%0 Journal Article
%T Cytotoxic CD8 + T lymphocytes expressing ALS-causing SOD1 mutant selectively trigger death of spinal motoneurons
%+ Institut des Neurosciences de Montpellier (INM)
%+ Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB)
%+ Laboratoire Charles Coulomb (L2C)
%+ Institut de transplantation urologie-néphrologie (ITUN)
%+ Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI)
%+ Université de Lausanne = University of Lausanne (UNIL)
%+ Laboratoire d'Immunologie [Hôpital de la Conception - APHM]
%+ Filière Neuromusculaire (FILNEMUS)
%+ Hungarian Academy of Sciences (MTA)
%+ Institut de Neurosciences de la Timone (INT)
%+ CHU Montpellier
%A Coque, Emmanuelle
%A Salsac, Céline
%A Espinosa-Carrasco, Gabriel
%A Varga, Bela
%A Degauque, Nicolas
%A Cadoux, Marion
%A Crabé, Roxane
%A Virenque, Anaïs
%A Soulard, Claire
%A Fierle, Julie, Katrin
%A Brodovitch, Alexandre
%A Libralato, Margot
%A Végh, Attila, G
%A Venteo, Stéphanie
%A Scamps, Frédérique
%A Boucraut, José
%A Laplaud, David
%A Hernandez, Javier
%A Gergely, Csilla
%A Vincent, Thierry
%A Raoul, Cédric
%< avec comité de lecture
%@ 0027-8424
%J Proceedings of the National Academy of Sciences of the United States of America
%I National Academy of Sciences
%V 116
%N 6
%P 2312-2317
%8 2019-02-05
%D 2019
%R 10.1073/pnas.1815961116
%M 30674678
%K amyotrophic lateral sclerosis
%K cytotoxic T lymphocytes
%K major histocompatibility complex I
%K motoneuron
%K neuroimmunity.
%Z Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/NeurobiologyJournal articles
%X 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.
%G English
%2 https://inserm.hal.science/inserm-03171288/document
%2 https://inserm.hal.science/inserm-03171288/file/PNAS%202019.pdf
%L inserm-03171288
%U https://inserm.hal.science/inserm-03171288
%~ INSERM
%~ UNIV-NANTES
%~ CNRS
%~ UNIV-AMU
%~ INM
%~ L2C
%~ INT
%~ MIPS
%~ BS
%~ UNIV-MONTPELLIER
%~ CRTI
%~ ANR
%~ NEUROMARSEILLE
%~ NANTES-UNIVERSITE
%~ UNIV-NANTES-AV2022
%~ UM-2015-2021
%~ CR2TI
%~ UFR-MEDECINE-NANTES