Cytotoxic CD8+ T lymphocytes expressing ALS-causing SOD1 mutant selectively trigger death of spinal motoneurons.
-
Coque E
The Neuroscience Institute of Montpellier, Inserm UMR1051, University of Montpellier, Saint Eloi Hospital, 34090 Montpellier, France.
-
Salsac C
The Neuroscience Institute of Montpellier, Inserm UMR1051, University of Montpellier, Saint Eloi Hospital, 34090 Montpellier, France.
-
Espinosa-Carrasco G
Inserm U1183, Institute for Regenerative Medicine and Biotherapy, University of Montpellier, 34090 Montpellier, France.
-
Varga B
Charles Coulomb laboratory, L2C, UMR5221, University of Montpellier, CNRS, 34095 Montpellier, France.
-
Degauque N
Centre de Recherche en Transplantation et Immunologie UMR1064, INSERM, Université de Nantes, 44093 Nantes, France.
-
Cadoux M
Centre de Recherche en Transplantation et Immunologie UMR1064, INSERM, Université de Nantes, 44093 Nantes, France.
-
Crabé R
The Neuroscience Institute of Montpellier, Inserm UMR1051, University of Montpellier, Saint Eloi Hospital, 34090 Montpellier, France.
-
Virenque A
The Neuroscience Institute of Montpellier, Inserm UMR1051, University of Montpellier, Saint Eloi Hospital, 34090 Montpellier, France.
-
Soulard C
The Neuroscience Institute of Montpellier, Inserm UMR1051, University of Montpellier, Saint Eloi Hospital, 34090 Montpellier, France.
-
Fierle JK
Ludwig Institute for Cancer Research, Lausanne University, CH 1015 Lausanne, Switzerland.
-
Brodovitch A
Referral Centre for ALS and Neuromuscular Diseases, La Timone University Hospital, Aix-Marseille University, 13005 Marseille, France.
-
Libralato M
The Neuroscience Institute of Montpellier, Inserm UMR1051, University of Montpellier, Saint Eloi Hospital, 34090 Montpellier, France.
-
Végh AG
Institute of Biophysics, Biological Research Centre, Hungarian Academy of Sciences, H 6726 Szeged, Hungary.
-
Venteo S
The Neuroscience Institute of Montpellier, Inserm UMR1051, University of Montpellier, Saint Eloi Hospital, 34090 Montpellier, France.
-
Scamps F
The Neuroscience Institute of Montpellier, Inserm UMR1051, University of Montpellier, Saint Eloi Hospital, 34090 Montpellier, France.
-
Boucraut J
Immunology Laboratory, Assistance Publique-Hôpitaux de Marseille, Conception Hospital, 13005 Marseille, France.
-
Laplaud D
Centre de Recherche en Transplantation et Immunologie UMR1064, INSERM, Université de Nantes, 44093 Nantes, France.
-
Hernandez J
Inserm U1183, Institute for Regenerative Medicine and Biotherapy, University of Montpellier, 34090 Montpellier, France.
-
Gergely C
Charles Coulomb laboratory, L2C, UMR5221, University of Montpellier, CNRS, 34095 Montpellier, France.
-
Vincent T
The Neuroscience Institute of Montpellier, Inserm UMR1051, University of Montpellier, Saint Eloi Hospital, 34090 Montpellier, France.
-
Raoul C
The Neuroscience Institute of Montpellier, Inserm UMR1051, University of Montpellier, Saint Eloi Hospital, 34090 Montpellier, France; cedric.raoul@inserm.fr.
Show more…
Published in:
- Proceedings of the National Academy of Sciences of the United States of America. - 2019
English
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.
-
Language
-
-
Open access status
-
hybrid
-
Identifiers
-
-
Persistent URL
-
https://sonar.ch/global/documents/115340
Statistics
Document views: 17
File downloads: