| First Author | Coque E | Year | 2019 |
| Journal | Proc Natl Acad Sci U S A | Volume | 116 |
| Issue | 6 | Pages | 2312-2317 |
| PubMed ID | 30674678 | Mgi Jnum | J:271178 |
| Mgi Id | MGI:6278447 | Doi | 10.1073/pnas.1815961116 |
| Citation | Coque E, et al. (2019) Cytotoxic CD8(+) T lymphocytes expressing ALS-causing SOD1 mutant selectively trigger death of spinal motoneurons. Proc Natl Acad Sci U S A 116(6):2312-2317 |
| abstractText | 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-gamma, 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. |
