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

Significance CD8 + T lymphocytes, which are typically devoted to eliminate malignant and infected cells, have been described in the central nervous system (CNS) of patients and mice with amyotrophic lateral sclerosis (ALS). However, their role in ALS pathogenesis has yet to be unraveled. Here, we show that ablation of CD8 + T cells in ALS mice increased the number of surviving motoneurons. CD8 + T cells expressing the ALS-causing superoxide dismutase-1 mutant protein recognize and selectively kill motoneurons in vitro. To exert their cytotoxic function, mutant CD8 + T cells required presentation of the antigen-MHC-I complex at the surface of the motoneurons. Analysis of T cell receptor diversity supports the evidence that self-reactive CD8 + T lymphocytes infiltrate the CNS of ALS mice to exert cytotoxic function.