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Conventional CSF markers often fail to distinguish immune-mediated neurologic disorders (IMNDs) from non-immune-mediated neurologic disorders (N-IMNDs). We performed multiparametric flow cytometric profiling of CSF T-cell developmental subsets in 37 IMND patients and 10 N-IMND controls to identify IMND-associated T-cell signatures. CSF CD8+ T-cells were detectable in 86% (32/37) of IMND patients versus 0% (0/10) of N-IMND controls (Padj < .001). Among CD8+ T-cell-positive IMND cases, effector memory (CD45RA-CCR7-, median, 65.0%; IQR, 45.5%-73.5%) and terminally differentiated effector memory T-cells (TEMRA, CD45RA+CCR7-, median, 35.0%; IQR, 0%-49.5%) predominated. Hierarchical clustering demonstrated significant separation between IMND and N-IMND driven by CD8+ T-cell subset profiles (R2 = 0.165, P = .001), whereas CD4+ T-cell subsets showed no disease-associated clustering. Paired blood-CSF analysis in 6 treatment-naïve IMND patients revealed compartmentalized enrichment of CD8+ effector memory (blood median 19.2%; IQR, 6.4%-26.9%; CSF median 47.3%; IQR, 42.2%-53.7%; P = .031), confirming CNS-restricted CD8+ T-cell activation. These findings identify CSF CD8+ effector memory profiles as a potential biomarker distinguishing IMNDs from N-IMNDs that may complement conventional biomarkers for CNS autoimmunity.
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