Persistent and compartmentalized T cell immunity in ALS

Amyotrophic lateral sclerosis is a fatal neurodegenerative disease increasingly linked to T cell responses, although the mechanisms driving T cell activation and disease progression remain unclear. Here we used single-cell RNA and T cell receptor sequencing, longitudinal immune profiling and imaging flow cytometry to identify long-lived intrathecal clonotypes and antigen-presenting cell-T cell complexes displaying features of immunological synapse formation, consistent with intrathecal antigen presentation. Higher frequencies of CD4⁺ effector, CD4⁺ regulatory and CD8⁺ T cells in cerebrospinal fluid (CSF) were associated with slower disease progression, whereas increased circulating CD4⁺ effector and regulatory T cells were associated with faster progression. T cell clonotypes shared between blood and CSF exhibited distinct transcriptional states. Finally, frequencies of cytomegalovirus-specific T cells in CSF and anticytomegalovirus serum antibodies were correlated with faster progression and shorter survival in sporadic amyotrophic lateral sclerosis. These findings reveal compartmentalized immune dynamics, largely contrasting protective intrathecal responses with harmful systemic activation.