Clonal CD8 T cells link peripheral and intrathecal immunity in ALS4 progression: a multiomics reference for ALS

Abstract

Abstract Dysregulated immune responses increasingly appear central to amyotrophic lateral sclerosis (ALS) pathology, but rapid progression and delayed diagnosis limit our understanding of how immune events evolve over the course of disease. By combining high parameter spectral flow cytometry with single cell RNA, TCR and BCR sequencing of peripheral blood and cerebrospinal fluid (CSF), we map the immune landscape in ALS4, a juvenile onset, slowly progressive ALS subtype, providing the first view of immune states spanning decades of disease progression. We identify an early emerging, progressively amplifying CD8 T cell program characterized by clonal expansion of peripheral GZMK⁺ and GZMB⁺ subsets and an abnormally high degree of TCR clonotype sharing between GZMK⁺ CSF and GZMB⁺ blood CD8 T cells. Our work defines a CD8 T cell trajectory that parallels clinical progression in ALS4 across CSF and blood and provides a reference for comparison with other ALS subtypes.