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1. Embryonic Lethality in Homozygous Human Her-2 Transgenic Mice Due to Disruption of the Pds5b Gene.

Author

Carmen S M Yong, Janelle Sharkey, Belinda Duscio, Ben Venville, Wei-Zen Wei, Richard F Jones, Clare Y Slaney, Gisela Mir Arnau, Anthony T Papenfuss, Jan Schröder, Phillip K Darcy, and Michael H Kershaw

Subjects
Medicine, Science
Abstract

The development of antigen-targeted therapeutics is dependent on the preferential expression of tumor-associated antigens (TAA) at targetable levels on the tumor. Tumor-associated antigens can be generated de novo or can arise from altered expression of normal basal proteins, such as the up-regulation of human epidermal growth factor receptor 2 (Her2/ErbB2). To properly assess the development of Her2 therapeutics in an immune tolerant model, we previously generated a transgenic mouse model in which expression of the human Her2 protein was present in both the brain and mammary tissue. This mouse model has facilitated the development of Her2 targeted therapies in a clinically relevant and suitable model. While heterozygous Her2+/- mice appear to develop in a similar manner to wild type mice (Her2-/-), it has proven difficult to generate homozygous Her2+/+ mice, potentially due to embryonic lethality. In this study, we performed whole genome sequencing to determine if the integration site of the Her2 transgene was responsible for this lethality. Indeed, we report that the Her2 transgene had integrated into the Pds5b (precocious dissociation of sisters) gene on chromosome 5, as a 162 copy concatemer. Furthermore, our findings demonstrate that Her2+/+ mice, similar to Pds5b-/- mice, are embryonic lethal and confirm the necessity for Pds5b in embryonic development. This study confirms the value of whole genome sequencing in determining the integration site of transgenes to gain insight into associated phenotypes.

Published
2015
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2. CD3bright signals on γδ T cells identify IL-17A-producing Vγ6Vδ1+ T cells

Author

François Trottein, Adam P Uldrich, Thierry Mallevaey, Christophe Paget, Paul J Neeson, Dale I. Godfrey, Geoffrey R. Hill, N. A. Gherardin, Paul A. Beavis, David Dombrowicz, Delphine Staumont-Sallé, Maya Hassane, Denis A. Mogilenko, N. K. Escalante, Mark J. Smyth, Fernando Souza-Fonseca-Guimaraes, Melvyn T. Chow, Helene Duret, David Ritchie, Gabrielle T. Belz, Derudas, Marie-Hélène, 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), Cancer immunology program, Peter MacCallum Cancer Center, Sir Peter MacCallum Department of Oncology and Department of Pathology, University of Melbourne, Department of Microbiology and Immunology, QIMR Berghofer Medical Research Institute, Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 (RNMCD), 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), European Genomic Institute of Diabetes (EGID), Service de dermatologie, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Department of Immunology, University of Toronto, Department of Bone Marrow Transplantation, Royal Brisbane Hospital, Division of Molecular Immunology, The Walter and Eliza Hall Institute of Medical Research (WEHI), School of Medicine, University of Queensland [Brisbane], his work was supported by an NHMRC Program Grant (454569 and 1013367). CP was supported by a postdoctoral fellowship from the US Department of Defense (W81XWH‐11‐1‐0585) and INSERM. MJS and FSFG were supported by a National Health and Medical Research Council of Australia (NHMRC) Australia Fellowship and Program Grant (1013367). MTC was supported by a Cancer Research Institute PhD scholarship. GTB was supported by an ARC Future Fellowship. FT was supported by CNRS. PN was supported by a National Health and Medical Research Council of Australia (NHMRC) Program Grant (1013367). DIG was supported by an NHMRC Senior Principal Research Fellowship (1020770). NAG was supported by a Leukaemia Foundation of Australia postgraduate scholarship. TM is supported by research grants from the Canadian Institutes of Health Research and the Crohn and Colitis Foundation of Canada, as well as a Tier 2 Canada Research Chair. NKE is a recipient of a Vanier Canada Graduate Scholarship. DAM, DS‐S and DD were supported by the Agence Nationale de la Recherche (ANR‐10‐LABX‐46) and the ‘Fondation de France’., We thank Josette Fontaine, Shin‐Foong Ngiow, Deborah Knight, Sébastien Fleury, Julien Wartelle and Kim Steegh for technical assistance. We thank Qerime Mundrea, Ben Venville, Jessica May, Joanne Sutton and Liam Town for maintaining and caring for the mice. We also thank the Peter MacCallum flow cytometry core facility for technical assistance., Institut Européen de Génomique du Diabète - European Genomic Institute for Diabetes - FR 3508 (EGID), 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 National de la Recherche Scientifique (CNRS), 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), and Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Male, CD3 Complex, Inflammasomes, T-Lymphocytes, Interleukin-1beta, MESH: Amino Acid Sequence, MESH: Interleukin-1beta/metabolism, Interleukin-23, MESH: Lung/drug effects, MESH: Skin/immunology, MESH: Lung/immunology, MESH: CD3 Complex/chemistry, MESH: Lymphocyte Subsets/immunology, Immunology and Allergy, Homeostasis, MESH: Animals, IL-2 receptor, MESH: Homeostasis/drug effects, Lung, MESH: Immunity, Skin, MESH: Interleukin-23, Orphan receptor, education.field_of_study, Imiquimod, biology, MESH: Nuclear Receptor Subfamily 1, Group F, Member 3/metabolism, Interleukin-17, Receptors, Antigen, T-Cell, gamma-delta, MESH: T-Lymphocytes/immunology, Nuclear Receptor Subfamily 1, Group F, Member 3, MESH: CD3 Complex/metabolism, 3. Good health, MESH: NLR Family, Pyrin Domain-Containing 3 Protein, medicine.anatomical_structure, Phenotype, MESH: Aminoquinolines/pharmacology, MESH: Carrier Proteins/metabolism, Aminoquinolines, [SDV.IMM]Life Sciences [q-bio]/Immunology, MESH: Interleukin-17/biosynthesis, [SDV.IMM] Life Sciences [q-bio]/Immunology, MESH: Skin/drug effects, CD3, T cell, MESH: T-Lymphocytes/drug effects, Immunology, Population, Molecular Sequence Data, MESH: Germ Cells/drug effects, MESH: Imiquimod, MESH: Phenotype, Immune system, Antigen, MESH: Mice, Inbred C57BL, NLR Family, Pyrin Domain-Containing 3 Protein, MESH: Inflammasomes/drug effects, medicine, Animals, Amino Acid Sequence, education, MESH: Molecular Sequence Data, Innate immune system, MESH: Inflammasomes/metabolism, Immunity, Cell Biology, MESH: Lymphocyte Subsets/drug effects, MESH: Male, Lymphocyte Subsets, Mice, Inbred C57BL, Germ Cells, MESH: Receptors, Antigen, T-Cell, gamma-delta/metabolism, biology.protein, Carrier Proteins
Abstract

International audience; Interleukin-17A (IL-17A) is a pro-inflammatory cytokine that has an important role at mucosal sites in a wide range of immune responses including infection, allergy and auto-immunity. γδ T cells are recognized as IL-17 producers, but based on the level of CD3 expression, we now define the remarkable ability of a CD3(bright) γδ T-cell subset with an effector memory phenotype to rapidly produce IL-17A, but not interferon-γ. CD3(bright) γδ T cells uniformly express the canonical germline encoded Vγ6/Vδ1(+) T-cell receptor. They are widely distributed with a preferential representation in the lungs and skin are negatively impacted in the absence of retinoic acid receptor-related orphan receptor gammat expression or endogenous flora. This population responded rapidly to various stimuli in a mechanism involving IL-23 and NOD-like receptor family, pyrin domain containing 3 (NLRP3)-inflammasome-dependent IL-1β. Finally, we demonstrated that IL-17-producing CD3(bright) γδ T cells responded promptly and strongly to pneumococcal infection and during skin inflammation. Here, we propose a new way to specifically analyze IL-17-producing Vγ6/Vδ1(+) T cells based on the level of CD3 signals. Using this gating strategy, our data reinforce the crucial role of this γδ T-cell subset in respiratory and skin disorders.

Published
2014
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