Author: "Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)" / Publication Year Range: Last 50 years - Searchworks@Jio Institute Digital Library Search Results

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Start Over Author "Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)" Publication Year Range Last 50 years

31 results on '"Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)"'

1. The fully synthetic glycopeptide MAG-Tn3 therapeutic vaccine induces tumor-specific cytotoxic antibodies in breast cancer patients

Author: Cecile Artaud, Marie-Paule Sablin, Jacques Medioni, Pierre Rosenbaum, Sylvie Bay, Olivier Tredan, Christelle Ganneau, Suzette Delaloge, Delphine Loirat, Mario Campone, François Pein, Claude Leclerc, Andrea Varga, Carole Gourmelon, Régulation Immunitaire et Vaccinologie, Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris], Centre de Recherche Translationnelle - Center for Translational Science (CRT), Institut Pasteur [Paris], Chimie des Biomolécules - Chemistry of Biomolecules, Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, Institut Gustave Roussy (IGR), Pathologie mammaire, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Institut Curie [Paris], Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Centre Léon Bérard [Lyon], Département d’Innovation Thérapeutique et essais précoces [Gustave Roussy] (DITEP), The work was funded by the donors of the MAG-Tn3 program. GlaxoSmithKline Biological SA provided AS15 and preparing the final formulation of the MAG/AS15 vaccine., Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institut Pasteur [Paris] (IP), and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Cancer Research, Antibodies, Neoplasm, Tn antigen, MESH: Adjuvants, Immunologic, Epitope, MESH: Cancer Vaccines, Jurkat Cells, 0302 clinical medicine, Immunogenicity, Vaccine, Breast cancer, Cancer vaccine, MESH: Jurkat Cells, Immunology and Allergy, Medicine, MESH: Animals, MESH: Treatment Outcome, MESH: Aged, education.field_of_study, Vaccines, Synthetic, MESH: Middle Aged, biology, MESH: Antigens, Tumor-Associated, Carbohydrate, Vaccination, Glycopeptides, MESH: Immunogenicity, Vaccine, Middle Aged, QS21, MESH: Injections, Intramuscular, Glycopeptide, 3. Good health, Treatment Outcome, Oncology, Female, Antibody, MESH: Neoplasm Recurrence, Local, Adult, MESH: Vaccines, Synthetic, Immunology, Population, Breast Neoplasms, Cancer Vaccines, Injections, Intramuscular, Antibodies, 03 medical and health sciences, Immune system, Adjuvants, Immunologic, Animals, Humans, Antigens, Tumor-Associated, Carbohydrate, education, Aged, MESH: Glycopeptides, MESH: Humans, business.industry, MESH: Adult, MESH: Vaccination, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, MESH: Antibodies, Neoplasm, biology.protein, Neoplasm Recurrence, Local, business, MESH: Female, MESH: Breast Neoplasms, 030215 immunology
Abstract: International audience; Cancer is one of the main causes of mortality worldwide and a major public health concern. Among various strategies, therapeutic vaccines have been developed to stimulate anti-tumoral immune responses. However, in spite of extensive studies, this approach suffers from a lack of efficacy. Recently, we designed the MAG-Tn3 vaccine, aiming to induce antibody responses against Tn, a tumor-associated carbohydrate antigen. The Tn antigen is of interest because it is expressed by several adenocarcinomas, but not normal cells. The fully synthetic glycopeptide vaccine MAG-Tn3 is composed of four arms built on three adjacent Tn moieties associated with the tetanus toxin-derived peptide TT830-844 CD4+ T-cell epitope. This promiscuous CD4+ T-cell epitope can bind to a wide range of HLA-DRB molecules and is thus expected to activate CD4+ T-cell responses in a large part of the human population. The MAG-Tn3 vaccine was formulated with the GSK-proprietary immunostimulant AS15, composed of CpG7909, MPL, and QS21, which has been shown to stimulate both innate and humoral responses, in addition to being well tolerated. Here, seven patients with localized breast cancer with a high-risk of relapse were immunized with the MAG-Tn3 vaccine formulated with AS15. The first results of phase I clinical trial demonstrated that all vaccinated patients developed high levels of Tn-specific antibodies. Moreover, these antibodies specifically recognized Tn-expressing human tumor cells and killed them through a complement-dependent cytotoxicity mechanism. Overall, this study establishes, for the first time, the capacity of a fully synthetic glycopeptide cancer vaccine to induce specific immune responses in humans.
Published: 2020

2. IL-17 suppresses the therapeutic activity of cancer vaccines through the inhibition of CD8 + T-cell responses

Author: Marine Oberkampf, Alexandre Tang, Eirik A Torheim, Pierre Rosenbaum, Gilles Dadaglio, Claude Leclerc, Francesc Rudilla, Catherine Fayolle, Isabelle Couillin, Couillin, Isabelle, Régulation Immunitaire et Vaccinologie, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Immunologie et Neurogénétique Expérimentales et Moléculaires (INEM), Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS), Ligue Contre le Cancer, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Centre National de la Recherche Scientifique (CNRS)-Université d'Orléans (UO), and Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris]
Subjects: 0301 basic medicine, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Immunology, Melanoma, Experimental, [SDV.CAN]Life Sciences [q-bio]/Cancer, CD8-Positive T-Lymphocytes, Cancer Vaccines, Mice, 03 medical and health sciences, 0302 clinical medicine, [SDV.IMM.VAC] Life Sciences [q-bio]/Immunology/Vaccinology, Adjuvants, Immunologic, neutrophils, [SDV.CAN] Life Sciences [q-bio]/Cancer, Immunity, Neoplasms, Tumor immunity, medicine, Animals, Immunology and Allergy, Cytotoxic T cell, Th17 cells, RC254-282, Original Research, Chemistry, cytotoxic T cells, Interleukin-17, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Immunotherapy, Th1 Cells, RC581-607, 3. Good health, Mice, Inbred C57BL, [SDV] Life Sciences [q-bio], CTL, Cytolysis, IL-17, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, Systemic administration, Cancer research, Female, Interleukin 17, Immunologic diseases. Allergy, [SDV.IMM.VAC]Life Sciences [q-bio]/Immunology/Vaccinology, CD8, Research Article
Abstract: International audience; Antitumor immunity is mediated by Th1 CD4+ and CD8+ T lymphocytes, which induce tumor-specific cytolysis, whereas Th17 CD4+ T cells have been described to promote tumor growth. Here, we explored the influence of IL-17 on the ability of therapeutic vaccines to induce the rejection of tumors in mice using several adjuvants known to elicit either Th1 or Th17-type immunity. Immunization of mice with Th1-adjuvanted vaccine induced high levels of IFN-γ-producing T cells, whereas injection with Th17-promoting adjuvants triggered the stimulation of both IL-17 and IFN-γ-producing T cells. However, despite their capacity to induce strong Th1 responses, these Th17-promoting adjuvants failed to induce the eradication of tumors. In addition, the systemic administration of IL-17A strongly decreases the therapeutic effect of Th1-adjuvanted vaccines in two different tumor models. This suppressive effect correlated with the capacity of systemically delivered IL-17A to inhibit the induction of CD8+ T-cell responses. The suppressive effect of IL-17A on the induction of CD8+ T-cell responses was abolished in mice depleted of neutrophils, clearly demonstrating the role played by these cells in the inhibitory effect of IL-17A in the induction of antitumor responses. These results demonstrate that even though strong Th1-type responses favor tumor control, the simultaneous activation of Th17 cells may redirect or curtail tumor-specific immunity through a mechanism involving neutrophils. This study establishes that IL-17 plays a detrimental role in the development of an effective antitumor T cell response and thus could strongly affect the efficiency of immunotherapy through the inhibition of CTL responses.
Published: 2020

3. Design, Synthesis, and Immunological Evaluation of a Multicomponent Construct Based on a Glycotripeptoid Core Comprising B and T Cell Epitopes and a Toll-like Receptor 7 Agonist That Elicits Potent Immune Responses

Author: Aurélie Job, Richard Lo-Man, Thomas Szekely, Olivier Roy, Claude Leclerc, Claude Taillefumier, Edith Dériaud, Institut de Chimie de Clermont-Ferrand (ICCF), SIGMA Clermont (SIGMA Clermont)-Institut de Chimie du CNRS (INC)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), Régulation Immunitaire et Vaccinologie, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), This work was supported by funding from the French Ministry of Higher Education and Research (MESR to T.S.) for the chemical syntheses and by the Ligue Nationale Contre le Cancer (Equipe Labellisée 2017) to C.L. for the immunological analyses., and Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)
Subjects: Agonist, medicine.drug_class, Epitopes, T-Lymphocyte, Chemistry Techniques, Synthetic, 010402 general chemistry, 01 natural sciences, Epitope, Mice, Immune system, Adjuvanticity, Drug Discovery, medicine, Animals, [CHIM]Chemical Sciences, Amino Acid Sequence, Receptor, Toll-like receptor, biology, 010405 organic chemistry, Chemistry, TLR7, 3. Good health, 0104 chemical sciences, Mice, Inbred C57BL, Toll-Like Receptor 7, Drug Design, Immunology, biology.protein, Epitopes, B-Lymphocyte, Molecular Medicine, Peptidomimetics, Antibody
Abstract: International audience; We present here for the first time the synthesis and immunological evaluation of a fully synthetic three-component anticancer vaccine candidate that consists of a β-glycotripeptoid core mimicking a cluster of Tn at the surface of tumor cells (B epitope), conjugated to the OVA 323–339 peptide (T-cell epitope) and a Toll-like receptor 7 (TLR7) agonist for potent adjuvanticity. The immunological evaluation of this construct and of precursor components demonstrated the synergistic activity of the components within the conjugate to stimulate innate and adaptive immune cells (DCs, T-helper, and B-cells). Surprisingly, immunization of mice with the tricomponent GalNAc-based construct elicited a low level of anti-Tn IgG but elicited a very high level of antibodies that recognize the TLR7 agonist. This finding could represent a potential vaccine therapeutic approach for the treatment of some autoimmune diseases such as lupus.
Published: 2018

4. Pore‐formation by adenylate cyclase toxoid activates dendritic cells to prime CD8+and CD4+T cells

Author: Marek Kovar, Jiri Masin, Peter Sebo, Irena Adkins, Martina Svedova, Ludmila Tučková, Marina A. Freudenberg, Jakub Tomala, Radovan Fišer, Gilles Dadaglio, Ondrej Cerny, Institute of Microbiology of the ASCR, v. v. i. [Prague, Czech Republic], Charles University [Prague] (CU), Albert-Ludwigs-Universität Freiburg, Régulation Immunitaire et Vaccinologie, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), This work was supported by grants No. GA13‐14547 S (P. S.) and GAP302/12/0460 (J. M.) of the Czech Science Foundation and the RVO61388971 of the Institute of Microbiology. We thank to Prof. Stefan F. Martin, University Medical Center, Freiburg, Germany, for providing the P2X7, ASC and NLRP3 knockout mice. Martina Svedova and Ondrej Cerny are doctoral students of the Charles University in Prague, Czech Republic. Martina Svedova was a recipient of a stipend from the Ministry of Education of the Czech Republic and of the support from the Specific Research Project No. 33779266 of Charles University in Prague, Czech Republic., The authors wish to thank Sona Kozubova and Hana Lukeova for excellent technical help., and Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)
Subjects: CD4-Positive T-Lymphocytes, 0301 basic medicine, Cell Membrane Permeability, [SDV]Life Sciences [q-bio], MESH: Adjuvants, Immunologic, CD8-Positive T-Lymphocytes, Lymphocyte Activation, p38 Mitogen-Activated Protein Kinases, MESH: Cancer Vaccines, Mice, Immunology and Allergy, MESH: Animals, MESH: Cell Membrane Permeability, Cells, Cultured, MESH: Cytokines, MESH: Pore Forming Cytotoxic Proteins, MESH: Dendritic Cells, Chemistry, Toxoid, MESH: CD4-Positive T-Lymphocytes, Cell Differentiation, Inflammasome, MESH: CD8-Positive T-Lymphocytes, Cell biology, Adenylate Cyclase Toxin, Cytokines, MESH: Protein Domains, [SDV.IMM]Life Sciences [q-bio]/Immunology, MESH: Cells, Cultured, medicine.drug, Pore Forming Cytotoxic Proteins, MESH: Cell Differentiation, Immunology, Adenylate kinase, Cancer Vaccines, Cyclase, 03 medical and health sciences, Adjuvants, Immunologic, Protein Domains, MESH: Mice, Inbred C57BL, medicine, Animals, Secretion, MESH: Lymphocyte Activation, MESH: Mice, Ion Transport, Chemotaxis, Dendritic Cells, Cell Biology, cyaA, MESH: Adenylate Cyclase Toxin, Mice, Inbred C57BL, MESH: Ion Transport, MESH: p38 Mitogen-Activated Protein Kinases, 030104 developmental biology, [SDV.IMM.VAC]Life Sciences [q-bio]/Immunology/Vaccinology
Abstract: International audience; The adenylate cyclase toxin-hemolysin (CyaA) of Bordetella pertussis is a bi-functional leukotoxin. It penetrates myeloid phagocytes expressing the complement receptor 3 and delivers into their cytosol its N-terminal adenylate cyclase enzyme domain (~400 residues). In parallel, ~1300 residue-long RTX hemolysin moiety of CyaA forms cation-selective pores and permeabilizes target cell membrane for efflux of cytosolic potassium ions. The non-enzymatic CyaA-AC(-) toxoid, has repeatedly been successfully exploited as an antigen delivery tool for stimulation of adaptive T-cell immune responses. We show that the pore-forming activity confers on the CyaA-AC(-) toxoid a capacity to trigger Toll-like receptor and inflammasome signaling-independent maturation of CD11b-expressing dendritic cells (DC). The DC maturation-inducing potency of mutant toxoid variants in vitro reflected their specifically enhanced or reduced pore-forming activity and K(+) efflux. The toxoid-induced in vitro phenotypic maturation of DC involved the activity of mitogen activated protein kinases p38 and JNK and comprised increased expression of maturation markers, interleukin 6, chemokines KC and LIX and granulocyte-colony-stimulating factor secretion, prostaglandin E2 production and enhancement of chemotactic migration of DC. Moreover, i.v. injected toxoids induced maturation of splenic DC in function of their cell-permeabilizing capacity. Similarly, the capacity of DC to stimulate CD8(+) and CD4(+) T-cell responses in vitro and in vivo was dependent on the pore-forming activity of CyaA-AC(-). This reveals a novel self-adjuvanting capacity of the CyaA-AC(-) toxoid that is currently under clinical evaluation as a tool for delivery of immunotherapeutic anti-cancer CD8(+) T-cell vaccines into DC.
Published: 2015

5. Mitochondrial reactive oxygen species regulate the induction of CD8+ T cells by plasmacytoid dendritic cells

Author: Claude Leclerc, Camille Guillerey, Catherine Fayolle, Jost Enninga, Gilles Dadaglio, Marine Oberkampf, Ariel Savina, Alexandre Bobard, Sebastian Amigorena, Juliette Mouriès, Eric Ogier-Denis, Pierre Rosenbaum, Régulation Immunitaire et Vaccinologie, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Dynamique des Interactions Hôte-Pathogène - Dynamics of Host-Pathogen Interactions, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire Roche [Boulogne-Billancourt], Faculté de Médecine Xavier Bichat, Centre de recherche biomédicale Bichat-Beaujon (CRB3), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), This work was supported by the Ligue Nationale Contre le Cancer (Equipe Labellisée 2017). J.E. acknowledges funding by the ERC (Consolidator grant EndoSubvert) and the ANR (program StopBugEntry and AutoHostPath)., ANR-15-CE15-0017,StopBugEntry,Identification des nouvelles molécules cellulaires cibles pour combattre les infections bactériennes(2015), ANR-15-CE15-0018,AutoHostPath,Rôles alternatifs pour les récepteurs de l'autophagie dans les interactions hôte-pathogène(2015), European Project: 682809,EndoSubvert(2017), Dynamique des Interactions Hôte-Pathogène, Institut Pasteur [Paris], Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Curie-Université Paris Descartes - Paris 5 (UPD5), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Mitochondrial ROS, Mice, 129 Strain, Science, General Physics and Astronomy, Priming (immunology), Mice, Transgenic, macromolecular substances, Mitochondrion, CD8-Positive T-Lymphocytes, Major histocompatibility complex, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Immune system, Cross-Priming, Antigen, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], Cytotoxic T cell, Animals, Antigens, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], lcsh:Science, Cells, Cultured, Mice, Knockout, Antigen Presentation, Mice, Inbred BALB C, Multidisciplinary, biology, Chemistry, Histocompatibility Antigens Class I, hemic and immune systems, General Chemistry, Dendritic Cells, 3. Good health, Cell biology, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], Mitochondria, Mice, Inbred C57BL, 030104 developmental biology, biology.protein, lcsh:Q, Reactive Oxygen Species, CD8
Abstract: Cross-presentation allows exogenous antigen presentation in association with major histocompatibility complex class I molecules, a process crucial for the priming of CD8+ T-cell responses against viruses and tumors. By contrast to conventional dendritic cells (cDC), which cross-present antigens in the steady state, plasmacytoid dendritic cells (pDC) acquire this ability only after stimulation by Toll-like receptor (TLR) ligands. The intracellular pathways accounting for this functional difference are still unknown. Here we show that the induction of cross-presentation by pDCs is regulated by mitochondria through a reactive oxygen species (ROS)-dependent mechanism, involving pH alkalization and antigen protection. The reduction of mitochondrial ROS production dramatically decreases the cross-presentation capacity of pDCs, leading to a strong reduction of their capacity to trigger CD8+ T-cell responses. Our results demonstrate the importance of mitochondrial metabolism in pDC biology, particularly for the induction of adaptive immune responses., Cross-presentation allows exogenous antigens to be presented by the major histocompatibility I pathway. Here the authors show that the inducible cross-presentation by plasmacytoid dendritic cells is modulated by mitochondria-originated reactive oxygen species.
Published: 2018

6. Tumor-Derived TGFβ Alters the Ability of Plasmacytoid Dendritic Cells to Respond to Innate Immune Signaling

Author: Claude Leclerc, Camille Guillerey, Pierre Rosenbaum, Mariana Terra, Marine Oberkampf, Gilles Dadaglio, Catherine Fayolle, Régulation Immunitaire et Vaccinologie, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Université Paris Diderot - Paris 7 (UPD7), This work was supported by the Ligue Nationale Contre le Cancer (Equipe Labellisée 2017). The research leading to these results has received funding from the People Programme (Marie Skłodowska-Curie Actions) of the European Union's Seventh Framework Programme FP7/2007–2013/ under REA grant agreement no. 317057., European Project: 317057,EC:FP7:PEOPLE,FP7-PEOPLE-2012-ITN,HOMIN(2013), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris], Dadaglio, Gilles, Host-microbe interactions in health and disease. Interface with the immune system - HOMIN - - EC:FP7:PEOPLE2013-04-01 - 2017-03-31 - 317057 - VALID, and Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)
Subjects: 0301 basic medicine, Cancer Research, Chemokine, [SDV.CAN]Life Sciences [q-bio]/Cancer, NK cells, T-Lymphocytes, Regulatory, Mice, 03 medical and health sciences, 0302 clinical medicine, Immune system, [SDV.CAN] Life Sciences [q-bio]/Cancer, Transforming Growth Factor beta, Tumor Microenvironment, medicine, Animals, Type I interferon, Tumor microenvironment, Innate immune system, Tumor, biology, hemic and immune systems, Dendritic Cells, Tumor-Derived, medicine.disease, Phenotype, Immunity, Innate, Killer Cells, Natural, Mice, Inbred C57BL, Disease Models, Animal, 030104 developmental biology, Oncology, Plasmacytoid dendritic cells, Cancer research, biology.protein, Female, Chemokines, Transforming growth factor, Infiltration (medical), Signal Transduction, 030215 immunology
Abstract: A growing number of observations has suggested that plasmacytoid dendritic cells (pDC) play a critical role in tumor biology. In patients, infiltration of tumors by pDCs generally correlates with a poor prognosis, suggesting that pDCs may play an important role in the host–tumor relationship. Here, we analyze the influence of pDCs in solid tumor development using two different tumor models: TC-1 and B16-OVA. Phenotypic and functional gene profiling analysis of tumor-associated pDCs showed that the tumor microenvironment affected their activation status and ability to produce cytokines and chemokines. In addition, tumor cells secreted factors that inhibit the ability of pDCs to produce type I IFN. Among the various cytokines and chemokines produced by the tumor cells, we demonstrate that TGFβ is the main factor responsible for this inhibition. Using a mouse model deficient for pDCs, we also show that pDCs promote TC-1 tumor growth and that natural killer (NK) cells and regulatory T cells are involved in the protumoral effect of pDCs. Overall, our results evidence the cross-talk among pDCs, NK, and regulatory T cells in the promotion of tumor growth and their role in the development of antitumor immune responses. Significance: These findings highlight the importance of pDCs in the cross-talk between tumor cells and the immune system. Cancer Res; 78(11); 3014–26. ©2018 AACR.
Published: 2018

7. Lack of MHC class II molecules favors CD8 + T- cell infiltration into tumors associated with an increased control of tumor growth

Author: Claude Leclerc, Marine Oberkampf, Belinda Desrues, Catherine Fayolle, Alexandre Tang, Daniel Ladant, Alexander Sainz-Perez, Nada Chaoul, Régulation Immunitaire et Vaccinologie, Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris], Biochimie des Interactions Macromoléculaires / Biochemistry of Macromolecular Interactions, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Ligue Nationale Contre le Cancer (Equipe Labellisee 2017). Conseil Regional IdF / Canceropole IdF et Fondation de France., Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, lcsh:Immunologic diseases. Allergy, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Immunology, [SDV.CAN]Life Sciences [q-bio]/Cancer, lcsh:RC254-282, Immune tolerance, 03 medical and health sciences, 0302 clinical medicine, Antigen, medicine, Immunology and Allergy, Cytotoxic T cell, tumor microenvironment, Original Research, Tumor microenvironment, MHC class II, immunosuppression, biology, Effector, CD8+ T-cells, Immunotherapy, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, regulatory T-cells, 3. Good health, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, biology.protein, [SDV.IMM]Life Sciences [q-bio]/Immunology, immunotherapy, lcsh:RC581-607, CD8
Abstract: Regulatory T-cells (Tregs) are crucial for the maintenance of immune tolerance and homeostasis as well as for preventing autoimmune diseases, but their impact on the survival of cancer patients remains controversial. In the TC-1 mouse model of human papillomavirus (HPV)-related carcinoma, we have previously demonstrated that the therapeutic efficacy of the CyaA-E7-vaccine, targeting the HPV-E7 antigen, progressively declines with tumor growth, in correlation with increased intratumoral recruitment of Tregs. In the present study, we demonstrated that these TC-1 tumor-infiltrating Tregs were highly activated, with increased expression of immunosuppressive molecules. Both intratumoral effector CD4+ T-cells (Teffs) and Tregs expressed high levels of PD-1, but anti-PD-1 antibody treatment did not impact the growth of the TC-1 tumor nor restore the therapeutic effect of the CyaA-E7 vaccine. To analyze the mechanisms by which Tregs are recruited to the tumor site, we used MHC-II KO mice with drastically reduced numbers of CD4+ effector T-cells. We demonstrated that these mice still had significant numbers of Tregs in their lymphoid organs which were recruited to the tumor. In MHC-II KO mice, the growth of the TC-1 tumor was delayed in correlation with a strong increase in the intratumoral recruitment of CD8+ T-cells. In addition, in mice that spontaneously rejected their tumors, the infiltration of E7-specific CD8+ T-cells was significantly higher than in MHC-II KO mice with a growing tumor. These results demonstrate that tumor-specific CD8+ T-cells can be efficiently activated and recruited in the absence of MHC class II molecules and of CD4+ T-cell help.
Published: 2017

8. Respiratory Syncytial Virus Infects Regulatory B Cells in Human Neonates via Chemokine Receptor CX3CR1 and Promotes Lung Disease Severity

Author: Pierre Tissieres, Benoit Beitz, Jean-François Eléouët, Maryline M Ripaux-Lefevre, Delphyne Descamps, Fabrice Porcheray, Marie-Anne Rameix-Welti, Sébastien Lemoine, Nicoletta Casartelli, Jenna Fix, Richard Lo-Man, Valérie Lorin, Sabine Riffault, Ahsen Morva, Hugo Mouquet, Pierre-Louis Hervé, Françoise Mascart, Liliane Schandené, Jordi Miatello, Dania Zhivaki, Pierre-Olivier Vidalain, Edith Dériaud, Brigitte Lemercier, Xiaoming X Zhang, Olivier Schwartz, Annick Lim, Histopathologie humaine et Modèles animaux, Institut Pasteur [Paris], Université Paris Diderot - Paris 7 (UPD7), Régulation Immunitaire et Vaccinologie, Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris], Département d'Immunologie - Department of Immunology, Génomique virale et vaccination, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Immunobiology Clinic, Hôpital Erasme [Bruxelles] (ULB), Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB)-Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), Virus et Immunité - Virus and immunity, Infection et inflammation (2I), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Laboratoire de Microbiologie, Hôpital Raymond Poincareé, Unité de recherche Virologie et Immunologie Moléculaires (VIM (UR 0892)), Institut National de la Recherche Agronomique (INRA), Université Paris-Saclay, Microbiology Technology Institute, BIOASTER Microbiology Technology Institute [Lyon], School of Medicine, University of Patras [Greece], UMR9196, Physiologie et Pathologie Moléculaires des Rétrovirus Endogènes et Infectieux, Centre National de la Recherche Scientifique (CNRS), APHP, Pediatric ICU and Neonatal Medicine, Hôpitaux Universitaires Paris Sud, Réponse humorale aux pathogènes, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratory of Vaccinology and Mucosal Immunity, Université libre de Bruxelles (ULB), Institut Pasteur de Shanghai, Académie des Sciences de Chine - Chinese Academy of Sciences (IPS-CAS), Réseau International des Instituts Pasteur (RIIP), This work was supported by an ANR grant (ANR 13-BSV3-0016) and by the Fondation pour la Recherche Médicale (grant no. DEQ20120323719). This study also received funding from the French Government’s Investissement d’Avenir program, Laboratoire d’Excellence 'Integrative Biology of Emerging Infectious Diseases' (grant no. ANR-10-LABX-62-IBEID). X.Z. and S.L. were supported by ANR and by the European Commission FP7 ADITEC program (HEALTH-F4-2011-280873). X.Z. was also partially supported by the Major Basic Research Project of Shanghai Science and Technology Commission (no. 13JC1405600), National Natural Science Foundation of China (31270961, 31470879), Interdisciplinary Innovation Team and External Cooperation Program (no. GJHZ201312), and Chinese Academy of Sciences. D.Z. was supported by DIM Malinf of Region IdF. Work in the O.S. lab is also supported by ANRS, Sidaction and Fondation Areva. We acknowledge the Center for Human Immunology at Institut Pasteur for support in conducting these studies., We are very grateful to T. Domet (Therapie Cellulaire, Hopital Saint-Louis) for the cord blood sample collection and M. Lucas-Hourani for some viral preparation. We thank F. Huetz for helpful discussion about B lymphocytes., ANR-13-BSV3-0016,SyncBreg,Signature moléculaire et fonction des lymphocytes B régulateurs dans l'infection VRS(2013), ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), European Project: 280873,EC:FP7:HEALTH,FP7-HEALTH-2011-single-stage,ADITEC(2011), Institut Pasteur [Paris] (IP), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Virus et Immunité - Virus and immunity (CNRS-UMR3569), University of Patras, Physiologie et physiopathologie des rétrovirus endogènes et infectieux (RETRO-ENDO), Institut Gustave Roussy (IGR)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Hôpitaux Universitaires Paris Sud [AP-HP] (HUPS), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Hôpital Erasme, Virus et Immunité, Infection et inflammation chronique (2I), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Unité de recherche Virologie et Immunologie Moléculaires (VIM), BIOASTER, Université Libre de Bruxelles [Bruxelles] (ULB), ANR-10-LABX-62-IBEID,IBEID,Laboratoire d'Excellence 'Integrative Biology of Emerging Infectious Diseases'(2010), and University of Patras [Patras]
Subjects: CD4-Positive T-Lymphocytes, 0301 basic medicine, Enzyme-Linked Immunospot Assay, Regulatory B cells, respiratory syncytial virus, [SDV]Life Sciences [q-bio], Immunology, B-cell receptor, CX3C Chemokine Receptor 1, Enzyme-Linked Immunosorbent Assay, Respiratory Syncytial Virus Infections, Biology, Lymphocyte Activation, Article, 03 medical and health sciences, Chemokine receptor, 0302 clinical medicine, newborn, CX3CR1, medicine, Bronchiolitis, Viral, Humans, Immunology and Allergy, B cell, Oligonucleotide Array Sequence Analysis, B-Lymphocytes, Regulatory, Respiratory tract infections, Gene Expression Profiling, Infant, Newborn, medicine.disease, Virology, Respiratory Syncytial Viruses, 3. Good health, Breg cell, Interleukin 10, 030104 developmental biology, Infectious Diseases, medicine.anatomical_structure, Bronchiolitis, 030220 oncology & carcinogenesis, [SDV.IMM]Life Sciences [q-bio]/Immunology, Receptors, Chemokine, bronchiolitis, Transcriptome
Abstract: International audience; Respiratory syncytial virus (RSV) is the major cause of lower respiratory tract infections in infants and is characterized by pulmonary infiltration of B cells in fatal cases. We analyzed the B cell compartment in human newborns and identified a population of neonatal regulatory B lymphocytes (nBreg cells) that produced interleukin 10 (IL-10) in response to RSV infection. The polyreactive B cell receptor of nBreg cells interacted with RSV protein F and induced upregulation of chemokine receptor CX3CR1. CX3CR1 interacted with RSV glycoprotein G, leading to nBreg cell infection and IL-10 production that dampened T helper 1 (Th1) cytokine production. In the respiratory tract of neonates with severe RSV-induced acute bronchiolitis, RSV-infected nBreg cell frequencies correlated with increased viral load and decreased blood memory Th1 cell frequencies. Thus, the frequency of nBreg cells is predictive of the severity of acute bronchiolitis disease and nBreg cell activity may constitute an early-life host response that favors microbial pathogenesis.
Published: 2017

9. Corrigendum: A Universal Influenza Vaccine Can Lead to Disease Exacerbation or Viral Control Depending on Delivery Strategies

Author: Cindy Bernelin-Cottet, Charlotte Deloizy, Ondrej Stanek, Céline Barc, Edwige Bouguyon, Céline Urien, Olivier Boulesteix, Jérémy Pezant, Charles-Adrien Richard, Mohammed Moudjou, Bruno Da Costa, Luc Jouneau, Christophe Chevalier, Claude Leclerc, Peter Sebo, Nicolas Bertho, Isabelle Schwartz-Cornil, Unité de recherche Virologie et Immunologie Moléculaires (VIM (UR 0892)), Institut National de la Recherche Agronomique (INRA), Institute of Microbiology, Czech Academy of Sciences [Prague] (CAS), Plateforme d'Infectiologie Expérimentale (PFIE), Régulation Immunitaire et Vaccinologie, Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris], Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), ProdInra, Migration, and Schwartz-Cornil, Isabelle
Subjects: lcsh:Immunologic diseases. Allergy, vaccin, Immunology, 02 engineering and technology, 01 natural sciences, adjuvant, 0103 physical sciences, Immunology and Allergy, human, dendritic cells, routes of administration, swine, vaccines, mode d'administration, [SDV.BA.MVSA]Life Sciences [q-bio]/Animal biology/Veterinary medicine and animal Health, 010304 chemical physics, [SDV.BA.MVSA] Life Sciences [q-bio]/Animal biology/Veterinary medicine and animal Health, 021001 nanoscience & nanotechnology, 3. Good health, Médecine vétérinaire et santé animal, Veterinary medicine and animal Health, humain, influenza, 0210 nano-technology, lcsh:RC581-607, porc
Abstract: [This corrects the article on p. 641 in vol. 7, PMID: 28082980.].; International audience; [This corrects the article on p. 641 in vol. 7, PMID: 28082980.].
Published: 2017

10. Colonization with Helicobacter is concomitant with modified gut microbiota and drastic failure of the immune control of Mycobacterium tuberculosis

Author: Marco Severgnini, Clelia Peano, Jean-François Bureau, Valérie Michel, Roland Brosch, Laleh Majlessi, C. Consolandi, Alexandre Pawlik, Michel Huerre, Fadel Sayes, Claude Leclerc, Grégory Jouvion, Eliette Touati, Pathogénomique mycobactérienne intégrée, Institut Pasteur [Paris] (IP), Régulation Immunitaire et Vaccinologie, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Génétique fonctionnelle des Maladies infectieuses - Functional Genetics of Infectious Diseases, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Pathogenèse de Helicobacter, Histopathologie humaine et Modèles animaux, Histotechnologie et Pathologie, Institut Curie [Paris], Istituto di Tecnologie Biomediche [Segrate] (ITB), National Research Council of Italy | Consiglio Nazionale delle Ricerche (CNR), This work was supported by grants from Institut Pasteur and by the European Union’s Seventh Framework Program (280873 ADITEC, to CL). FS was supported by the University of Damas, Syria and the Programme Transversal de Recherche (No. 441) from Institut Pasteur. RB acknowledges support from the Fondation pour la Recherche Medicale (DEQ20130326471)., European Project: 280873,EC:FP7:HEALTH,FP7-HEALTH-2011-single-stage,ADITEC(2011), Touati, Eliette, Advanced Immunization Technologies - ADITEC - - EC:FP7:HEALTH2011-10-01 - 2016-09-30 - 280873 - VALID, Consiglio Nazionale delle Ricerche [Roma] (CNR), Institut Pasteur [Paris], Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris], and Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Tuberculosis, T-Lymphocytes, 030106 microbiology, Immunology, Gut flora, Lung injury, Lymphocyte Activation, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, Helicobacter Infections, Microbiology, Mycobacterium tuberculosis, Mice, 03 medical and health sciences, Immune system, mucosal immunology, medicine, Animals, Humans, Immunology and Allergy, Colonization, Helicobacter, Lung, [SDV.IMM.II] Life Sciences [q-bio]/Immunology/Innate immunity, Inflammation, biology, biology.organism_classification, medicine.disease, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Bacterial Load, Gastrointestinal Microbiome, 3. Good health, Mice, Inbred C57BL, 030104 developmental biology, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, [SDV.IMM.IA] Life Sciences [q-bio]/Immunology/Adaptive immunology, Host-Pathogen Interactions, Helicobacter hepaticus, [SDV.MP.BAC] Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology
Abstract: International audience; Epidemiological and experimental observations suggest that chronic microbial colonization can impact the immune control of other unrelated pathogens contracted in a concomitant or sequential manner. Possible interactions between Mycobacterium tuberculosis infection and persistence of other bacteria have scarcely been investigated. Here we demonstrated that natural colonization of the digestive tract with Helicobacter hepaticus in mice is concomitant with modification of the gut microbiota, subclinical inflammation, and drastic impairment of immune control of the growth of subsequently administered M. tuberculosis, which results in severe lung tissue injury. Our results provided insights upon the fact that this prior H. hepaticus colonization leads to failures in the mechanisms that could prevent the otherwise balanced cross-talk between M. tuberculosis and the immune system. Such disequilibrium ultimately leads to the inhibition of control of mycobacterial growth, outbreak of inflammation, and lung pathology. Among the dysregulated immune signatures, we noticed a correlation between the detrimental lung injury and the accumulation of activated T-lymphocytes. Our findings suggest that the impact of prior Helicobacter spp. colonization and subsequent M. tuberculosis parasitism might be greater than previously thought, which is a key point given that both species are among the most frequent invasive bacteria in human populations.
Published: 2017

11. Genomic analysis of smooth tubercle bacilli provides insights into ancestry and pathoadaptation of Mycobacterium tuberculosis

Author: Wafa Frigui, Fadel Sayes, Camille Locht, Gregory Salvignol, Varun Khanna, Eve Willery, Danielle Walker, Anne-Sophie Debrie, Philip Supply, Michael Marceau, Timothy P. Stinear, Alessandro Cascioferro, Roland Brosch, Sylvain Brisse, Michael A. Quail, Stephen D. Bentley, Michel Fabre, Sophie Mangenot, Laurence Fiette, Claudine Médigue, Stéphane Cruveiller, Carine Rouanet, Claude Leclerc, Alexandre Pawlik, Julien Tap, Torsten Seemann, Laleh Majlessi, Christiane Bouchier, Roxane Simeone, Laurence Ma, David Roche, Cecile Parmentier, Valérie Barbe, Mickael Orgeur, Julian Parkhill, Eva C. Boritsch, Alexis Criscuolo, Maria-Cristina Gutierrez, Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Génomique métabolique (UMR 8030), Genoscope - Centre national de séquençage [Evry] (GENOSCOPE), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université d'Évry-Val-d'Essonne (UEVE)-Centre National de la Recherche Scientifique (CNRS), Pathogénomique mycobactérienne intégrée, Institut Pasteur [Paris] (IP), Régulation Immunitaire et Vaccinologie, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Génotypage des Pathogènes et Santé Publique (Plate-forme) (PF8), Histopathologie humaine et Modèles animaux, Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), HIA Percy, Mécanismes moléculaires de la pathogénie microbienne, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM), The Wellcome Trust Sanger Institute [Cambridge], Génomique (Plate-Forme) - Genomics Platform, Victorian Bioinformatics Consortium [Clayton], Monash University [Clayton], Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Mécanismes moléculaires de la pathogenèse bactérienne, Département Infection et Epidémiologie - Department of Infection and Epidemiology, University of Melbourne, The work was supported in part by the Institut Pasteur (PTR 314 and PTR 383), European Community's Framework Programme 7 grant 260872, Wellcome Trust grant 098051 and Genoscope collaborative grant 114., European Project: 260872,EC:FP7:HEALTH,FP7-HEALTH-2010-single-stage,MM4TB(2011), Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université d'Évry-Val-d'Essonne (UEVE), Institut Pasteur [Paris], and Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)
Subjects: MESH: Sequence Analysis, DNA, MESH: Mycobacterium tuberculosis, Tuberculosis, MESH: Spleen, [SDV]Life Sciences [q-bio], MESH: Mice, Inbred BALB C, Virulence, Genomics, MESH: Virulence, MESH: Base Sequence, MESH: Genome, Bacterial, Genome, DNA sequencing, Mycobacterium tuberculosis, 03 medical and health sciences, Genetic variation, Genetics, medicine, MESH: Species Specificity, MESH: Animals, MESH: Lung, MESH: Mice, 030304 developmental biology, 0303 health sciences, MESH: Molecular Sequence Data, biology, 030306 microbiology, MESH: Adaptation, Biological, MESH: Genomics, MESH: Polymorphism, Single Nucleotide, biology.organism_classification, medicine.disease, MESH: Cluster Analysis, 3. Good health, MESH: Inverted Repeat Sequences, Mycobacterium
Abstract: International audience; Global spread and limited genetic variation are hallmarks of M. tuberculosis, the agent of human tuberculosis. In contrast, Mycobacterium canettii and related tubercle bacilli that also cause human tuberculosis and exhibit unusual smooth colony morphology are restricted to East Africa. Here, we sequenced and analyzed the whole genomes of five representative strains of smooth tubercle bacilli (STB) using Sanger (4-5× coverage), 454/Roche (13-18× coverage) and/or Illumina DNA sequencing (45-105× coverage). We show that STB isolates are highly recombinogenic and evolutionarily early branching, with larger genome sizes, higher rates of genetic variation, fewer molecular scars and distinct CRISPR-Cas systems relative to M. tuberculosis. Despite the differences, all tuberculosis-causing mycobacteria share a highly conserved core genome. Mouse infection experiments showed that STB strains are less persistent and virulent than M. tuberculosis. We conclude that M. tuberculosis emerged from an ancestral STB-like pool of mycobacteria by gain of persistence and virulence mechanisms, and we provide insights into the molecular events involved.
Published: 2013

12. B cells promote tumor progression in a mouse model of HPV-mediated cervical cancer

Author: Alexandre, Tang, Gilles, Dadaglio, Marine, Oberkampf, Selene, Di Carlo, Lucie, Peduto, Daphné, Laubreton, Belinda, Desrues, Cheng-Ming, Sun, Xavier, Montagutelli, Claude, Leclerc, Régulation Immunitaire et Vaccinologie, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Cellule Pasteur, Université Paris Diderot - Paris 7 (UPD7)-PRES Sorbonne Paris Cité, Microenvironnement et Immunité - Microenvironment and Immunity, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique fonctionnelle de la Souris, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Ligue Nationale Contre le Cancer (Equipe Labellisée 2014), Conseil Régional IdF/Cancéropôle IdF, Banque Privée Européenne, Fondation ARC pour la Recherche sur le Cancer (to A.T.), We gratefully acknowledge Ruben Leandro Batista for his excellent assistance in defining the impact of the SNPs on gene expression., Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Dadaglio, Gilles, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris]
Subjects: MESH: Interleukin-10, B-Lymphocyte Subsets, Uterine Cervical Neoplasms, MESH: Lymph Nodes, [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH: T-Lymphocyte Subsets, Lymphocyte Activation, MESH: Papillomavirus Infections, MESH: Phenotype, Polymorphism, Single Nucleotide, Mice, [SDV.CAN] Life Sciences [q-bio]/Cancer, MESH: Papillomaviridae, Cell Movement, T-Lymphocyte Subsets, MESH: B-Lymphocytes, Animals, tumor microenvironment, MESH: Animals, MESH: Lymphocyte Activation, Papillomaviridae, MESH: Mice, MESH: Cell Movement, B-Lymphocytes, B cells, MESH: Toll-Like Receptor 9, immunosuppression, MESH: Polymorphism, Single Nucleotide, Papillomavirus Infections, Interleukin-10, MESH: Uterine Cervical Neoplasms, Disease Models, Animal, Phenotype, Toll-Like Receptor 9, MESH: Genome-Wide Association Study, Disease Progression, Female, MESH: Disease Progression, Lymph Nodes, MESH: B-Lymphocyte Subsets, MESH: Disease Models, Animal, MESH: Female, Genome-Wide Association Study
Abstract: International audience; Enhancing anti-tumor immunity and preventing tumor escape are efficient strategies to increase the efficacy of therapeutic cancer vaccines. However, the treatment of advanced tumors remains difficult, mainly due to the immunosuppressive tumor microenvironment. Regulatory T cells and myeloid-derived suppressor cells have been extensively studied, and their role in suppressing tumor immunity is now well established. In contrast, the role of B lymphocytes in tumor immunity remains unclear because B cells can promote tumor immunity or display regulatory functions to control excessive inflammation, mainly through IL-10 secretion. Here, in a mouse model of HPV-related cancer, we demonstrate that B cells accumulated in the draining lymph node of tumor-bearing mice, due to a prolonged survival, and showed a decreased expression of MHC class II and CD86 molecules and an increased expression of Ly6A/E, PD-L1 and CD39, suggesting potential immunoregulatory properties. However, B cells from tumor-bearing mice did not show an increased ability to secrete IL-10 and a deficiency in IL-10 production did not impair tumor growth. In contrast, in B cell-deficient μMT mice, tumor rejection occurred due to a strong T cell-dependent anti-tumor response. Genetic analysis based on single nucleotide polymorphisms identified genetic variants associated with tumor rejection in μMT mice, which could potentially affect reactive oxygen species production and NK cell activity. Our results demonstrate that B cells play a detrimental role in anti-tumor immunity and suggest that targeting B cells could enhance the anti-tumor response and improve the efficacy of therapeutic cancer vaccines.
Published: 2016

13. CD4+ T Cells Recognizing PE/PPE Antigens Directly or via Cross Reactivity Are Protective against Pulmonary Mycobacterium tuberculosis Infection

Author: Daria Bottai, Roland Brosch, Wafa Frigui, Fadel Sayes, Claude Leclerc, Catherine Fayolle, Alexandre Pawlik, Felipe Cia, Laleh Majlessi, Gregory J. Bancroft, Matthias I. Gröschel, Samuel Crommelynck, Pathogénomique mycobactérienne intégrée - Integrated Mycobacterial Pathogenomics, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Régulation Immunitaire et Vaccinologie, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), London School of Hygiene and Tropical Medicine (LSHTM), University of Pisa - Università di Pisa, This work was supported by grants from DARRI (Direction des Applications de la Recherche et des Relations Industrielles, Institut Pasteur) #2012/1 and PTR (Programme Transversal de Recherche, Institut Pasteur) #441 to LM. FS has been supported by the University of Damascus, Syria. Support by the European Community (Grant H2020-PHC-643381), the Fondation pour la Recherche Médicale FRM (DEQ 20130326471) and TBVAC2020 to RB, and TBVAC2020 to FC is gratefully acknowledged., European Project: 643381,H2020,H2020-PHC-2014-single-stage,TBVAC2020(2015), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), SAYES, FADEL, TBVAC2020, and Advancing novel and promising TB vaccine candidates from discovery to preclinical and early clinical development - TBVAC2020 - - H20202015-01-01 - 2018-12-31 - 643381 - VALID
Subjects: MESH: Mycobacterium tuberculosis, MESH: Flow Cytometry, PE/PPE proteins, Biochemistry, Epitope, Inflammasome, Cell-Mediated Immunity, mouse model of tuberculosis infection, Epitopes, Mice, Animal Cells, CD4+ Th1 cells, EspC, MESH: Animals, Public and Occupational Health, lcsh:QH301-705.5, MESH: Bacterial Proteins, Immune Response, Attenuated vaccine, Effector, Flow Cytometry, 3. Good health, [SDV] Life Sciences [q-bio], Actinobacteria, IL-17, aerosol challenge, live-attenuated vaccine candidate, T-cell activation and recruitment, Mycobacterium tuberculosis, prime-boost, cytokines, T-cell activation markers, intracellular staining, pulmonary tuberculosis, cross-reactivity, antigenic repertoire, T-cell immunogenicity, sequence homology, type seven secretion systems, T7SS, ESX-1, ESX-5, ESAT-6, CFP-10, EccD5, Peptide, IFN-gamma, TNF-alpha, IL-2, phagosomal rupture, CpG, DOTAP, Protection, Type I IFN, cGas, STING, CCF-4, IL-1 beta, adjuvant, sub-unit vaccine, protector antigen, immunogen, T-cell subset, Cellular Types, Immune Cells, 030106 microbiology, Immunology, Cross Reactions, Microbiology, 03 medical and health sciences, Antigen, Bacterial Proteins, Genetics, T Helper Cells, Molecular Biology, Tuberculosis, Pulmonary, MESH: Tuberculosis, Pulmonary, Blood Cells, Bacteria, Organisms, Immunity, Biology and Life Sciences, Proteins, Mice, Inbred C57BL, 030104 developmental biology, MESH: Th1 Cells, Parasitology, Preventive Medicine, MESH: Disease Models, Animal, lcsh:RC581-607, MESH: Female, Developmental Biology, 0301 basic medicine, CD4-Positive T-Lymphocytes, Immunogen, Physiology, [SDV]Life Sciences [q-bio], MESH: Cross Reactions, White Blood Cells, Immune Physiology, Medicine and Health Sciences, Tuberculosis Vaccines, Vaccines, Immune System Proteins, T Cells, MESH: CD4-Positive T-Lymphocytes, Cell Differentiation, Vaccination and Immunization, Female, Research Article, lcsh:Immunologic diseases. Allergy, Attenuated Vaccines, chemical and pharmacologic phenomena, Biology, Immune system, MESH: Mice, Inbred C57BL, Virology, Animals, Antigens, MESH: Mice, Antigens, Bacterial, Innate immune system, Cell Biology, Th1 Cells, MESH: Tuberculosis Vaccines, Disease Models, Animal, lcsh:Biology (General), MESH: Antigens, Bacterial
Abstract: Mycobacterium tuberculosis (Mtb), possesses at least three type VII secretion systems, ESX-1, -3 and -5 that are actively involved in pathogenesis and host-pathogen interaction. We recently showed that an attenuated Mtb vaccine candidate (Mtb Δppe25-pe19), which lacks the characteristic ESX-5-associated pe/ppe genes, but harbors all other components of the ESX-5 system, induces CD4+ T-cell immune responses against non-esx-5-associated PE/PPE protein homologs. These T cells strongly cross-recognize the missing esx-5-associated PE/PPE proteins. Here, we characterized the fine composition of the functional cross-reactive Th1 effector subsets specific to the shared PE/PPE epitopes in mice immunized with the Mtb Δppe25-pe19 vaccine candidate. We provide evidence that the Mtb Δppe25-pe19 strain, despite its significant attenuation, is comparable to the WT Mtb strain with regard to: (i) its antigenic repertoire related to the different ESX systems, (ii) the induced Th1 effector subset composition, (iii) the differentiation status of the Th1 cells induced, and (iv) its particular features at stimulating the innate immune response. Indeed, we found significant contribution of PE/PPE-specific Th1 effector cells in the protective immunity against pulmonary Mtb infection. These results offer detailed insights into the immune mechanisms underlying the remarkable protective efficacy of the live attenuated Mtb Δppe25-pe19 vaccine candidate, as well as the specific potential of PE/PPE proteins as protective immunogens., Author Summary Mycobacterium tuberculosis (Mtb), the causative agent of human tuberculosis, is one of the most widely spread human pathogens, responsible for more than 9.6 million of new tuberculosis cases and 1.5 million deaths, annually. The resurgence of pulmonary tuberculosis in immuno-compromised patients, including HIV-co-infected populations, and increasing spread of drug-resistant Mtb strains are worrying. Given the estimated 2 billion cases of latent Mtb infections and the only partial efficacy of the unique, currently available tuberculosis-vaccine Mycobacterium bovis BCG (Bacille Calmette-Guerin) it is necessary to develop improved vaccines. Here, we demonstrate that the host cellular immunity, mediated by CD4+ T lymphocytes, specific to the “PE/PPE” families of mycobacterial antigens, contribute to the protection against Mtb-induced disease. We revealed the fine composition of the PE/PPE-specific T cells by characterizing their effector functions and differentiation status. We previously described a live attenuated mycobacterial strain as a vaccine candidate that is able to induce such CD4+ T cells and which displays particular properties at stimulating the cells of the innate immune system. These responses play a central role in the initiation of the host defense and in the protection against tuberculosis. Our results pave the way for further development of candidates in preclinical models of anti-tuberculosis vaccination.
Published: 2016

14. The fully synthetic MAG-Tn3 therapeutic vaccine containing the tetanus toxoid-derived TT830-844 universal epitope provides anti-tumor immunity

Author: Claude Leclerc, Christine Sedlik, Sylvie Bay, Sebastian Amigorena, Christelle Ganneau, Richard Lo-Man, Cecile Artaud, Anne-Laure Puaux, Catherine Gérard, Edith Dériaud, Sophie Viel, Daphné Laubreton, Régulation Immunitaire et Vaccinologie, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Chimie des biomolécules, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Pôle Intégré de Recherche Clinique (PIRC), Institut Pasteur [Paris] (IP), GSK Vaccines - Belgium, Laboratoire de Mathématiques d'Orsay (LM-Orsay), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), The work was funded by the Ligue Nationale Contre le Cancer (Equipe Labellisée 2014), the Banque Privée Européenne, the European Union’s Seventh Framework Programme under Grant Agreement No: 280873 ADITEC and the donors of the MAG-Tn3 program. The authors thank the PIRC (Pôle Integré de Recherche Clinique, Institut Pasteur, Paris, France) for their help in the organization of experiments on cynomolgus monkeys. The authors thank Nancy Dezutter, Valentine Wascotte and David Bouffard for developing the MAG-Tn3 formulation and for discussions, European Project: 280873,EC:FP7:HEALTH,FP7-HEALTH-2011-single-stage,ADITEC(2011), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris], Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris], Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11), RIBIERRE, Helene, and Advanced Immunization Technologies - ADITEC - - EC:FP7:HEALTH2011-10-01 - 2016-09-30 - 280873 - VALID
Subjects: 0301 basic medicine, CD4-Positive T-Lymphocytes, Cancer Research, [SDV]Life Sciences [q-bio], Tn antigen, Epitopes, T-Lymphocyte, MESH: Amino Acid Sequence, Epitope, MESH: Cancer Vaccines, Mice, 0302 clinical medicine, MESH: Tetanus Toxoid, Tetanus Toxoid, Immunology and Allergy, MESH: Animals, MESH: Peptide Fragments, MESH: HLA-DRB1 Chains, Universal epitope, education.field_of_study, Vaccines, Synthetic, MESH: Antigens, Tumor-Associated, Carbohydrate, Vaccination, Toxoid, MESH: CD4-Positive T-Lymphocytes, MAG-Tn3, 3. Good health, [SDV] Life Sciences [q-bio], Myelin-Associated Glycoprotein, medicine.anatomical_structure, Oncology, Antibody response, Female, Original Article, Synthetic vaccine, MESH: Vaccines, Synthetic, T cell, Population, Molecular Sequence Data, Immunology, Mice, Inbred Strains, Anticancer vaccine, Biology, Cancer Vaccines, MESH: Mice, Inbred Strains, MESH: H-2 Antigens, MESH: Epitopes, T-Lymphocyte, 03 medical and health sciences, Antigen, medicine, Animals, Humans, Antigens, Tumor-Associated, Carbohydrate, Amino Acid Sequence, education, MESH: Myelin-Associated Glycoprotein, MESH: Mice, MESH: Humans, MESH: Molecular Sequence Data, H-2 Antigens, MESH: Vaccination, MESH: Haplotypes, Peptide Fragments, Macaca fascicularis, 030104 developmental biology, Haplotypes, MESH: Macaca fascicularis, MESH: Female, 030215 immunology, HLA-DRB1 Chains, TT830-844
Abstract: Malignant transformations are often associated with aberrant glycosylation processes that lead to the expression of new carbohydrate antigens at the surface of tumor cells. Of these carbohydrate antigens, the Tn antigen is particularly highly expressed in many carcinomas, especially in breast carcinoma. We designed MAG-Tn3, a fully synthetic vaccine based on three consecutive Tn moieties that are O-linked to a CD4+ T cell epitope, to induce anti-Tn antibody responses that could be helpful for therapeutic vaccination against cancer. To ensure broad coverage within the human population, the tetanus toxoid-derived peptide TT830-844 was selected as a T-helper epitope because it can bind to various HLA-DRB molecules. We showed that the MAG-Tn3 vaccine, which was formulated with the GSK proprietary immunostimulant AS15 and designed for human cancer therapy, is able to induce an anti-Tn antibody response in mice of various H-2 haplotypes, and this response correlates with the ability to induce a specific T cell response against the TT830-844 peptide. The universality of the TT830-844 peptide was extended to new H-2 and HLA-DRB molecules that were capable of binding this T cell epitope. Finally, the MAG-Tn3 vaccine was able to induce anti-Tn antibody responses in cynomolgus monkeys, which targeted Tn-expressing tumor cells and mediated tumor cell death both in vitro and in vivo. Thus, MAG-Tn3 is a highly promising anticancer vaccine that is currently under evaluation in a phase I clinical trial. Electronic supplementary material The online version of this article (doi:10.1007/s00262-016-1802-0) contains supplementary material, which is available to authorized users.
Published: 2016

15. A Universal Influenza Vaccine Can Lead to Disease Exacerbation or Viral Control Depending on Delivery Strategies

Author: Olivier Boulesteix, Peter Sebo, Isabelle Schwartz-Cornil, Bruno Da Costa, Claude Leclerc, Ondrej Stanek, Cindy Bernelin-Cottet, Luc Jouneau, Charles-Adrien Richard, Edwige Bouguyon, Charlotte Deloizy, Céline Barc, Nicolas Bertho, Christophe Chevalier, Jérémy Pezant, Mohammed Moudjou, Céline Urien, Unité de recherche Virologie et Immunologie Moléculaires (VIM (UR 0892)), Institut National de la Recherche Agronomique (INRA), Institute of Microbiology, Czech Academy of Sciences [Prague] (CAS), Plateforme d'Infectiologie Expérimentale (PFIE), Régulation Immunitaire et Vaccinologie, Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris], Agence National de la Recherche grant DCskin-VacFlu, ANR 2011-ISV3-001-01 (CD, EB, NB, IS-C) - grants M200201213 of the CAS (PS) - TA03010331 of TACR (PS) - QJ1210041 of MZe (OS) of the Czech Republic., Schwartz-Cornil, Isabelle, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), and ProdInra, Archive Ouverte
Subjects: 0301 basic medicine, vaccin, [SDV.IMM] Life Sciences [q-bio]/Immunology, Influenza vaccine, medicine.drug_class, Immunology, Biology, medicine.disease_cause, Monoclonal antibody, interdigitating cell, 03 medical and health sciences, [SDV.IMM.VAC] Life Sciences [q-bio]/Immunology/Vaccinology, 0302 clinical medicine, Antigen, Immunity, vaccine, Immunologie, Influenza A virus, medicine, Immunology and Allergy, dendritic cells, human, Viral shedding, Original Research, mode d'administration, [SDV.BA.MVSA]Life Sciences [q-bio]/Animal biology/Veterinary medicine and animal Health, [SDV.BA.MVSA] Life Sciences [q-bio]/Animal biology/Veterinary medicine and animal Health, Correction, human influenza, swine, Dendritic cell, routes of administration, vaccines, Virology, 3. Good health, Vaccination, Vaccinology, 030104 developmental biology, Médecine vétérinaire et santé animal, Vaccinologie, influenza, [SDV.IMM]Life Sciences [q-bio]/Immunology, Veterinary medicine and animal Health, cellule dendritique, [SDV.IMM.VAC]Life Sciences [q-bio]/Immunology/Vaccinology, 030215 immunology, porc
Abstract: Corrigendum dans Front Immunol. 2017; 8: 831. The Supplementary Material for this article can be found online at http://journal.frontiersin.org/article/10.3389/fimmu.2016.00641/full#supplementary-material; The development of influenza A virus (IAV) vaccines, which elicits cross-strain immunity against seasonal and pandemic viruses is a major public health goal. As pigs are susceptible to human, avian, and swine-adapted IAV, they would be key targets of so called universal IAV vaccines, for reducing both the zoonotic risk and the economic burden in the swine industry. They also are relevant preclinical models. However, vaccination with conserved IAV antigens (AGs) in pigs was reported to elicit disease exacerbation. In this study, we assessed whether delivery strategies, i.e., dendritic cell (DC) targeting by the intradermal (ID) or intramuscular (IM) routes, impact on the outcome of the vaccination with three conserved IAV AGs (M2e, NP, and HA2) in pigs. The AGs were addressed to CD11c by non-covalent binding to biotinylated anti-CD11c monoclonal antibody. The CD11c-targeted AGs given by the ID route exacerbated disease. Conversely, CD11c-targeted NP injected by the IM route promoted T cell response compared to non-targeted NP. Furthermore, the conserved IAV AGs injected by the IM route, independently of DC targeting, induced both a reduction of viral shedding and a broader IgG response as compared to the ID route. Our findings highlight in a relevant animal species that the route of vaccine delivery impacts on the protection induced by conserved IAV AGs and on vaccine adverse effects. Finally, our results indicate that HA2 stands as the most promising conserved IAV AG for universal vaccine development.
Published: 2016

16. Strong Immunogenicity and Cross-Reactivity of Mycobacterium tuberculosis ESX-5 Type VII Secretion -Encoded PE-PPE Proteins Predicts Vaccine Potential

Author: Claude Leclerc, Lin Sun, Fadel Sayes, Daria Bottai, Nathalie Degaiffier, Roland Brosch, Semih Esin, Mariagrazia Di Luca, Laleh Majlessi, Laurence Fiette, Roxane Simeone, Régulation Immunitaire et Vaccinologie, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Dipartimento di Patologia Sperimentale Biotecnologie Mediche Infettivologia ed Epidemiologia, University of Pisa - Università di Pisa, Pathogénomique mycobactérienne intégrée, Institut Pasteur [Paris], Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Histopathologie humaine et Modèles animaux, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano = University of Milan (UNIMI), European Project: 201762,EC:FP7:HEALTH,FP7-HEALTH-2007-A,NOVSEC-TB(2008), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institut Pasteur [Paris] (IP), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris], and Università degli Studi di Milano [Milano] (UNIMI)
Subjects: Cancer Research, Amino Acid Motifs, Molecular Sequence Data, Virulence, Mice, SCID, Cross Reactions, Biology, Microbiology, Epitope, Mycobacterium tuberculosis, Mice, 03 medical and health sciences, Bacterial Proteins, Virology, Immunology and Microbiology(all), Antigenic variation, Animals, Humans, Tuberculosis, Secretion, Amino Acid Sequence, Tuberculosis Vaccines, Bacterial Secretion Systems, Molecular Biology, 030304 developmental biology, Mice, Inbred BALB C, 0303 health sciences, 030306 microbiology, Immunogenicity, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, biology.organism_classification, Antibodies, Bacterial, Antigenic Variation, Transmembrane protein, 3. Good health, Mice, Inbred C57BL, Protein Transport, Female, Parasitology, [SDV.IMM.VAC]Life Sciences [q-bio]/Immunology/Vaccinology, Tuberculosis vaccines
Abstract: International audience; The genome of Mycobacterium tuberculosis (Mtb) encodes five type VII secretion systems, ESX-1 to ESX-5, most of which are associated with genes encoding PE/PPE proteins, named after their N-terminal Pro-Glu (PE) or Pro-Pro-Glu (PPE) motifs. Here, we describe the strong T cell immunogenicity of the ESX-5-encoded PE/PPE proteins, which share a large panel of cross-reactive CD4(+) epitopes with substantial numbers of their ESX-5-nonassociated PE/PPE homologs. The immunogenicity of these numerous PE/PPE proteins is dependent on their export by a functional EccD(5), the predicted transmembrane channel of the ESX-5 secretion apparatus. The Mtb Δppe25-pe19 mutant deleted for all ESX-5-associated pe and ppe genes, although highly attenuated in immunocompetent mice, remains able to induce immunity against the ESX-5-associated PE/PPE virulence factors, via cross-reactivity with their numerous homologs, and against the ESX-1 virulence factors ESAT-6/CFP-10. The Δppe25-pe19 strain is strongly protective against Mtb infection in mice and represents a potential antituberculosis vaccine candidate.
Published: 2012
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17. Dectin-1 activation unlocks IL12A expression and reveals the TH1 potency of neonatal dendritic cells

Author: Barbara Jaron, Dania Zhivaki, Odile Launay, Pierre Tissieres, Sabrine Tabka, Richard Lo-Man, Chourouk Ettreiki, Claude Leclerc, Sébastien Lemoine, Edith Dériaud, Laleh Majlessi, Camille Le Ray, Régulation Immunitaire et Vaccinologie, Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris], Service de Réanimation Pédiatrique et Médecine Néonatale, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Institut de génétique et microbiologie [Orsay] (IGM), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Service de Gynécologie-Obstétrique de Port-Royal, Université Paris Descartes - Paris 5 (UPD5), CIC Cochin Pasteur (CIC 1417), Institut National de la Santé et de la Recherche Médicale (INSERM)-Groupe hospitalier Broca-Université Paris Descartes - Paris 5 (UPD5)-Hôtel-Dieu-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Pathogénomique mycobactérienne intégrée, Institut Pasteur [Paris], Institut Pasteur [Paris] - Institut National de la Santé et de la Recherche Médicale (INSERM) - Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Assistance publique - Hôpitaux de Paris (AP-HP) - AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Université Paris-Sud - Paris 11 (UP11) - Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) - CHU Cochin [AP-HP] - Hôtel-Dieu - Université Paris Descartes - Paris 5 (UPD5) - Groupe hospitalier Broca - Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôtel-Dieu-Université Paris Descartes - Paris 5 (UPD5)-Groupe hospitalier Broca-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institut Pasteur [Paris] (IP), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), and Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Cochin [AP-HP]-Hôtel-Dieu-Université Paris Descartes - Paris 5 (UPD5)-Groupe hospitalier Broca-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Agonist, medicine.drug_class, C-type lectin receptor, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Immunology, Syk, Plasmacytoid dendritic cell, Biology, Interleukin-12 Subunit p35, Monocytes, Mice, Th2 Cells, T(H)1, Adjuvants, Immunologic, adjuvant, Toll-like receptor, medicine, Immunology and Allergy, Animals, Humans, Lectins, C-Type, dendritic cells, Receptor, innate immunity, Mice, Inbred BALB C, Innate immune system, Vaccination, Cell Differentiation, Dendritic cell, Th1 Cells, Newborn, Interleukin-12, Immunity, Innate, 3. Good health, Mice, Inbred C57BL, Proto-Oncogene Proteins c-raf, [SDV] Life Sciences [q-bio], Animals, Newborn, Adjuvant
Abstract: Background Early life is characterized by a high susceptibility to infection and a T H 2-biased CD4 T-cell response to vaccines. Toll-like receptor (TLR) agonists are currently being implemented as new vaccine adjuvants for T H 1 activation, but their translation to the field of pediatric vaccines is facing the impairment of neonatal innate TLR responses. Objective We sought to analyze C-type lectin receptor pathways as an alternative or a coactivator to TLRs for neonatal dendritic cell activation for T H 1 polarization. Methods Neonatal monocyte-derived dendritic cells (moDCs) were exposed to various combinations of TLR agonists with or without Dectin-1 agonist. IL-12 and IL-23 responses were analyzed at the transcriptional and protein levels after stimulation. The intracellular pathways triggered by combined TLR plus Dectin-1 stimulation was determined by using pharmacologic inhibitors. The capacity of neonatal moDCs to differentiate naive CD4 T H cells was evaluated in cocultures with heterologous neonatal naive T cells. Curdlan was finally tested as an adjuvant within a subunit tuberculosis vaccine in neonatal mice. Results Simultaneous coactivation through Dectin-1 and TLRs induced robust secretion of IL-12p70 by neonatal moDCs by unlocking transcriptional control on the p35 subunit of IL-12. Both the spleen tyrosine kinase and Raf-1 pathways were involved in this process, allowing differentiation of neonatal naive T cells toward IFN-γ–producing T H 1 cells. In vivo a Dectin-1 agonist as adjuvant was sufficient to induce T H 1 responses after vaccination of neonatal mice. Conclusion Coactivation of neonatal moDCs through Dectin-1 allows TLR-mediated IL-12p70 secretion and T H 1 polarization of neonatal T cells. Dectin-1 agonists represent a promising T H 1 adjuvant for pediatric vaccination.
Published: 2015

18. Rapamycin Impairs Antitumor CD8+ T-cell Responses and Vaccine-Induced Tumor Eradication

Author: Catherine Fayolle, Nada Chaoul, Daniel Ladant, Alexandre Tang, Belinda Desrues, Claude Leclerc, Marine Oberkampf, Régulation Immunitaire et Vaccinologie, Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris], Biochimie des Interactions Macromoléculaires / Biochemistry of Macromolecular Interactions, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), This work was supported by grants from the Ligue Nationale Contre le Cancer (Equipe Labellisée 2014), Conseil Régional IdF/Cancéropôle IdF, and Banque Privée Européenne. N. Chaoul was supported by Conseil Régional IdF/Cancéropôle IdF and Fondation de France.The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact., Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Cancer Research, Papillomavirus E7 Proteins, [SDV]Life Sciences [q-bio], CD8-Positive T-Lymphocytes, Biology, Pharmacology, Cancer Vaccines, T-Lymphocytes, Regulatory, 03 medical and health sciences, 0302 clinical medicine, Immune system, Cell Line, Tumor, Neoplasms, medicine, Animals, Humans, Cytotoxic T cell, Myeloid Cells, PI3K/AKT/mTOR pathway, 030304 developmental biology, Sirolimus, 0303 health sciences, Antibiotics, Antineoplastic, TOR Serine-Threonine Kinases, Flow Cytometry, Tumor Burden, 3. Good health, Mice, Inbred C57BL, Immunosurveillance, MESH: Antibiotics, Antineoplastic/immunology, Disease Models, Animal, Myeloid Cells/metabolism, T-Lymphocytes, Regulatory/immunology, Oncology, 030220 oncology & carcinogenesis, Cancer cell, Female, Cancer vaccine, T-Lymphocytes, Cytotoxic, medicine.drug
Abstract: The metabolic sensor mTOR broadly regulates cell growth and division in cancer cells, leading to a significant focus on studies of rapamycin and its analogues as candidate anticancer drugs. However, mTOR inhibitors have failed to produce useful clinical efficacy, potentially because mTOR is also critical in T cells implicated in immunosurveillance. Indeed, recent studies using rapamycin have demonstrated the important role of mTOR in differentiation and induction of the CD8+ memory in T-cell responses associated with antitumor properties. In this study, we demonstrate that rapamycin harms antitumor immune responses mediated by T cells in the setting of cancer vaccine therapy. Specifically, we analyzed how rapamycin affects the antitumor efficacy of a human papilloma virus E7 peptide vaccine (CyaA-E7) capable of eradicating tumors in the TC-1 mouse model of cervical cancer. In animals vaccinated with CyaA-E7, rapamycin administration completely abolished recruitment of CD8+ T cells into TC-1 tumors along with the ability of the vaccine to reduce infiltration of T regulatory cells and myeloid-derived suppressor cells. Moreover, rapamycin completely abolished vaccine-induced cytotoxic T-cell responses and therapeutic activity. Taken together, our results demonstrate the powerful effects of mTOR inhibition in abolishing T-cell–mediated antitumor immune responses essential for the therapeutic efficacy of cancer vaccines. Cancer Res; 75(16); 3279–91. ©2015 AACR.
Published: 2015

19. Antigen targeting to CD11b+ dendritic cells in association with TLR4/TRIF signaling promotes strong CD8+ T cell responses

Author: Catherine Fayolle, Radim Osicka, Sandra Hervas-Stubbs, Marine Oberkampf, Bernard Ryffel, Peter Sebo, Tristan Felix, Gilles Dadaglio, Daniel Ladant, Claude Leclerc, Xiaoming Zhang, Régulation Immunitaire et Vaccinologie, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Immunologie et Neurogénétique Expérimentales et Moléculaires (INEM), Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS), Universidad de Navarra [Pamplona] (UNAV), Institute of Microbiology of the ASCR, v. v. i. [Prague, Czech Republic], Biochimie des Interactions Macromoléculaires / Biochemistry of Macromolecular Interactions, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), This work was supported by the Ligue Nationale contre le Cancer (Equipe Labellisée 2014), l'Institut National du Cancer/Cancéropole Ile de France, European Union's Seventh Framework Programme Grant 280873, Advanced Immunization Technologies, Czech Science Foundation Grants P302/11/0580 and P302/12/0460, and Banque Privée Européenne., European Project: 280873,EC:FP7:HEALTH,FP7-HEALTH-2011-single-stage,ADITEC(2011), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Centre National de la Recherche Scientifique (CNRS)-Université d'Orléans (UO), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Dadaglio, Gilles, and Advanced Immunization Technologies - ADITEC - - EC:FP7:HEALTH2011-10-01 - 2016-09-30 - 280873 - VALID
Subjects: MESH: Signal Transduction, [SDV]Life Sciences [q-bio], Interleukin-1beta, Receptor, Interferon alpha-beta, MESH: Mice, Knockout, Bordetella pertussis, MESH: Tyrosine, MESH: Bordetella pertussis, Mice, MESH: Interleukin-1beta, Immunology and Allergy, Cytotoxic T cell, MESH: Animals, Cells, Cultured, Mice, Knockout, CD11b Antigen, biology, MESH: Dendritic Cells, Cell Differentiation, MESH: Toll-Like Receptor 4, 3. Good health, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, B7-1 Antigen, [SDV.IMM]Life Sciences [q-bio]/Immunology, Adenylate Cyclase Toxin, Female, MESH: B7-2 Antigen, MESH: Cells, Cultured, Signal Transduction, MESH: Cell Differentiation, [SDV.IMM] Life Sciences [q-bio]/Immunology, T cell, Immunology, Major histocompatibility complex, MESH: Receptors, Interleukin-1, MESH: CD11b Antigen, Proinflammatory cytokine, Immune system, [SDV.IMM.VAC] Life Sciences [q-bio]/Immunology/Vaccinology, MESH: Mice, Inbred C57BL, medicine, MESH: Receptor, Interferon alpha-beta, Animals, MESH: Mice, MESH: Interferon-beta, Interleukin-6, Tumor Necrosis Factor-alpha, Receptors, Interleukin-1, MESH: Adaptor Proteins, Vesicular Transport, Dendritic Cells, Interferon-beta, cyaA, MESH: Adenylate Cyclase Toxin, MESH: Interleukin-6, Mice, Inbred C57BL, Toll-Like Receptor 4, Adaptor Proteins, Vesicular Transport, TRIF, MESH: Tumor Necrosis Factor-alpha, Cancer research, biology.protein, Tyrosine, MESH: B7-1 Antigen, B7-2 Antigen, [SDV.IMM.VAC]Life Sciences [q-bio]/Immunology/Vaccinology, MESH: Female, MESH: T-Lymphocytes, Cytotoxic, CD8, T-Lymphocytes, Cytotoxic
Abstract: Deciphering the mechanisms that allow the induction of strong immune responses is crucial to developing efficient vaccines against infectious diseases and cancer. Based on the discovery that the adenylate cyclase from Bordetella pertussis binds to the CD11b/CD18 integrin, we developed a highly efficient detoxified adenylate cyclase-based vector (CyaA) capable of delivering a large variety of Ags to the APC. This vector allows the induction of protective and therapeutic immunity against viral and tumoral challenges as well as against transplanted tumors in the absence of any added adjuvant. Two therapeutic vaccine candidates against human papilloma viruses and melanoma have been developed recently, based on the CyaA vector, and are currently in clinical trials. We took advantage of one of these highly purified vaccines, produced under good manufacturing practice–like conditions, to decipher the mechanisms by which CyaA induces immune responses. In this study, we demonstrate that CyaA binds both human and mouse CD11b+ dendritic cells (DCs) and induces their maturation, as shown by the upregulation of costimulatory and MHC molecules and the production of proinflammatory cytokines. Importantly, we show that DCs sense CyaA through the TLR4/Toll/IL-1R domain–containing adapter-inducing IFN-β pathway, independent of the presence of LPS. These findings show that CyaA possesses the intrinsic ability to not only target DCs but also to activate them, leading to the induction of strong immune responses. Overall, this study demonstrates that Ag delivery to CD11b+ DCs in association with TLR4/Toll/IL-1R domain–containing adapter-inducing IFN-β activation is an efficient strategy to promote strong specific CD8+ T cell responses.
Published: 2014

20. B lymphocytes undergo TLR2-dependent apoptosis upon Shigella infection

Author: Ilia Belotserkovsky, Armelle Phalipon, Premkumar Dinadayala, Philippe J. Sansonetti, Claude Parsot, Rubhana Raqib, Brian Mozeleski, Anke Burger-Kentischer, Laurie Pinaud, Katharina Nothelfer, Michel Neunlist, Ellen T. Arena, Pathogénie Microbienne Moléculaire, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Cellule Pasteur UPMC, Institut Pasteur [Paris] (IP)-Sorbonne Université (SU), Neuropathies du système nerveux entérique et pathologies digestives, implication des cellules gliales entériques, Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut des Maladies de l'Appareil Digestif, Université de Nantes (UN), Régulation Immunitaire et Vaccinologie, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Sanofi Pasteur [Marcy-l'Étoile, France], Fraunhofer Institute for Interfacial Engineering and Biotechnology (Fraunhofer IGB), Fraunhofer (Fraunhofer-Gesellschaft), International Centre for Diarrhoeal Diseases Research (ICDDRB), Collège de France - Chaire Microbiologie et Maladies infectieuses, Collège de France (CdF (institution)), K. Nothelfer was funded by the Pasteur-Paris University International PhD Program, the Pasteur Weizmann Foundation, and the Transversal Research Program (project no. 415). E.T. Arena is a Pasteur Foundation fellow and L. Pinaud is a fellow from the University Paris Diderot. I. Belotserkovsky has received funding from the French Ministry of Foreign Affairs and the Transversal Research Program (project no. 415). P.J. Sansonetti is supported by the European Research Council (ERC, project Homeopith), he is a Howard Hughes Medical Institute Foreign Scholar. This study has received funding from the French Government’s Investissement d’Avenir program, Laboratoire d’Excellence 'Integrative Biology of Emerging Infectious Diseases' (grant no. ANR-10-LABEX-62-IBEID)., We thank the Institut Pasteur Imagopole (PFID) for their contribution to imaging studies, Andrea Cerrutti for kindly providing us with the CL-01 B cell line, and Philippe Aubert, Angela Mattes, and Françoise Thouron for technical help and kind assistance. We are grateful to several people who have contributed to this work with helpful discussions, advice, and critical reading of the manuscript, namely Paulo Vieira, Gérard Eberl, François Huetz, Jean-Claude Weill, Menno van Zelm, Bana Jabri, Geneviève Renauld, Paul Erlich, Daniel Scott, Nathalie Sauvonnet, Christoph Konradt, Elisabetta Frigimelica, Giulia Nigro, François-Xavier Campbell-Valois, and the whole PMM unit., ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris]-Sorbonne Université (SU), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris], Chaire Microbiologie et Maladies infectieuses, and Publica
Subjects: MESH: Shigella flexneri, Lymphocyte, Apoptosis, MESH: Flow Cytometry, Shigella flexneri, Mice, MESH: Reverse Transcriptase Polymerase Chain Reaction, Immunology and Allergy, MESH: Microscopy, Confocal, MESH: Animals, MESH: Bacterial Proteins, Cells, Cultured, B-Lymphocytes, Microscopy, Confocal, MESH: Immunoblotting, Reverse Transcriptase Polymerase Chain Reaction, MESH: Toll-Like Receptor 2, Flow Cytometry, 3. Good health, medicine.anatomical_structure, Host-Pathogen Interactions, Female, RNA Interference, Protein Binding, MESH: Cells, Cultured, Adult, Programmed cell death, MESH: Mutation, MESH: Dysentery, Bacillary, Colon, Immunoblotting, Immunology, Naive B cell, MESH: RNA Interference, Biology, Article, Cell Line, Microbiology, Immune system, Bacterial Proteins, MESH: Mice, Inbred C57BL, MESH: B-Lymphocytes, medicine, Animals, Humans, MESH: Protein Binding, MESH: Colon, MESH: Mice, B cell, Dysentery, Bacillary, Antigens, Bacterial, MESH: Humans, MESH: Apoptosis Regulatory Proteins, MESH: Apoptosis, MESH: Host-Pathogen Interactions, MESH: Adult, biochemical phenomena, metabolism, and nutrition, biology.organism_classification, Molecular biology, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, digestive system diseases, Toll-Like Receptor 2, MESH: Cell Line, Mice, Inbred C57BL, B-1 cell, Mutation, NIH 3T3 Cells, bacteria, Apoptosis Regulatory Proteins, MESH: Female, MESH: Antigens, Bacterial, MESH: NIH 3T3 Cells
Abstract: Shigella flexneri interacts with B cells and induces apoptosis via IpaD binding to TLR2., Antibody-mediated immunity to Shigella, the causative agent of bacillary dysentery, requires several episodes of infection to get primed and is short-lasting, suggesting that the B cell response is functionally impaired. We show that upon ex vivo infection of human colonic tissue, invasive S. flexneri interacts with and occasionally invades B lymphocytes. The induction of a type three secretion apparatus (T3SA)–dependent B cell death is observed in the human CL-01 B cell line in vitro, as well as in mouse B lymphocytes in vivo. In addition to cell death occurring in Shigella-invaded CL-01 B lymphocytes, we provide evidence that the T3SA needle tip protein IpaD can induce cell death in noninvaded cells. IpaD binds to and induces B cell apoptosis via TLR2, a signaling receptor thus far considered to result in activation of B lymphocytes. The presence of bacterial co-signals is required to sensitize B cells to apoptosis and to up-regulate tlr2, thus enhancing IpaD binding. Apoptotic B lymphocytes in contact with Shigella-IpaD are detected in rectal biopsies of infected individuals. This study therefore adds direct B lymphocyte targeting to the diversity of mechanisms used by Shigella to dampen the host immune response.
Published: 2014
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21. CD4 T cells with effector memory phenotype and function develop in the sterile environment of the fetus

Author: Claude Leclerc, Richard Lo-Man, Annick Lim, Gwenaelle Roguet, Anne Vanet, Camille Le Ray, Edith Dériaud, Sébastien Lemoine, Xiaoming Zhang, Dania Zhivaki, Elie Azria, Brian Mozeleski, Odile Launay, Régulation Immunitaire et Vaccinologie, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Key Laboratory of Molecular Virology & Immunology (LMVI), Institut Pasteur de Shanghai, Académie des Sciences de Chine - Chinese Academy of Sciences (IPS-CAS), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Département d'Immunologie - Department of Immunology, Institut Pasteur [Paris], Department of Obstetrics and Gynecology, AP-HP - Hôpital Bichat - Claude Bernard [Paris]-Université Paris Diderot - Paris 7 (UPD7), Maternité Port-Royal [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Cochin [AP-HP], CIC Cochin Pasteur (CIC 1417), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Cochin [AP-HP]-Hôtel-Dieu-Université Paris Descartes - Paris 5 (UPD5)-Groupe hospitalier Broca-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Jacques Monod (IJM (UMR_7592)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Atelier de Bio Informatique, Université Paris Diderot - Paris 7 (UPD7), Agence Nationale de la Recherche (ANR) (ANR 09-MIEN-017 ), Fondation pour la Recherche Medicale (DEQ20120323719 ), French Government's Investissement d'Avenir program, Laboratoire d'Excellence 'Integrative Biology of Emerging Infectious Diseases' (ANR-10-LABX-62-IBEID), European Commission FP7 ADITEC program HEALTH-F4-2011-280873, Shanghai Rising-Star Program, Pasteur-Paris University (PPU) International PhD program, Institut Carnot, DIM Malinf et region IdF, Center for Human Immunology at the Institut Pasteur, Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris], AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôtel-Dieu-Université Paris Descartes - Paris 5 (UPD5)-Groupe hospitalier Broca-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institut Pasteur [Paris] (IP), Institut Pasteur [Paris] - Institut National de la Santé et de la Recherche Médicale (INSERM) - Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Réseau International des Instituts Pasteur (RIIP) - Institut Pasteur de Shanghai - Académie des Sciences de Chine, Département d'Immunologie, AP-HP - Hôpital Bichat - Claude Bernard [Paris] - Université Paris Diderot - Paris 7 (UPD7), Assistance publique - Hôpitaux de Paris (AP-HP) - CHU Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) - CHU Cochin [AP-HP] - Hôtel-Dieu - Université Paris Descartes - Paris 5 (UPD5) - Groupe hospitalier Broca - Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Jacques Monod (IJM), and Université Paris Diderot - Paris 7 (UPD7) - Centre National de la Recherche Scientifique (CNRS)
Subjects: CD4-Positive T-Lymphocytes, T cell, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Immunophenotyping, 03 medical and health sciences, Interleukin 21, 0302 clinical medicine, Fetus, medicine, Cytotoxic T cell, Humans, IL-2 receptor, Antigen-presenting cell, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, 030304 developmental biology, 0303 health sciences, CD40, General Medicine, Natural killer T cell, Cell biology, medicine.anatomical_structure, Immunology, biology.protein, Interleukin 12, Immunologic Memory, 030215 immunology
Abstract: International audience; The T cell compartment is considered to be naïve and dedicated to the development of tolerance during fetal development. We have identified and characterized a population of fetally developed CD4 T cells with an effector memory phenotype (TEM), which are present in cord blood. This population is polyclonal and has phenotypic features similar to those of conventional adult memory T cells, such as CD45RO expression. These cells express low levels of CD25 but are distinct from regulatory T cells because they lack Foxp3 expression. After T cell receptor activation, neonatal TEM cells readily produced tumor necrosis factor-α (TNF-α) and granulocyte-macrophage colony-stimulating factor (GM-CSF). We also detected interferon-γ (IFN-γ)-producing T helper 1 (TH1) cells and interleukin-4 (IL-4)/IL-13-producing TH2-like cells, but not IL-17-producing cells. We used chemokine receptor expression patterns to divide this TEM population into different subsets and identified distinct transcriptional programs using whole-genome microarray analysis. IFN-γ was found in CXCR3(+) TEM cells, whereas IL-4 was found in both CXCR3(+) TEM cells and CCR4(+) TEM cells. CCR6(+) TEM cells displayed a genetic signature that corresponded to TH17 cells but failed to produce IL-17A. However, the TH17 function of TEM cells was observed in the presence of IL-1β and IL-23. In summary, in the absence of reported pathology or any major infectious history, T cells with a memory-like phenotype develop in an environment thought to be sterile during fetal development and display a large variety of inflammatory effector functions associated with CD4 TH cells at birth.
Published: 2014

22. Poly(I:C)-induced protection of neonatal mice against intestinal Cryptosporidium parvum infection requires an additional TLR5 signal provided by the gut flora

Author: Roselyne Mancassola, William Guesdon, Catherine Werts, Fabrice Laurent, Louis Lantier, Richard Lo-Man, Sonia Lacroix-Lamandé, Coralie Metton, Françoise Drouet, Infectiologie et Santé Publique (UMR ISP), Institut National de la Recherche Agronomique (INRA)-Université de Tours (UT), Régulation Immunitaire et Vaccinologie, Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris], Biologie et Génétique de la Paroi bactérienne - Biology and Genetics of Bacterial Cell Wall (BGPB), Institut Pasteur [Paris], This work was supported by INRA and by a grant from ICSA, the French Carnot Institute for Animal Health., Institut National de la Recherche Agronomique (INRA)-Université de Tours, ProdInra, Migration, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institut Pasteur [Paris] (IP), and Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)
Subjects: CD11c, Cryptosporidiosis, Biology, Gut flora, neonatal mice, Microbiology, Mice, Immune system, Adjuvants, Immunologic, microbiota, Immunology and Allergy, Animals, dendritic cells, TLR3, [SDV.MP] Life Sciences [q-bio]/Microbiology and Parasitology, intestine, Cryptosporidium parvum, biology.organism_classification, 3. Good health, Gastrointestinal Tract, Mice, Inbred C57BL, Toll-Like Receptor 5, Infectious Diseases, Poly I-C, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Animals, Newborn, TRIF, TLR5, Immunology, Myeloid Differentiation Factor 88, Signal transduction, poly(I:C), Signal Transduction
Abstract: International audience; The neonatal intestinal immune system is still undergoing development at birth, leading to a higher susceptibility to mucosal infections. In this study, we investigated the effect of poly(I:C) on controlling enteric infection by the protozoan Cryptosporidium parvum in neonatal mice. After poly(I:C) administration, a rapid reduction in parasite burden was observed and proved to be dependent on CD11c(+) cells and TLR3/TRIF signaling. Protection against C. parvum required additional signals provided by the gut flora through TLR5 and MyD88 signaling. This cooperation gave rise to higher levels of expression of critical mutually dependent cytokines such as interleukin 12p40 and type 1 and type 2 interferons, the last 2 being known to play a key role in the elimination of infected enterocytes. Our findings demonstrate in neonatal mice how gut flora synergizes with poly(I:C) to elicit protective intestinal immunity against an intracellular pathogen.
Published: 2014

23. Decoration of outer membrane vesicles with multiple antigens using an autotransporter approach

Author: Sander R. Piersma, Karin de Punder, Joen Luirink, Nicole N. van der Wel, Laleh Majlessi, Zora Soprova, Corinne M. ten Hagen-Jongman, Tristan Felix, Connie R. Jimenez, Jan-Willem de Gier, Maria H. Daleke-Schermerhorn, Joep Beskers, Thang V. Pham, Wouter S. P. Jong, David Vikström, Frank Follmann, Thomas Baumgarten, Peter van Ulsen, Claude Leclerc, Molecular Microbiology, AIMMS, LaserLaB - Analytical Chemistry and Spectroscopy, Section Molecular Microbiology, Department of Molecular Cell Biology, Faculty of Earth and Life Sciences, VU University, Abera Bioscience, Régulation Immunitaire et Vaccinologie, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Center for Biomembrane Research, Department of Biochemistry and Biophysics, Stockholm University, Xbrane Bioscience, Xbrane Bioscience (AB), Chlamydia Vaccine Research, Department of Infectious Disease Immunology, Statens Serum Institut [Copenhagen], The Netherlands Cancer Institute, Antonie van Leeuwenhoek Hospital, Department of Medical Oncology, OncoProteomics Laboratory, VU University Medical Center [Amsterdam], The research leading to these results has received funding from the EuropeanUnion’s Seventh Framework Programme (FP7/2007-2013) undergrant agreement number 280873 ADITEC. In addition, W.S.P.J. was supportedby a grant from the Dutch Technology Foundation, and Z.S. wassupported by a Mosaic Grant from the Netherlands Organization for ScientificResearch., European Project: 280873,EC:FP7:HEALTH,FP7-HEALTH-2011-single-stage,ADITEC(2011), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris], Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Medical oncology laboratory, and CCA - Immuno-pathogenesis
Subjects: Serotype, Salmonella typhimurium, T cell, [SDV]Life Sciences [q-bio], Heterologous, Context (language use), Chlamydia trachomatis, Biology, Applied Microbiology and Biotechnology, Epitope, Microbiology, 03 medical and health sciences, Immune system, Antigen, Bacterial Proteins, SDG 3 - Good Health and Well-being, Endopeptidases, medicine, Escherichia coli, 030304 developmental biology, 0303 health sciences, Antigens, Bacterial, Ecology, 030306 microbiology, Secretory Vesicles, Membrane Transport Proteins, Mycobacterium tuberculosis, Protein Transport, medicine.anatomical_structure, [SDV.IMM]Life Sciences [q-bio]/Immunology, Bacterial outer membrane, Acyltransferases, Food Science, Biotechnology
Abstract: Outer membrane vesicles (OMVs) are spherical nanoparticles that naturally shed from Gram-negative bacteria. They are rich in immunostimulatory proteins and lipopolysaccharide but do not replicate, which increases their safety profile and renders them attractive vaccine vectors. By packaging foreign polypeptides in OMVs, specific immune responses can be raised toward heterologous antigens in the context of an intrinsic adjuvant. Antigens exposed at the vesicle surface have been suggested to elicit protection superior to that from antigens concealed inside OMVs, but hitherto robust methods for targeting heterologous proteins to the OMV surface have been lacking. We have exploited our previously developed hemoglobin protease (Hbp) autotransporter platform for display of heterologous polypeptides at the OMV surface. One, two, or three of the Mycobacterium tuberculosis antigens ESAT6, Ag85B, and Rv2660c were targeted to the surface of Escherichia coli OMVs upon fusion to Hbp. Furthermore, a hypervesiculating Δ tolR Δ tolA derivative of attenuated Salmonella enterica serovar Typhimurium SL3261 was generated, enabling efficient release and purification of OMVs decorated with multiple heterologous antigens, exemplified by the M. tuberculosis antigens and epitopes from Chlamydia trachomatis major outer membrane protein (MOMP). Also, we showed that delivery of Salmonella OMVs displaying Ag85B to antigen-presenting cells in vitro results in processing and presentation of an epitope that is functionally recognized by Ag85B-specific T cell hybridomas. In conclusion, the Hbp platform mediates efficient display of (multiple) heterologous antigens, individually or combined within one molecule, at the surface of OMVs. Detection of antigen-specific immune responses upon vesicle-mediated delivery demonstrated the potential of our system for vaccine development.
Published: 2014

24. Whole-exome sequencing identifies Coronin-1A deficiency in 3 siblings with immunodeficiency and EBV-associated B-cell lymphoproliferation

Author: Capucine Picard, Annick Lim, Patrick Revy, Jacek Majewski, Jeremy Schwartzentruber, Emmanuel Martin, Despina Moshous, Danielle Canioni, Jean-Pierre de Villartay, Fabian Hauck, Nicolas Sirvent, Wassila Carpentier, Pierre Frange, Sylvain Latour, Isabelle Callebaut, Alain Fischer, Stéphane Blanche, Nada Jabado, Patrick Nitschke, Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Plateforme Post-génomique de la Pitié-Salpêtrière (P3S), UMS omique (OMIQUE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Université Pierre et Marie Curie - Paris 6 - UFR de Médecine Pierre et Marie Curie (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC), Régulation Immunitaire et Vaccinologie, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institut de minéralogie et de physique des milieux condensés (IMPMC), Université Pierre et Marie Curie - Paris 6 (UPMC)-IPG PARIS-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), McGill University and Genome Quebec Innovation Centre, Université Paris Descartes - Paris 5 (UPD5), Hôpital Arnaud de Villeneuve [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Génétique Humaine des Maladies Infectieuses (Inserm U980), Chaire Médecine expérimentale (A. Fischer), Collège de France (CdF (institution)), McGill University = Université McGill [Montréal, Canada], Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7)-Institut de Physique du Globe de Paris (IPG Paris)-Centre National de la Recherche Scientifique (CNRS), Collège de France - Chaire Médecine expérimentale (A. Fischer), and Gestionnaire, Hal Sorbonne Université
Subjects: Genetics, 0303 health sciences, Severe combined immunodeficiency, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, [SDV]Life Sciences [q-bio], Immunology, Inborn immunodeficiency, Biology, medicine.disease, Disease gene identification, 3. Good health, [SDV] Life Sciences [q-bio], 03 medical and health sciences, 0302 clinical medicine, medicine, Primary immunodeficiency, Immunology and Allergy, Missense mutation, T-Cell Immunodeficiency, Exome sequencing, Immunodeficiency, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 030304 developmental biology, 030215 immunology
Abstract: International audience; Background: Primary immunodeficiencies are a rare group of inborn diseases characterized by a broad clinical and genetic heterogeneity. Substantial advances in the identification of the underlying molecular mechanisms can be achieved through the study of patients with increased susceptibility to specific infections and immune dysregulation. We evaluated 3 siblings from a consanguineous family presenting with EBV-associated B-cell lymphoproliferation at an early age (12, 7½, and 14 months, respectively) and profound naive T-cell lymphopenia.Objective: On the basis of the hypothesis of a rare inborn immunodeficiency of autosomal recessive inheritance, we sought to characterize the underlying genetic defect.Methods: We performed genome-wide homozygosity mapping, followed by whole-exome sequencing.Results: We identified a homozygous inherited missense mutation in the gene encoding Coronin-1A (CORO1A) in the 3 siblings. This mutation, p. V134M, results in the substitution of an evolutionarily conserved amino acid within the β-propeller domain, which abrogates almost completely the protein expression in the patients' cells. In addition to a significant diminution of naive T-cell numbers, we found impaired development of a diverse T-cell repertoire, near-to-absent invariant natural killer T cells, and severely diminished mucosal-associated invariant T cell numbers.Conclusions: Our findings define a new clinical entity of a primary immunodeficiency with increased susceptibility to EBV-induced lymphoproliferation in patients associated with hypomorphic Coronin-1A mutation.
Published: 2013

25. Intestinal CD103+ dendritic cells are key players in the innate immune control of [i]Cryptosporidium parvum[/i] infection in neonatal mice

Author: Aurore Fenis, Coralie Metton, Yves Le Vern, Audrey Gnahoui-David, William Guesdon, Fabrice Laurent, Louis Lantier, Catherine Werts, Laurent Potiron, Françoise Drouet, Edith Dériaud, Sylvie Rabot, Sonia Lacroix-Lamandé, Amandine Descamps, ProdInra, Archive Ouverte, Servicing the European Biomedical Research Community: Archiving and Dissemination of Mouse Models of Human Disease - EMMASERVICE - - EC:FP7:INFRA2009-01-01 - 2012-12-31 - 227490 - VALID, Infectiologie et Santé Publique (UMR ISP), Institut National de la Recherche Agronomique (INRA)-Université de Tours (UT), Régulation Immunitaire et Vaccinologie, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), 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), MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Biologie et Génétique de la Paroi bactérienne - Biology and Genetics of Bacterial Cell Wall (BGPB), Institut Pasteur [Paris] (IP), INRA, ICSA, the French Carnot Institute for Animal Health, EMMA service under the EU of the EC FP7 Capacities Specific Programme [227490], Region Centre, European Project: 227490,EC:FP7:INFRA,FP7-INFRASTRUCTURES-2008-1,EMMASERVICE(2009), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Institut Pasteur [Paris], and Institut National de la Recherche Agronomique (INRA)-Université de Tours
Subjects: Chemokine, parasitose, Cryptosporidiosis, chémokine, Mice, 0302 clinical medicine, Child, lcsh:QH301-705.5, Mice, Knockout, 0303 health sciences, biology, Microbiology and Parasitology, Age Factors, hemic and immune systems, maladie parasitaire, Intestinal epithelium, Microbiologie et Parasitologie, 3. Good health, Intestines, Cryptosporidium parvum, medicine.anatomical_structure, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, infection gastrique, Integrin alpha Chains, Research Article, chimiokine, lcsh:Immunologic diseases. Allergy, Immunology, chemical and pharmacologic phenomena, Microbiology, Gastrointestinal epithelium, 03 medical and health sciences, Immunity, Antigens, CD, Virology, parasitic diseases, Genetics, medicine, Animals, Humans, Molecular Biology, [SDV.MP] Life Sciences [q-bio]/Microbiology and Parasitology, oocyste, 030304 developmental biology, Lamina propria, Innate immune system, nouveau né, Dendritic Cells, biology.organism_classification, Immunity, Innate, Mice, Inbred C57BL, Neonatal infection, lcsh:Biology (General), Animals, Newborn, biology.protein, Parasitology, Cattle, lcsh:RC581-607, 030215 immunology
Abstract: International audience; Cryptosporidium parvum is a zoonotic protozoan parasite found worldwide, that develops only in the gastrointestinal epithelium and causes profuse diarrhea. Using a mouse model of C. parvum infection, we demonstrated by conditional depletion of CD11c+ cells that these cells are essential for the control of the infection both in neonates and adults. Neonates are highly susceptible to C. parvum but the infection is self-limited, whereas adults are resistant unless immunocompromised. We investigated the contribution of DC to the age-dependent susceptibility to infection. We found that neonates presented a marked deficit in intestinal CD103+ DC during the first weeks of life, before weaning, due to weak production of chemokines by neonatal intestinal epithelial cells (IEC). Increasing the number of intestinal CD103+ DC in neonates by administering FLT3-L significantly reduced susceptibility to the infection. During infections in neonates, the clearance of the parasite was preceded by a rapid recruitment of CD103+ DC mediated by CXCR3-binding chemokines produced by IEC in response to IFN gamma. In addition to this key role in CD103+ DC recruitment, IFN gamma is known to inhibit intracellular parasite development. We demonstrated that during neonatal infection CD103+ DC produce IL-12 and IFN gamma in the lamina propria and the draining lymph nodes. Thus, CD103+ DC are key players in the innate immune control of C. parvum infection in the intestinal epithelium. The relative paucity of CD103+ DC in the neonatal intestine contributes to the high susceptibility to intestinal infection.
Published: 2013

26. Neonatal Plasmacytoid Dendritic Cells (pDCs) Display Subset Variation but Can Elicit Potent Anti-Viral Innate Responses

Author: Xiaoming Zhang, Claude Leclerc, Pierre Lebon, Richard Lo-Man, Gwenaelle Roguet, Elie Azria, Olivier Schwartz, Odile Launay, Alice Lepelley, Institut Pasteur de Shanghai, Académie des Sciences de Chine - Chinese Academy of Sciences (IPS-CAS), Réseau International des Instituts Pasteur (RIIP), Régulation Immunitaire et Vaccinologie, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Virus et Immunité - Virus and immunity, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Université Sorbonne Paris Cité (USPC), Department of Obstetrics and Gynecology, AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CIC - Biotherapie - AP-HP (cochin - Pasteur), Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Faculté de Médecine (UPD5 Médecine), Université Paris Descartes - Paris 5 (UPD5), ANR-09-MIEN-0017,NEOSYK,ETUDE DES DES VOIES SYK ET MYD88 POUR L'ACTIVATION EFFICACE DU SYSTEME IMMUNITAIRE NEONATAL(2009), ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Virus et Immunité - Virus and immunity (CNRS-UMR3569), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur in Shanghai - Chinese Academy of Sciences ( IPS-CAS ), Réseau International des Instituts Pasteur ( RIIP ) -Institut Pasteur de Shanghai - Académie des Sciences de Chine, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), Virus et Immunité, Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 ( UPD7 ) -Centre National de la Recherche Scientifique ( CNRS ), Université Sorbonne Paris Cité ( USPC ), AP-HP - Hôpital Bichat - Claude Bernard [Paris]-Université Paris Diderot - Paris 7 ( UPD7 ), CHU Cochin [AP-HP], Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Paris Descartes - Faculté de Médecine ( UPD5 Médecine ), Université Paris Descartes - Paris 5 ( UPD5 ), ANR-09-MIEN-0017,NEOSYK,ETUDE DES DES VOIES SYK ET MYD88 POUR L'ACTIVATION EFFICACE DU SYSTEME IMMUNITAIRE NEONATAL ( 2009 ), ANR-10-LABX-62-IBEID,IBEID,Laboratoire d'Excellence 'Integrative Biology of Emerging Infectious Diseases' ( 2010 ), Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], AP-HP - Hôpital Bichat - Claude Bernard [Paris]-Université Paris Diderot - Paris 7 (UPD7), ANR-10-LABX-62-IBEID,IBEID,Laboratoire d'Excellence 'Integrative Biology of Emerging Infectious Diseases'(2010), and Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris]
Subjects: Chemokine, [SDV]Life Sciences [q-bio], lcsh:Medicine, [ SDV.IMM.IA ] Life Sciences [q-bio]/Immunology/Adaptive immunology, medicine.disease_cause, 0302 clinical medicine, Influenza A virus, lcsh:Science, Immune Response, Cells, Cultured, 0303 health sciences, education.field_of_study, Multidisciplinary, biology, Interleukin-12 Subunit p40, hemic and immune systems, Middle Aged, Flow Cytometry, Innate Immunity, 3. Good health, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, Oligodeoxyribonucleotides, Cord blood, Chemokines, Research Article, Adult, Adolescent, Population, Immunology, CD2 Antigens, CD5 Antigens, Virus, 03 medical and health sciences, Immune system, medicine, Humans, education, Biology, Immunity to Infections, 030304 developmental biology, [ SDV ] Life Sciences [q-bio], Tumor Necrosis Factor-alpha, lcsh:R, Immunity, Infant, Newborn, TLR9, Interferon-alpha, Immune Defense, TLR7, Dendritic Cells, Virology, Immunity, Innate, Toll-Like Receptor 7, Toll-Like Receptor 9, biology.protein, lcsh:Q, 030215 immunology
Abstract: International audience; Neonates are highly susceptible to infectious diseases and defective antiviral pDC immune responses have been proposed to contribute to this phenomenon. Isolated cord blood pDCs innately responded to a variety of TLR7 and TLR9 dependent viruses, including influenza A virus (IAV), human immunodeficiency virus (HIV) or herpes-simplex virus (HSV) by efficiently producing IFN-α, TNF-α as well as chemokines. Interestingly, following activation by CpGA, but not viruses, cord pDCs tend to survive less efficiently. We found that a hallmark of pDCs in neonates is an extended CD2+pDCs compartment compared to adult pDCs without affecting the antiviral IFN-α response. Within CD2+pDCs, we identified a subpopulation expressing CD5 and responsible for IL-12p40 production, however this population is significantly decreased in cord blood compared to adult blood. Therefore, neonatal pDCs clearly display variation in phenotype and subset composition, but without major consequences for their antiviral responses.
Published: 2013

27. Pivotal role of plasmacytoid dendritic cells in inflammation and NK-cell responses after TLR9 triggering in mice

Author: Susan Chan, Claude Leclerc, Philippe Kastner, Helen K. W. Law, Noëlle Doyen, Gilles Dadaglio, Juliette Mouriès, Camille Guillerey, Giulia Polo, Régulation Immunitaire et Vaccinologie, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Cytokines et Inflammation, Institut Pasteur [Paris] (IP), Centre d'immunologie humaine (CIH), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), This work was supported by Ligue Nationale Contre le Cancer (équipe labellisée 2010) and Banque Privée Européenne., The authors thank M. Rojas for technical assistance and M. Albert and J. Di Santo for the gift of β2m−/− and Ragγc−/− mice, respectively., Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris], Institut Pasteur [Paris], Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), and Dadaglio, Gilles
Subjects: MESH: Signal Transduction, Chemokine, Neutrophils, T-Lymphocytes, [SDV]Life Sciences [q-bio], MESH: Neutrophils, MESH: Monocytes, Biochemistry, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, Monocytes, Mice, 0302 clinical medicine, MESH: Leishmania major, Cell Movement, Macrophage, Leishmania major, MESH: Animals, MESH: Tuberculosis, MESH: Cell Movement, Escherichia coli Infections, B-Lymphocytes, 0303 health sciences, MESH: Toll-Like Receptor 9, MESH: Cytokines, biology, MESH: Dendritic Cells, hemic and immune systems, Hematology, MESH: Chemokines, 3. Good health, Cell biology, DNA-Binding Proteins, Killer Cells, Natural, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, Cytokines, [SDV.IMM]Life Sciences [q-bio]/Immunology, MESH: Immunity, Innate, Chemokines, medicine.symptom, Signal transduction, MESH: Infection, Signal Transduction, MESH: Killer Cells, Natural, Mice, 129 Strain, [SDV.IMM] Life Sciences [q-bio]/Immunology, MESH: Mice, Transgenic, Immunology, Mice, Transgenic, Inflammation, Infections, 03 medical and health sciences, MESH: Mice, 129 Strain, MESH: Mice, Inbred C57BL, MESH: B-Lymphocytes, medicine, Animals, Tuberculosis, [SDV.IMM.II] Life Sciences [q-bio]/Immunology/Innate immunity, MESH: Mice, 030304 developmental biology, MESH: Escherichia coli Infections, Innate immune system, Macrophages, Monocyte, TLR9, MESH: Macrophages, Dendritic Cells, Cell Biology, biology.organism_classification, Immunity, Innate, Mice, Inbred C57BL, MESH: T-Lymphocytes, Toll-Like Receptor 9, biology.protein, MESH: DNA-Binding Proteins, 030215 immunology
Abstract: The physiologic role played by plasmacytoid dendritic cells (pDCs) in the induction of innate responses and inflammation in response to pathogen signaling is not well understood. Here, we describe a new mouse model lacking pDCs and establish that pDCs are essential for the in vivo induction of NK-cell activity in response to Toll-like receptor 9 (TLR9) triggering. Furthermore, we provide the first evidence that pDCs are critical for the systemic production of a wide variety of chemokines in response to TLR9 activation. Consequently, we observed a profound alteration in monocyte, macrophage, neutrophil, and NK-cell recruitment at the site of inflammation in the absence of pDCs in response to CpG-Dotap and stimulation by microbial pathogens, such as Leishmania major, Escherichia coli, and Mycobacterium bovis. This study, which is based on the development of a constitutively pDC-deficient mouse model, highlights the pivotal role played by pDCs in the induction of innate immune responses and inflammation after TLR9 triggering.
Published: 2012

28. Phagosomal Rupture by Mycobacterium tuberculosis Results in Toxicity and Host Cell Death

Author: Jost Enninga, Roxane Simeone, Roland Brosch, Juliane Lippmann, Alexandre Bobard, Wilbert Bitter, Laleh Majlessi, Pathogénomique mycobactérienne intégrée, Institut Pasteur [Paris] (IP), Dynamique des Interactions Hôte-Pathogène - Dynamics of Host-Pathogen Interactions, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Vrije Universiteit Amsterdam [Amsterdam] (VU), Régulation Immunitaire et Vaccinologie, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), This work was supported by the Institut Pasteur PTR372 (to R.B.), the European Community's Seventh Framework Program under grant agreements n°201762 (to L.M., W.B. and R.B.) and n°241745 (to R.B.), a European Research Council Starting Grant Award n° 261166 (to J.E.), and a grant n° ANR-09-MIEN-020-01 from the Agence Nationale pour la Recherche (to J.E.)., We would like to thank Alexandre Pawlik for help with the figure layout, ANR-09-MIEN-0020,SignRupVac,Signalisation cellulaire associée à la rupture vacuolaire des bactéries à réplication intracytoplasmique(2009), European Project: 201762,EC:FP7:HEALTH,FP7-HEALTH-2007-A,NOVSEC-TB(2008), Institut Pasteur [Paris], Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Langlais, Laurence, MIE : Maladies infectieuses, immunité et environnement - Signalisation cellulaire associée à la rupture vacuolaire des bactéries à réplication intracytoplasmique - - SignRupVac2009 - ANR-09-MIEN-0020 - MIE - VALID, Novel secretion systems of Mycobacterium tuberculosis and their role in host-pathogen interaction - NOVSEC-TB - - EC:FP7:HEALTH2008-01-01 - 2011-06-30 - 201762 - VALID, Medical Microbiology and Infection Prevention, CCA - Immuno-pathogenesis, Vrije universiteit = Free university of Amsterdam [Amsterdam] (VU), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris], Molecular Microbiology, AIMMS, and VU University Amsterdam
Subjects: MESH: Cell Death, MESH: Mycobacterium tuberculosis, MESH: Shigella flexneri, MESH: Fluorescence Resonance Energy Transfer, Host cells, [SDV.BC.IC] Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], Fluorescence imaging, Cytosol, Fluorescence resonance energy transfer, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], MESH: Immune Evasion, Pathogen, [SDV.BBM.BC] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], lcsh:QH301-705.5, Phagosome, Fluorescence microscopy, 0303 health sciences, biology, 3. Good health, Research Article, lcsh:Immunologic diseases. Allergy, Programmed cell death, Tuberculosis, Immunology, Virulence, Microbiology, MESH: Mycobacterium marinum, Mycobacterium tuberculosis, 03 medical and health sciences, Necrosis, MESH: Phagosomes, SDG 3 - Good Health and Well-being, Virology, MESH: Homeodomain Proteins, Genetics, medicine, Secretion, MESH: Mycobacterium Infections, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Molecular Biology, Biology, Mycobacterium marinum, 030304 developmental biology, MESH: Humans, 030306 microbiology, Macrophages, MESH: Macrophages, MESH: Salmonella typhimurium, medicine.disease, biology.organism_classification, MESH: Cell Line, lcsh:Biology (General), Parasitology, lcsh:RC581-607
Abstract: Survival within macrophages is a central feature of Mycobacterium tuberculosis pathogenesis. Despite significant advances in identifying new immunological parameters associated with mycobacterial disease, some basic questions on the intracellular fate of the causative agent of human tuberculosis in antigen-presenting cells are still under debate. To get novel insights into this matter, we used a single-cell fluorescence resonance energy transfer (FRET)-based method to investigate the potential cytosolic access of M. tuberculosis and the resulting cellular consequences in an unbiased, quantitative way. Analysis of thousands of THP-1 macrophages infected with selected wild-type or mutant strains of the M. tuberculosis complex unambiguously showed that M. tuberculosis induced a change in the FRET signal after 3 to 4 days of infection, indicating phagolysosomal rupture and cytosolic access. These effects were not seen for the strains M. tuberculosisΔRD1 or BCG, both lacking the ESX-1 secreted protein ESAT-6, which reportedly shows membrane-lysing properties. Complementation of these strains with the ESX-1 secretion system of M. tuberculosis restored the ability to cause phagolysosomal rupture. In addition, control experiments with the fish pathogen Mycobacterium marinum showed phagolysosomal translocation only for ESX-1 intact strains, further validating our experimental approach. Most importantly, for M. tuberculosis as well as for M. marinum we observed that phagolysosomal rupture was followed by necrotic cell death of the infected macrophages, whereas ESX-1 deletion- or truncation-mutants that remained enclosed within phagolysosomal compartments did not induce such cytotoxicity. Hence, we provide a novel mechanism how ESX-1 competent, virulent M. tuberculosis and M. marinum strains induce host cell death and thereby escape innate host defenses and favor their spread to new cells. In this respect, our results also open new research directions in relation with the extracellular localization of M. tuberculosis inside necrotic lesions that can now be tackled from a completely new perspective., Author Summary Mycobacterium tuberculosis is one of the most life-threatening pathogens of all time. Despite the development of vaccines and antibiotics, this pathogen is still a major public health problem. Also the HIV epidemic has an important impact on the rise of M. tuberculosis infections since immunodeficient people are highly susceptible. Commonly, M. tuberculosis has been thought to reside in a membrane-bound compartment within its host cells during the entire infection cycle from invasion to cell death. Using a fluorescence-based method, we provide evidence that M. tuberculosis is able to rupture its membrane-bound compartment and gain access to the host cytosol, where it can elicit cell death. Furthermore, we show that this effect is dependent on a functional type VII secretion system named ESX-1. Most importantly, we were able to track the dynamics of infection to understand the consequences of M. tuberculosis phagosomal rupture. This revealed that phagosomal rupture results in cell toxicity and host cell death involving necrosis. Together, our data provide a new angle in the worldwide fight against M. tuberculosis and could lead to new approaches in the development of innovative treatments.
Published: 2012

29. Disruption of the ESX-5 system of Mycobacterium tuberculosis causes loss of PPE protein secretion, reduction of cell wall integrity and strong attenuation

Author: Bottai, Daria, Di Luca, Mariagrazia, Majlessi, Laleh, Frigui, Wafa, Simeone, Roxane, Sayes, Fadel, Bitter, Wilbert, Brennan, Michael, Leclerc, Claude, Batoni, Giovanna, Campa, Mario, Brosch, Roland, Esin, Semih, Dipartimento di Patologia Sperimentale Biotecnologie Mediche Infettivologia ed Epidemiologia, University of Pisa - Università di Pisa, Régulation Immunitaire et Vaccinologie, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Pathogénomique mycobactérienne intégrée - Integrated Mycobacterial Pathogenomics, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Pathogénomique mycobactérienne intégrée, Institut Pasteur [Paris], VU University Medical Center [Amsterdam], Aeras [Rockville, MD], Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), This work received funding from the European Community's Seventh Framework Programme [(FP7/2007–2013)] under grant agreement n°201762., European Project: 201762,EC:FP7:HEALTH,FP7-HEALTH-2007-A,NOVSEC-TB(2008), Medical Microbiology and Infection Prevention, CCA - Immuno-pathogenesis, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), AIMMS, and Molecular Microbiology
Subjects: MESH: Protein Transport, MESH: Mycobacterium tuberculosis, [SDV]Life Sciences [q-bio], Amino Acid Motifs, Mice, SCID, MESH: Virulence, Mice, MESH: Amino Acid Motifs, MESH: Cell Wall, SDG 3 - Good Health and Well-being, Bacterial Proteins, Cell Wall, Animals, Humans, Tuberculosis, MESH: Animals, MESH: Tuberculosis, SDG 14 - Life Below Water, MESH: Mice, SCID, Bacterial Secretion Systems, MESH: Bacterial Proteins, MESH: Mice, Cells, Cultured, MESH: Humans, Virulence, Macrophages, MESH: Macrophages, Mycobacterium tuberculosis, Protein Transport, MESH: Cells, Cultured
Abstract: International audience; The chromosome of Mycobacterium tuberculosis encodes five type VII secretion systems (ESX-1-ESX-5). While the role of the ESX-1 and ESX-3 systems in M. tuberculosis has been elucidated, predictions for the function of the ESX-5 system came from data obtained in Mycobacterium marinum, where it transports PPE and PE_PGRS proteins and modulates innate immune responses. To define the role of the ESX-5 system in M. tuberculosis, in this study, we have constructed five M. tuberculosis H37Rv ESX-5 knockout/deletion mutants, inactivating eccA(5), eccD(5), rv1794 and esxM genes or the ppe25-pe19 region. Whereas the Mtbrv1794ko displayed no obvious phenotype, the other four mutants showed defects in secretion of the ESX-5-encoded EsxN and PPE41, a representative member of the large PPE protein family. Strikingly, the MtbeccD(5) ko mutant also showed enhanced sensitivity to detergents and hydrophilic antibiotics. When the virulence of the five mutants was evaluated, the MtbeccD(5) ko and MtbΔppe25-pe19 mutants were found attenuated both in macrophages and in the severe combined immune-deficient mouse infection model. Altogether these findings indicate an essential role of ESX-5 for transport of PPE proteins, cell wall integrity and full virulence of M. tuberculosis, thereby opening interesting new perspectives for the study of this human pathogen
Published: 2012

30. Immunization Route Dictates Cross-Priming Efficiency and Impacts the Optimal Timing of Adjuvant Delivery

Author: Sandrine Leroy, Hélène Jusforgues-Saklani, Isabelle Bouvier, Charlotte Auriau, Fabrice Lemaître, Philippe Bousso, Annick Lim, Matthew L. Albert, Antonio Bandeira, Helen K. W. Law, Brigitte Lemercier, Marie-Anne Nicola, James J. Moon, Immunobiologie des Cellules Dendritiques, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Régulation Immunitaire et Vaccinologie, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Dynamiques des Réponses Immunes, Imagerie Dynamique (Plate-Forme) (PFID), Institut Pasteur [Paris], Epidémiologie des Maladies Emergentes - Emerging Diseases Epidemiology, Pasteur-Cnam Risques infectieux et émergents (PACRI), Institut Pasteur [Paris]-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Institut Pasteur [Paris]-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM), Centre d'immunologie humaine (CIH), Biologie des Populations Lymphocytaires, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Department of Microbiology and Center for Immunology, University of Minnesota Medical School, University of Minnesota System-University of Minnesota System, This work was supported by La Ligue contre le cancer and the EURYIscheme and by the Association pour la Recherche sur le Cancer (projectDOC20110603227)., Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institut Pasteur [Paris] (IP), Institut Pasteur [Paris] (IP)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Institut Pasteur [Paris] (IP)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris]-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Institut Pasteur [Paris]-Conservatoire National des Arts et Métiers [CNAM] (CNAM), Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], and Vougny, Marie-Christine
Subjects: lcsh:Immunologic diseases. Allergy, [SDV.IMM] Life Sciences [q-bio]/Immunology, T cell, medicine.medical_treatment, Antigen presentation, Immunology, Priming (immunology), adjuvant delivery, 03 medical and health sciences, polyfunctional T cells, 0302 clinical medicine, Antigen, dentritic cells, Immunology and Allergy, Medicine, Intradermal injection, 030304 developmental biology, Original Research, 0303 health sciences, business.industry, Dendritic Cells, Vaccination, medicine.anatomical_structure, [SDV.IMM]Life Sciences [q-bio]/Immunology, cross-priming, business, lcsh:RC581-607, Adjuvant, CD8, 030215 immunology
Abstract: International audience; Delivery of cell-associated antigen represents an important strategy for vaccination. While many experimental models have been developed in order to define the critical parameters for efficient cross-priming, few have utilized quantitative methods that permit the study of the endogenous repertoire. Comparing different strategies of immunization, we report that local delivery of cell-associated antigen results in delayed T cell cross-priming due to the increased time required for antigen capture and presentation. In comparison, delivery of disseminated antigen resulted in rapid T cell priming. Surprisingly, local injection of cell-associated antigen, while slower, resulted in the differentiation of a more robust, polyfunctional, effector response. We also evaluated the combination of cell-associated antigen with poly I:C delivery and observed an immunization route-specific effect regarding the optimal timing of innate immune stimulation. These studies highlight the importance of considering the timing and persistence of antigen presentation, and suggest that intradermal injection with delayed adjuvant delivery is the optimal strategy for achieving CD8⁺ T cell cross-priming.
Published: 2011
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31. Primary T-cell immunodeficiency with immunodysregulation caused by autosomal recessive LCK deficiency

Author: Fabien Touzot, Stéphane Gérart, Sylvain Latour, Isabelle Callebaut, André Veillette, Frédéric Rieux-Laucat, Alain Fischer, Capucine Picard, Sébastien Héritier, Claire Hivroz, Zosia Maciorowski, Clotilde Randriamampita, Nathalie Lambert, Stéphane Blanche, Emmanuel Martin, Pierre Quartier, Despina Moshous, Nicole Brousse, Annick Lim, Jean Soulier, Fabian Hauck, Laboratoire du D eveloppement Normal et Pathologique du Syst eme Immunitaire, Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Référence Déficits Immunitaires Héréditaires (CEREDIH), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Régulation Immunitaire et Vaccinologie, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Pathologie cellulaire : aspects moléculaires et viraux / Pathologie et Virologie Moléculaire, Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), Flow Cytometry Core Facility, Unite d'Immunologie et H ematologie P ediatrique and iService d'Anatomie et de Cytologie Pathologiques, Service d'Anatomie et de Cytologie Pathologiques, Institut de minéralogie et de physique des milieux condensés (IMPMC), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7)-Institut de Physique du Globe de Paris (IPG Paris)-Centre National de la Recherche Scientifique (CNRS), Molecular Oncology Research Unit, Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), INSERM 980, Laboratory of Human Genetics of Infectious Disease, Laboratory of Human Genetics of Infectious Disease, Imagine - Institut des maladies génétiques ( IMAGINE - U1163 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut Cochin ( UM3 (UMR 8104 / U1016) ), Centre de Référence Déficits Immunitaires Héréditaires ( CEREDIH ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), Université Paris Diderot - Paris 7 ( UPD7 ) -Institut Universitaire d'Hématologie ( IUH ), Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris]-Centre National de la Recherche Scientifique ( CNRS ), Institut de minéralogie et de physique des milieux condensés ( IMPMC ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -IPG PARIS-Université Paris Diderot - Paris 7 ( UPD7 ) -Centre National de la Recherche Scientifique ( CNRS ), Immunité et cancer ( U932 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut Curie-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC)-IPG PARIS-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), [Institut Cochin] Departement Infection, immunité, inflammation, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Centre National de la Recherche Scientifique (CNRS), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Curie-Université Paris Descartes - Paris 5 (UPD5)
Subjects: CD4-Positive T-Lymphocytes, DNA Mutational Analysis, chemistry.chemical_compound, 0302 clinical medicine, recurrent infections, Immunology and Allergy, ComputingMilieux_MISCELLANEOUS, Cells, Cultured, Immunodeficiency, 0303 health sciences, CD28, hemic and immune systems, lymphopenia, autoinflammation, Pedigree, LCK, 3. Good health, Child, Preschool, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, France, T-Cell Immunodeficiency, Tyrosine kinase, Primary Immunodeficiency Diseases, genetic defect, Immunology, Mutation, Missense, Receptors, Antigen, T-Cell, Genes, Recessive, chemical and pharmacologic phenomena, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, 03 medical and health sciences, SRC tyrosine kinase, medicine, Humans, Genetic Predisposition to Disease, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Calcium Signaling, Kinase activity, T-Lymphocytopenia, Idiopathic CD4-Positive, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, 030304 developmental biology, Polymorphism, Genetic, T-cell receptor, Immunologic Deficiency Syndromes, Tyrosine phosphorylation, medicine.disease, CD4, chemistry, Lymphocyte Specific Protein Tyrosine Kinase p56(lck), Cancer research, immunodeficiency, T-cell receptor signaling, CD8, 030215 immunology
Abstract: Background Signals emanating from the antigen T-cell receptor (TCR) are required for T-cell development and function. The T lymphocyte–specific protein tyrosine kinase (Lck) is a key component of the TCR signaling machinery. On the basis of its function, we considered LCK a candidate gene in patients with combined immunodeficiency. Objective We identify and describe a child with a T-cell immunodeficiency caused by a homozygous missense mutation of the LCK gene (c.1022T>C) resulting from uniparental disomy. Methods Genetic, molecular, and functional analyses were performed to characterize the Lck deficiency, and the associated clinical and immunologic phenotypes are reported. Results The mutant LCK protein (p.L341P) was weakly expressed with no kinase activity and failed to reconstitute TCR signaling in LCK-deficient T cells. The patient presented with recurrent respiratory tract infections together with predominant early-onset inflammatory and autoimmune manifestations. The patient displayed CD4 + T-cell lymphopenia and low levels of CD4 and CD8 expression on the T-cell surface. The residual T lymphocytes had an oligoclonal T-cell repertoire and exhibited a profound TCR signaling defect, with only weak tyrosine phosphorylation signals and no Ca 2+ mobilization in response to TCR stimulation. Conclusion We report a new form of T-cell immunodeficiency caused by a LCK gene defect, highlighting the essential role of Lck in human T-cell development and responses. Our results also point out that defects in the TCR signaling cascade often result in abnormal T-cell differentiation and functions, leading to an important risk factor for inflammation and autoimmunity.
Published: 2012

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31 results on '"Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)"'

1. The fully synthetic glycopeptide MAG-Tn3 therapeutic vaccine induces tumor-specific cytotoxic antibodies in breast cancer patients

2. IL-17 suppresses the therapeutic activity of cancer vaccines through the inhibition of CD8 + T-cell responses

3. Design, Synthesis, and Immunological Evaluation of a Multicomponent Construct Based on a Glycotripeptoid Core Comprising B and T Cell Epitopes and a Toll-like Receptor 7 Agonist That Elicits Potent Immune Responses

4. Pore‐formation by adenylate cyclase toxoid activates dendritic cells to prime CD8+and CD4+T cells

5. Mitochondrial reactive oxygen species regulate the induction of CD8+ T cells by plasmacytoid dendritic cells

6. Tumor-Derived TGFβ Alters the Ability of Plasmacytoid Dendritic Cells to Respond to Innate Immune Signaling

7. Lack of MHC class II molecules favors CD8 + T- cell infiltration into tumors associated with an increased control of tumor growth

8. Respiratory Syncytial Virus Infects Regulatory B Cells in Human Neonates via Chemokine Receptor CX3CR1 and Promotes Lung Disease Severity

9. Corrigendum: A Universal Influenza Vaccine Can Lead to Disease Exacerbation or Viral Control Depending on Delivery Strategies

10. Colonization with Helicobacter is concomitant with modified gut microbiota and drastic failure of the immune control of Mycobacterium tuberculosis

11. Genomic analysis of smooth tubercle bacilli provides insights into ancestry and pathoadaptation of Mycobacterium tuberculosis

12. B cells promote tumor progression in a mouse model of HPV-mediated cervical cancer

13. CD4+ T Cells Recognizing PE/PPE Antigens Directly or via Cross Reactivity Are Protective against Pulmonary Mycobacterium tuberculosis Infection

14. The fully synthetic MAG-Tn3 therapeutic vaccine containing the tetanus toxoid-derived TT830-844 universal epitope provides anti-tumor immunity

15. A Universal Influenza Vaccine Can Lead to Disease Exacerbation or Viral Control Depending on Delivery Strategies

16. Strong Immunogenicity and Cross-Reactivity of Mycobacterium tuberculosis ESX-5 Type VII Secretion -Encoded PE-PPE Proteins Predicts Vaccine Potential

17. Dectin-1 activation unlocks IL12A expression and reveals the TH1 potency of neonatal dendritic cells

18. Rapamycin Impairs Antitumor CD8+ T-cell Responses and Vaccine-Induced Tumor Eradication

19. Antigen targeting to CD11b+ dendritic cells in association with TLR4/TRIF signaling promotes strong CD8+ T cell responses

20. B lymphocytes undergo TLR2-dependent apoptosis upon Shigella infection

21. CD4 T cells with effector memory phenotype and function develop in the sterile environment of the fetus

22. Poly(I:C)-induced protection of neonatal mice against intestinal Cryptosporidium parvum infection requires an additional TLR5 signal provided by the gut flora

23. Decoration of outer membrane vesicles with multiple antigens using an autotransporter approach

24. Whole-exome sequencing identifies Coronin-1A deficiency in 3 siblings with immunodeficiency and EBV-associated B-cell lymphoproliferation

25. Intestinal CD103+ dendritic cells are key players in the innate immune control of [i]Cryptosporidium parvum[/i] infection in neonatal mice

26. Neonatal Plasmacytoid Dendritic Cells (pDCs) Display Subset Variation but Can Elicit Potent Anti-Viral Innate Responses

27. Pivotal role of plasmacytoid dendritic cells in inflammation and NK-cell responses after TLR9 triggering in mice

28. Phagosomal Rupture by Mycobacterium tuberculosis Results in Toxicity and Host Cell Death

29. Disruption of the ESX-5 system of Mycobacterium tuberculosis causes loss of PPE protein secretion, reduction of cell wall integrity and strong attenuation

30. Immunization Route Dictates Cross-Priming Efficiency and Impacts the Optimal Timing of Adjuvant Delivery

31. Primary T-cell immunodeficiency with immunodysregulation caused by autosomal recessive LCK deficiency

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31 results on '"Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)"'

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