Journal article

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.
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  • 2019-01-25
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
  • English
Open access status
hybrid
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Persistent URL
https://sonar.ch/global/documents/115340
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