Aydin, SidarSidarAydinPareja Román, JavierJavierPareja RománSchallenberg, Vivianne MVivianne MSchallenbergKlopstein, ArmelleArmelleKlopsteinGruber, ThomasThomasGruber0000-0001-5210-1995Page, NicolasNicolasPageBouillet, Elisa CatherineElisa CatherineBouilletBlanchard, NicolasNicolasBlanchardLiblau, RolandRolandLiblauKörbelin, JakobJakobKörbelinSchwaninger, MarkusMarkusSchwaningerJohnson, Aaron JAaron JJohnsonSchenk, MirjamMirjamSchenk0000-0002-1637-0730Deutsch, UrbanUrbanDeutschMerkler, DoronDoronMerklerEngelhardt, BrittaBrittaEngelhardt0000-0003-3059-98462024-10-252024-10-252023-05-30https://boris-portal.unibe.ch/handle/20.500.12422/167537Blood-brain barrier (BBB) breakdown and immune cell infiltration into the central nervous system (CNS) are early hallmarks of multiple sclerosis (MS). High numbers of CD8+ T cells are found in MS lesions, and antigen (Ag) presentation at the BBB has been proposed to promote CD8+ T cell entry into the CNS. Here, we show that brain endothelial cells process and cross-present Ag, leading to effector CD8+ T cell differentiation. Under physiological flow in vitro, endothelial Ag presentation prevented CD8+ T cell crawling and diapedesis resulting in brain endothelial cell apoptosis and BBB breakdown. Brain endothelial Ag presentation in vivo was limited due to Ag uptake by CNS-resident macrophages but still reduced motility of Ag-specific CD8+ T cells within CNS microvessels. MHC class I-restricted Ag presentation at the BBB during neuroinflammation thus prohibits CD8+ T cell entry into the CNS and triggers CD8+ T cell-mediated focal BBB breakdown.en600 - Technology::610 - Medicine & health500 - Science::570 - Life sciences; biologyarticle10.48350/1830453725374410.1038/s41467-023-38703-2