CD8 T cells are sufficient to induce blood-brain barrier disruption as sole perforin expressing cell type during viral infection (VIR6P.1167)

Abstract

Abstract Despite numerous neurological disorders characterized by central nervous system (CNS) vascular permeability, the immune factors leading to pathology associated with blood-brain barrier (BBB) disruption remains poorly understood. To address this, we developed an inducible model of BBB disruption using Theiler’s murine encephalomyelitis virus (TMEV). This peptide induced fatal syndrome (PIFS) model is initiated by virus-specific CD8 T cells and is perforin dependent. However, the cellular source of perforin has remained unidentified. Various immune cells, including CD8 T cells, express perforin and therefore could each contribute to BBB disruption. In order to investigate this, we isolated the CD8 T cell as the sole perforin-expressing cell type in the PIFS model through adoptive transfer techniques. Using small animal magnetic resonance imaging (MRI), confocal microscopy, among other techniques, we determined C57BL/6 perforin-/- mice reconstituted with perforin competent CD8 T cells and induced to undergo PIFS exhibited: 1) heightened CNS vascular permeability, 2) increased astrocyte activation as measured by GFAP expression, and 3) loss of linear organization of BBB tight junction proteins in areas of CNS vascular permeability when compared to mock-treated controls. These results are consistent with those associated with PIFS in perforin competent mice. Therefore, CD8 T cells are sufficient as a sole perforin-expressing cell type to cause BBB disruption in the PIFS model.