Cytotoxic CD8⁺ T lymphocytes expressing ALS-causing SOD1 mutant selectively trigger death of spinal motoneurons

• Published in: Proceedings of the National Academy of Sciences - PNAS 2019-02, Vol.116 (6), p.2312-2317
• Main Authors: Coque, Emmanuelle, Salsac, Céline, Espinosa-Carrasco, Gabriel, Varga, Béla, Degauque, Nicolas, Cadoux, Marion, Crabé, Roxane, Virenque, Anaïs, Soulard, Claire, Fierle, Julie K., Brodovitch, Alexandre, Libralato, Margot, Végh, Attila G., Venteo, Stéphanie, Scamps, Frédérique, Boucraut, José, Laplaud, David, Hernandez, Javier, Gergely, Csilla, Vincent, Thierry, Raoul, Cédric
• Format: Article
• Language: English
• Subjects: Amyotrophic Lateral Sclerosis - diagnosis; Amyotrophic Lateral Sclerosis - genetics; Amyotrophic Lateral Sclerosis - metabolism; Amyotrophic Lateral Sclerosis - physiopathology; Animals; Biological Sciences; Cell Communication - immunology; Cell Death; Cell Survival - genetics; Disease Models, Animal; fas Receptor - metabolism; Gene Expression; Granzymes - metabolism; Histocompatibility Antigens Class I - immunology; Life Sciences; Lymphocyte Activation - immunology; Mice; Mice, Transgenic; Motor Neurons - immunology; Motor Neurons - metabolism; Mutation; Neurobiology; Neurons and Cognition; Phenotype; Severity of Illness Index; Spinal Cord - cytology; Superoxide Dismutase-1 - genetics; T-Lymphocytes, Cytotoxic - immunology; T-Lymphocytes, Cytotoxic - metabolism
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1815961116

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 SOD1G93A 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.