK in mTECs. Lymphotoxin in turn drives mTEC development in synergy with RANKL and CD40L. Our results show that Ag-dependent interactions between autoreactive CD4⁺ thymocytes and mTECs fine-tune homeostasis of the medulla by completing the signaling axes implicated in mTEC expansion and medullary organization.

Published
2012
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43. Nidogen-1 Contributes to the Interaction Network Involved in Pro-B Cell Retention in the Peri-sinusoidal Hematopoietic Stem Cell Niche.

Author

Balzano M, De Grandis M, Vu Manh TP, Chasson L, Bardin F, Farina A, Sergé A, Bidaut G, Charbord P, Hérault L, Bailly AL, Cartier-Michaud A, Boned A, Dalod M, Duprez E, Genever P, Coles M, Bajenoff M, Xerri L, Aurrand-Lions M, Schiff C, and Mancini SJC

Subjects
Animals, Hematopoietic Stem Cells cytology, Interleukin-7 genetics, Interleukin-7 immunology, Membrane Glycoproteins genetics, Mice, Mice, Knockout, Precursor Cells, B-Lymphoid cytology, Stromal Cells cytology, Stromal Cells immunology, Hematopoietic Stem Cells immunology, Membrane Glycoproteins immunology, Precursor Cells, B-Lymphoid immunology, Stem Cell Niche immunology
Abstract

In the bone marrow, CXCL12 and IL-7 are essential for B cell differentiation, whereas hematopoietic stem cell (HSC) maintenance requires SCF and CXCL12. Peri-sinusoidal stromal (PSS) cells are the main source of IL-7, but their characterization as a pro-B cell niche remains limited. Here, we characterize pro-B cell supporting stromal cells and decipher the interaction network allowing pro-B cell retention. Preferential contacts are found between pro-B cells and PSS cells, which homogeneously express HSC and B cell niche genes. Furthermore, pro-B cells are frequently located in the vicinity of HSCs in the same niche. Using an interactome bioinformatics pipeline, we identify Nidogen-1 as essential for pro-B cell retention in the peri-sinusoidal niche as confirmed in Nidogen-1 -/- mice. Finally, human pro-B cells and hematopoietic progenitors are observed close to similar IL-7 + stromal cells. Thus, a multispecific niche exists in mouse and human supporting both early progenitors and committed hematopoietic lineages., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

Published
2019
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44. Genetic, structural, and chemical insights into the dual function of GRASP55 in germ cell Golgi remodeling and JAM-C polarized localization during spermatogenesis.

Author

Cartier-Michaud A, Bailly AL, Betzi S, Shi X, Lissitzky JC, Zarubica A, Sergé A, Roche P, Lugari A, Hamon V, Bardin F, Derviaux C, Lembo F, Audebert S, Marchetto S, Durand B, Borg JP, Shi N, Morelli X, and Aurrand-Lions M

Subjects
Animals, Binding Sites, Carrier Proteins chemistry, Carrier Proteins genetics, Cells, Cultured, Golgi Apparatus ultrastructure, Intracellular Signaling Peptides and Proteins, Male, Membrane Proteins chemistry, Membrane Proteins genetics, Mice, Mice, Inbred C57BL, Protein Binding, Protein Transport, Spermatogonia cytology, Carrier Proteins metabolism, Cell Adhesion Molecules metabolism, Golgi Apparatus metabolism, Immunoglobulins metabolism, Membrane Proteins metabolism, Spermatogenesis, Spermatogonia metabolism
Abstract

Spermatogenesis is a dynamic process that is regulated by adhesive interactions between germ and Sertoli cells. Germ cells express the Junctional Adhesion Molecule-C (JAM-C, encoded by Jam3), which localizes to germ/Sertoli cell contacts. JAM-C is involved in germ cell polarity and acrosome formation. Using a proteomic approach, we demonstrated that JAM-C interacted with the Golgi reassembly stacking protein of 55 kDa (GRASP55, encoded by Gorasp2) in developing germ cells. Generation and study of Gorasp2-/- mice revealed that knock-out mice suffered from spermatogenesis defects. Acrosome formation and polarized localization of JAM-C in spermatids were altered in Gorasp2-/- mice. In addition, Golgi morphology of spermatocytes was disturbed in Gorasp2-/- mice. Crystal structures of GRASP55 in complex with JAM-C or JAM-B revealed that GRASP55 interacted via PDZ-mediated interactions with JAMs and induced a conformational change in GRASP55 with respect of its free conformation. An in silico pharmacophore approach identified a chemical compound called Graspin that inhibited PDZ-mediated interactions of GRASP55 with JAMs. Treatment of mice with Graspin hampered the polarized localization of JAM-C in spermatids, induced the premature release of spermatids and affected the Golgi morphology of meiotic spermatocytes.

Published
2017
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45. [Cellular and molecular motions: order and disorder].

Author

Sergé A and Irla M

Subjects
Algorithms, Fluorescent Dyes, Green Fluorescent Proteins, Microscopy, Fluorescence, Microscopy, Video, Quantum Dots, Receptors, Cell Surface analysis, Receptors, Cell Surface metabolism, Signal Transduction, Cell Movement
Abstract

Video-microscopy allows monitoring the dynamics of biological components, specifically labeled, usually by fluorescent tags such as GFP or quantum dots, either at the cellular or at the molecular scale. Reconstructing trajectories over time with dedicated algorithms allows to characterize on both scale different categories of movement, such as random, linear or confined, and to report events such as transient confinements among recorded species and with their environment. Single cell or molecule measurements hence provide detailed access not only to mean values of relevant descriptors, such as speed or interaction duration, but also to the exhaustive distribution of recorded values., (© 2013 médecine/sciences – Inserm / SRMS.)

Published
2013
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