Clonally expanded CD8 T cells characterize amyotrophic lateral sclerosis-4

Area of Science:

• Neuroimmunology
• Genetics of neurodegenerative diseases
• Motor neuron diseases

Background:

• Amyotrophic lateral sclerosis (ALS) is a diverse neurodegenerative disorder affecting motor neurons and muscle control.
• ALS heterogeneity is not fully explained by genetic factors, and the role of immune system features remains unclear.
• Amyotrophic lateral sclerosis type 4 (ALS4), caused by SETX mutations, presents with juvenile onset and slow progression.

Purpose of the Study:

• To investigate the immunological signature associated with ALS4.
• To explore the role of the immune system in ALS4 pathogenesis.
• To identify potential biomarkers for ALS4.

Main Methods:

• Utilized Setx knock-in mouse models carrying the ALS4-causative L389S mutation.
• Analyzed immune cell populations, specifically CD8 T cells, in the central nervous system and blood of mice.
• Conducted bone marrow transplantation experiments to assess the immune system's role.
• Examined peripheral blood of ALS4 patients for T cell characteristics.

Main Results:

• Identified an immunological signature in ALS4 mice characterized by clonally expanded, terminally differentiated effector memory (T_EMRA) CD8 T cells in the CNS and blood.
• Observed increased frequencies of antigen-specific CD8 T cells correlating with disease progression and anti-glioma immunity.
• Demonstrated the immune system's crucial role in ALS4 neurodegeneration through transplantation studies.
• Confirmed the presence of clonally expanded T_EMRA CD8 T cells in the peripheral blood of ALS4 patients.

Conclusions:

• An antigen-specific CD8 T cell response is evident in ALS4.
• The identified immunological signature, particularly T_EMRA CD8 T cells, may contribute to understanding ALS4 disease mechanisms.
• These findings suggest potential utility of T_EMRA CD8 T cells as a biomarker for ALS4 disease state.