Cytotoxic CD8 + T lymphocytes expressing ALS-causing SOD1 mutant selectively trigger death of spinal motoneurons
| Autor: | Nicolas Degauque, Claire Soulard, Frédérique Scamps, David Laplaud, Attila Gergely Végh, Céline Salsac, Margot Libralato, Cédric Raoul, Emmanuelle Coque, Stéphanie Ventéo, Csilla Gergely, José Boucraut, Gabriel Espinosa-Carrasco, Roxane Crabé, Béla Varga, Alexandre Brodovitch, Thierry Vincent, Anaïs Virenque, Javier Hernandez, Julie K. Fierle, Marion Cadoux |
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| Přispěvatelé: | Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Laboratoire Charles Coulomb (L2C), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut de transplantation urologie-néphrologie (ITUN), Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Université de Lausanne (UNIL), Laboratoire d'Immunologie [Hôpital de la Conception - APHM], Assistance Publique - Hôpitaux de Marseille (APHM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital de la Conception [CHU - APHM] (LA CONCEPTION)-Centre National de la Recherche Scientifique (CNRS), Filière Neuromusculaire (FILNEMUS), Hungarian Academy of Sciences (MTA), Institut de Neurosciences de la Timone (INT), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), CHU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Immunoregulation And Immunointervention in Transplantation and Autoimmunity (Team 4 - U1064 Inserm - CRTI), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Ludwig Institute for Cancer Research, University Hospital La Timone, 13005 Marseille, Assistance Publique - Hôpitaux de Marseille (APHM), Biological Research Center [Hungarian Academy of Sciences], CHU Saint-Eloi, Raoul, Cédric, Institut des Neurosciences de Montpellier (INM), Université de Lausanne = University of Lausanne (UNIL), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM) |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
amyotrophic lateral sclerosis T cell [PHYS.PHYS.PHYS-BIO-PH]Physics [physics]/Physics [physics]/Biological Physics [physics.bio-ph] [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology Major histocompatibility complex cytotoxic T lymphocytes 03 medical and health sciences 0302 clinical medicine Immune system medicine Cytotoxic T cell motoneuron Amyotrophic Lateral Sclerosis/diagnosis Amyotrophic Lateral Sclerosis/genetics Amyotrophic Lateral Sclerosis/metabolism Amyotrophic Lateral Sclerosis/physiopathology Animals Cell Communication/immunology Cell Death Cell Survival/genetics Disease Models Animal Gene Expression Granzymes/metabolism Histocompatibility Antigens Class I/immunology Lymphocyte Activation/immunology Mice Mice Transgenic Motor Neurons/immunology Motor Neurons/metabolism Mutation Phenotype Severity of Illness Index Spinal Cord/cytology Superoxide Dismutase-1/genetics T-Lymphocytes Cytotoxic/immunology T-Lymphocytes Cytotoxic/metabolism fas Receptor/metabolism major histocompatibility complex I neuroimmunity Multidisciplinary biology Chemistry T-cell receptor [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology Acquired immune system major histocompatibility complex 3. Good health Cell biology 030104 developmental biology medicine.anatomical_structure Granzyme nervous system biology.protein 030217 neurology & neurosurgery CD8 |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America Proceedings of the National Academy of Sciences of the United States of America, National Academy of Sciences, 2019, 116 (6), pp.2312-2317. ⟨10.1073/pnas.1815961116⟩ Proceedings of the National Academy of Sciences of the United States of America, 2019, 116 (6), pp.2312-2317. ⟨10.1073/pnas.1815961116⟩ Proceedings of the National Academy of Sciences of the United States of America, vol. 116, no. 6, pp. 2312-2317 |
| ISSN: | 0027-8424 1091-6490 |
| DOI: | 10.1073/pnas.1815961116⟩ |
| Popis: | Adaptive immune response is part of the dynamic changes that accompany motoneuron loss in amyotrophic lateral sclerosis (ALS). CD4 + T cells that regulate a protective immunity during the neurodegenerative process have received the most attention. CD8 + T cells are also observed in the spinal cord of patients and ALS mice although their contribution to the disease still remains elusive. Here, we found that activated CD8 + T lymphocytes infiltrate the central nervous system (CNS) of a mouse model of ALS at the symptomatic stage. Selective ablation of CD8 + T cells in mice expressing the ALS-associated superoxide dismutase-1 (SOD1) G93A mutant decreased spinal motoneuron loss. Using motoneuron-CD8 + T cell coculture systems, we found that mutant SOD1-expressing CD8 + T lymphocytes selectively kill motoneurons. This cytotoxicity activity requires the recognition of the peptide-MHC-I complex (where MHC-I represents major histocompatibility complex class I). Measurement of interaction strength by atomic force microscopy-based single-cell force spectroscopy demonstrated a specific MHC-I-dependent interaction between motoneuron and SOD1 G93A CD8 + T cells. Activated mutant SOD1 CD8 + T cells produce interferon-γ, which elicits the expression of the MHC-I complex in motoneurons and exerts their cytotoxic function through Fas and granzyme pathways. In addition, analysis of the clonal diversity of CD8 + T cells in the periphery and CNS of ALS mice identified an antigen-restricted repertoire of their T cell receptor in the CNS. Our results suggest that self-directed immune response takes place during the course of the disease, contributing to the selective elimination of a subset of motoneurons in ALS. |
| Databáze: | OpenAIRE |
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