Localized PD-1 CAR T therapy reprograms neuroinflammation - mouse CAR T data.

B cell-depleting therapies are effective in multiple sclerosis (MS), yet many patients continue to accumulate disability, underscoring the need for more precise 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 further identified a rare subset of activated, TCR-restricted, PD-1⁺ T follicular helper-like cells with B-cell recruiting features that was enriched in the CSF of patients with MS. To target this population therapeutically, we developed PD-1-directed CAR T cells that selectively depleted pathogenic PD-1⁺ CD4 T cells and, in armored versions, released IL-10 at inflammatory sites. This strategy attenuated CNS inflammation, reprogrammed the local immune milieu, and improved clinical outcomes across murine neuroinflammation models. Together, these findings define a cellular framework for CNS-localized adaptive immunity in MS and nominate a selective strategy to disrupt it.