The brain is a site of relative immune privilege. We used a combination of imaging, single cell, and surgical approaches to identify a CD69+ CD4 T cell population in both the mouse and human brain, distinct from circulating CD4 T cells.

Brain CD4 T cells interact with microglia and regulate brain development. Next we explored the therapeutic potential of a subset of brain-resident T cells, the Tregs. We identified brain IL2 levels as a limiting factor for brain-resident Tregs.

We developed a gene-delivery approach for astrocytes, with a small-molecule on-switch to allow temporal control, and enhanced production in reactive astrocytes to spatially-direct delivery to inflammatory sites.

We validated brain-specific IL2 gene-delivery as effective protection against neuroinflammation, and provide a versatile platform for delivery of diverse biologics to neuroinflammatory patients.