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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-?, 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.

SUBMITTER: Coque E

PROVIDER: S-EPMC6369778 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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

Coque Emmanuelle E Salsac Céline C Espinosa-Carrasco Gabriel G Varga Béla B Degauque Nicolas N Cadoux Marion M Crabé Roxane R Virenque Anaïs A Soulard Claire C Fierle Julie K JK Brodovitch Alexandre A Libralato Margot M Végh Attila G AG Venteo Stéphanie S Scamps Frédérique F Boucraut José J Laplaud David D Hernandez Javier J Gergely Csilla C Vincent Thierry T Raoul Cédric C

Proceedings of the National Academy of Sciences of the United States of America 20190123 6

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 ...[more]

PMID: 30674678

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Project description:While the death of motor neuron is a pathological hallmark of amyotrophic lateral sclerosis (ALS), defects in other cell types or organs may also actively contribute to ALS disease progression. ALS patients experience progressive skeletal muscle wasting that may not only exacerbate neuronal degeneration, but likely has a significant impact on bone function. In our previous published study, we have discovered severe bone loss in an ALS mouse model with overexpression of ALS-associated mutation SOD1G93A (G93A). Here we further provide a mechanistic understanding of the bone loss in ALS animal and cellular models. Combining mitochondrial fluorescent indicators and confocal live cell imaging, we discovered abnormalities in mitochondrial network and dynamics in primary osteocytes derived from the same ALS mouse model G93A. Those mitochondrial defects occur in ALS mice after the onset of neuromuscular symptoms, indicating that mitochondria in bone cells respond to muscle atrophy during ALS disease progression. To examine whether ALS mutation has a direct contribution to mitochondrial dysfunction independent of muscle atrophy, we evaluated mitochondrial morphology and motility in cultured osteocytes (MLO-Y4) with overexpression of mitochondrial targeted SOD1G93A. Compared with osteocytes overexpressing the wild type SOD1 as a control, the SOD1G93A osteocytes showed similar defects in mitochondrial network and dynamic as that of the primary osteocytes derived from the ALS mouse model. In addition, we further discovered that overexpression of SOD1G93A enhanced the expression level of dynamin-related protein 1 (Drp1), a key protein promoting mitochondrial fission activity, and reduced the expression level of optic atrophy protein 1 (OPA1), a key protein related to mitochondrial fusion. A specific mitochondrial fission inhibitor (Mdivi-1) partially reversed the effect of SOD1G93A on mitochondrial network and dynamics, indicating that SOD1G93A likely promotes mitochondrial fission, but suppresses the fusion activity. Our data provide the first evidence that mitochondria show abnormality in osteocytes derived from an ALS mouse model. The accumulation of mutant SOD1G93A protein inside mitochondria directly causes dysfunction in mitochondrial dynamics in cultured MLO-Y4 osteocytes. In addition, the ALS mutation SOD1G93A-mediated dysfunction in mitochondrial dynamics is associated with an enhanced apoptosis in osteocytes, which could be a potential mechanism underlying the bone loss during ALS progression.

Dataset Information

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

Publications

Cytotoxic CD8<sup>+</sup> T lymphocytes expressing ALS-causing SOD1 mutant selectively trigger death of spinal motoneurons.

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