AbstractMost tissues are populated by tissue-resident memory T cells (T_RM cells), which are adapted to their niche and appear to be indispensable for local protection against pathogens. Here we show that human white matter-derived brain CD8⁺ T cells can be subsetted into CD103⁻CD69⁺ and CD103⁺CD69⁺ T cells both with a phenotypic and transcription factor profile consistent with T_RM cells. Specifically, CD103 expression in brain CD8⁺ T cells correlates with reduced expression of differentiation markers, increased expression of tissue-homing chemokine receptors, intermediate and low expression of the transcription factors T-bet and eomes, increased expression of PD-1 and CTLA-4, and low expression of cytolytic enzymes with preserved polyfunctionality upon activation. Brain CD4⁺ T cells also display T_RM cell-associated markers but have low CD103 expression. We conclude that the human brain is surveilled by T_RM cells, providing protection against neurotropic virus reactivation, whilst being under tight control of key immune checkpoint molecules.