Osteopontin associates with brain T_RM-cell transcriptome and compartmentalization in donors with and without multiple sclerosis

The human brain is populated by perivascular T cells with a tissue-resident memory T (T_RM)-cell phenotype, which in multiple sclerosis (MS) associate with lesions. We investigated the transcriptional and functional profile of freshly isolated T cells from white and gray matter. RNA sequencing of CD8⁺ and CD4⁺ CD69⁺ T cells revealed T_RM-cell signatures. Notably, gene expression hardly differed between lesional and normal-appearing white matter T cells in MS brains. Genes up-regulated in brain T_RM cells were MS4A1 (CD20) and SPP1 (osteopontin, OPN). OPN is also abundantly expressed by microglia and has been shown to inhibit T cell activity. In line with their parenchymal localization and the increased presence of OPN in active MS lesions, we noticed a reduced production of inflammatory cytokines IL-2, TNF, and IFNγ by lesion-derived CD8⁺ and CD4⁺ T cells ex vivo. Our study reports traits of brain T_RM cells and reveals their tight control in MS lesions.