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

Abstract

The human brain is populated by perivascular Tcells with a tissue-resident memory T (TRM)-cell phenotype, which in multiple sclerosis (MS) associate with lesions. We investigated the transcriptional and functional profile of freshly isolated Tcells from white and gray matter. RNA sequencing of CD8+ and CD4+ CD69+ Tcells revealed TRM-cell signatures. Notably, gene expression hardly differed between lesional and normal-appearing white matter Tcells in MS brains. Genes up-regulated in brain TRM cells were MS4A1 (CD20) and SPP1 (osteopontin, OPN). OPN is also abundantly expressed by microglia and has been shown to inhibit Tcell 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+ Tcells exvivo. Our study reports traits of brain TRM cells and reveals their tight control in MS lesions.