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

Proc Natl Acad Sci U S A. 2019 Feb 5;116(6):2312-2317. doi: 10.1073/pnas.1815961116. Epub 2019 Jan 23.


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.

Keywords: amyotrophic lateral sclerosis; cytotoxic T lymphocytes; major histocompatibility complex I; motoneuron; neuroimmunity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyotrophic Lateral Sclerosis / diagnosis
  • Amyotrophic Lateral Sclerosis / genetics*
  • Amyotrophic Lateral Sclerosis / metabolism*
  • Amyotrophic Lateral Sclerosis / physiopathology
  • Animals
  • Cell Communication / immunology
  • Cell Death
  • Cell Survival / genetics
  • Disease Models, Animal
  • Gene Expression*
  • Granzymes / metabolism
  • Histocompatibility Antigens Class I / immunology
  • Lymphocyte Activation / immunology
  • Mice
  • Mice, Transgenic
  • Motor Neurons / immunology
  • Motor Neurons / metabolism*
  • Mutation*
  • Phenotype
  • Severity of Illness Index
  • Spinal Cord / cytology
  • Superoxide Dismutase-1 / genetics*
  • T-Lymphocytes, Cytotoxic / immunology
  • T-Lymphocytes, Cytotoxic / metabolism*
  • fas Receptor / metabolism


  • Histocompatibility Antigens Class I
  • fas Receptor
  • Superoxide Dismutase-1
  • Granzymes