Localized PD-1 CAR T therapy reprograms neuroinflammation - human CSF data.

B cell-depleting therapies are effective in multiple sclerosis (MS), yet many patients progress toward disability, highlighting the need for improved interventions. To identify new therapeutic targets, we generated a single-cell RNA-seq atlas of cerebrospinal fluid (CSF), brain, and blood from non-inflammatory controls and patients with MS or other neuroinflammatory diseases. We found disease-associated enrichment of class-switched IgG⁺ B cells and plasma cells in the CSF of patients with MS. Unbiased analysis revealed a rare subset of activated PD-1⁺, TCR-restricted, B-cell recruiting T follicular helper-like cells enriched in MS CSF. To therapeutically target this population, we developed PD-1-directed CAR T cells that selectively depleted pathogenic PD-1⁺ CD4 T cells. In a murine model of neuroinflammation, this approach attenuated CNS inflammation and improved clinical outcomes, particularly when using an IL-10-armored CAR construct. These findings establish a cellular framework for CNS-localized adaptive immunity in MS and outline a strategy for its selective disruption.