Last Updated: 15/10/2025
CD8 T cell mediated disruption of Blood Brain Barrier Tight Junctions
Objectives
This research investigates how CD8 T cells disrupt blood-brain barrier (BBB) tight junctions, contributing to neurological diseases characterized by BBB permeability. The study aims to elucidate the mechanisms by which CD8 T cells promote neuronal expression of vascular endothelial growth factor (VEGF), leading to vascular changes, using innovative murine models and various advanced techniques.
The specific aims are to:
- Determine the extent direct engagement of antigen specific CD8 T cells with neurons promotes VEGF expression and ensuing vascular changes;
- Determine the extent neuronal expression of VEGF and its receptors contribute to CD8 T cell-initiated BBB disruption; and
- Evaluate the contribution of neuronal VEGF to CD8 T cell-mediated BBB disruption in the Plasmodium berghei ANKA (PbA) model of experimental cerebral malaria.
Blood–brain barrier (BBB) disruption is an integral feature of neurological diseases as diverse as multiple sclerosis, acute hemorrhagic leukoencephalitis (AHLE), traumatic brain injury, stroke, cerebral malaria, viral hemorrhagic fevers, epilepsy, glioblastoma, Alzheimer’s disease, and HIV dementia. A fundamental question in these diseases is the extent to which inflammatory immune cells contribute to CNS vascular permeability. This lack of understanding currently undermines therapeutic approaches to treat neurological conditions in which uncontrolled BBB disruption contributes to pathology. The research team was the first to demonstrate that CD8 T cells have the capacity to disrupt BBB tight junctions using a novel murine model. Using this model, the investigators developed a tractable approach to dissect immune-mediated mechanisms of vascular endothelial growth factor (VEGF)–mediated BBB disruption by employing variations of Theiler’s Murine Encephalomyelitis Virus (TMEV) and the Plasmodium berghei ANKA (PbA) model systems. The central hypothesis is that CD8 T cells promote neuronal expression of VEGF, which results in the disruption of cerebral endothelial cell tight junctions and increased vascular permeability. To the team’s knowledge, no other laboratory has developed a model comparable to PIFS, which enables readily inducible acute CNS vascular permeability mediated by a well-defined immune cell type. Confirming the existence of homologous inflammatory mechanisms in humans would be a critical step toward therapeutic interventions for neurological diseases in which neuroinflammation-induced CNS vascular permeability plays a major role. To accomplish these aims, the investigators will employ (a) flow cytometry, (b) behavioral studies, (c) high-resolution confocal microscopy and immunohistochemistry, (d) two-photon intravital microscopy, (e) protein biochemistry, and (f) small-mammal MRI.
Jul 2016 — Dec 2017
$397,500
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