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

Abstract : 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.
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https://www.hal.inserm.fr/inserm-03171288
Contributor : Cédric Raoul <>
Submitted on : Tuesday, March 16, 2021 - 7:58:24 PM
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Long-term archiving on: : Thursday, June 17, 2021 - 8:05:04 PM

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Emmanuelle Coque, Céline Salsac, Gabriel Espinosa-Carrasco, Bela Varga, Nicolas Degauque, et al.. Cytotoxic CD8 + T lymphocytes expressing ALS-causing SOD1 mutant selectively trigger death of spinal motoneurons. 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⟩. ⟨inserm-03171288⟩

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