A framework for reparative CAR T engineering in the CNS

Summary Chimeric antigen receptor (CAR) T cells have shown remarkable therapeutic promise in hematological malignancies and, more recently, in autoimmunity. They also hold considerable potential for neurodegenerative diseases and CNS injury, where the therapeutic objective shifts from cell depletion to immune modulation and tissue repair. Using ischemic stroke as proof-of-concept, we engineered MOG-targeting CAR T cells to dissect how distinct CAR designs shape the CNS microenvironment. CD4/CD8 CAR T cells (a mixture of CD4⁺ and CD8⁺ subsets) proliferated robustly and efficiently infiltrated the ischemic hemisphere, but induced broad immune recruitment and exacerbated neuroinflammation. In contrast, CD4⁺ restricted CAR T cells markedly reduced immune infiltration, reprogrammed microglia, and minimized inflammatory activation. We engineered CD4⁺ CAR T cells to secrete brain-derived neurotrophic factor (BDNF) to determine whether they could be redirected toward a reparative, non-cytotoxic phenotype. CD4⁺ BDNF-CAR T cells further attenuated inflammation, reduced immune infiltration, and promoted the expansion of regulatory T cells. CD4⁺ BDNF-CAR T treated mice showed significantly improved gait performance following stroke. Together, these findings establish a cellular framework and outline principles for engineering reparative CAR T platforms for neurological diseases.