UCSF

Although the central nervous system (CNS) undergoes dynamic immune surveillance, the mechanisms limiting brain T cell accumulation remain poorly understood. Here, we show that T cell scarcity in the brain parenchyma reflects a persistence checkpoint that selectively permits memory-biased states. We developed an ITAM-tuned chimeric antigen receptor (CAR) termed 4X3 that calibrates signaling to achieve this state. A single systemic injection of brain-antigen-targeting 4X3 CAR T cells yields hundreds of thousands of cells in the healthy brain without compromising blood-brain barrier integrity, whereas conventional CARs with identical binders fail even when locally injected. This accumulation reflects persistence of a 4X3-driven stem-like memory state, not enhanced entry. The modular 4X3 platform extends to Alzheimer’s disease models, where payload-armed, amyloid-β (Aβ)-targeting 4X3 CAR T cells localize to Aβ plaques, promote clearance, and rescue behavioral deficits. Thus, neuroimmune privilege is enforced by a state-selective persistence checkpoint, enabling durable, systemically delivered CNS T cell therapies.