Acquisition of residency programs by T cells entering the human brain

T cell surveillance is mandatory for maintaining central nervous system (CNS) homeostasis, while aberrant accumulation is linked to neuroinflammation. To explore the residency programs acquired by T cells through different anatomical locations of the human brain, we isolated CD8⁺ and CD4⁺ T cells from CNS border compartments (choroid plexus and leptomeninges), intrathecal compartments (cerebrospinal fluid [CSF] and subcortical white matter [WM]), and paired peripheral blood of brain donors. Flow cytometry revealed a shared effector memory phenotype across CNS compartments that was partially induced in circulating T cells interacting with brain endothelium in vitro. Intrathecal T cells expressed full tissue-residency traits, yet T cells from WM, compared to CSF, showed reduced expression of migratory, co-stimulatory, and recent activation markers despite a similar cytokine response upon ex vivo activation. This work demonstrates the versatility of T cell phenotypes across CNS compartments and provides insight into the programs regulating their recruitment and maintenance within the CNS.