Laboratoire Charles Coulomb UMR 5221 CNRS/UM2 (L2C)


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

Auteur(s): Coque Emmanuelle, Salsac Céline, Espinosa-carrasco Gabriel, Varga B., Degauque Nicolas, Cadoux Marion, Crabé Roxane, Virenque Anaïs, Soulard Claire, Fierle Julie K., Brodovitch Alexandre, Libralato Margot, Vegh Attila Gergely, Venteo Stéphanie, Scamps Frédérique, Boucraut José, Laplaud David, Hernandez Javier, Gergely C., Vincent Thierry, Raoul Cedric

(Article) Publié: Proceedings Of The National Academy Of Sciences Of The United States Of America, vol. 116 p.2312-2317 (2019)

Ref HAL: hal-02012190_v1
DOI: 10.1073/pnas.1815961116
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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 neu- rodegenerative 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 spi- nal motoneuron loss. Using motoneuron-CD8+ T cell coculture sys- tems, 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 interac- tion strength by atomic force microscopy-based single-cell force spec- troscopy 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.