Perforin Competent CD8 T Cells Are Sufficient to Cause Immune-Mediated Blood-Brain Barrier Disruption

Abstract

Numerous neurological disorders are characterized by central nervous system (CNS) vascular permeability. However, the underlying contribution of inflammatory-derived factors leading to pathology associated with blood-brain barrier (BBB) disruption remains poorly understood. In order to address this, we developed an inducible model of BBB disruption using a variation of the Theiler's murine encephalomyelitis virus (TMEV) model of multiple sclerosis. This peptide induced fatal syndrome (PIFS) model is initiated by virus-specific CD8 T cells and results in severe CNS vascular permeability and death in the C57BL/6 mouse strain. While perforin is required for BBB disruption, the cellular source of perforin has remained unidentified. In addition to CD8 T cells, various innate immune cells also express perforin and therefore could also contribute to BBB disruption. To investigate this, we isolated the CD8 T cell as the sole perforin-expressing cell type in the PIFS model through adoptive transfer techniques. We determined that 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 claudin-5 and occludin in areas of CNS vascular permeability when compared to mock-treated controls. These results are consistent with the characteristics 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.

The peripheral immune response after stroke—A double edge sword for blood‐brain barrier integrity

“…They initiate BBB breakdown through perforin‐mediated disruption of TJs. In turn, leakage from the vasculature into the parenchyma causes brain swelling and edema …”

The role of the blood–brain barrier in hypertension

“…) and multiple sclerosis (Johnson et al . ). These neurological diseases lead to both widespread and sparse BBB disruption.…”

“…This highly regulated system is essential to CNS homeostasis, allowing only minimal movement of small, lipid-soluble molecules into the CNS. However, the BBB can become compromised in neurological diseases, such as Alzheimer's (Kook et al 2013), Parkinson's (Chung et al 2013) and multiple sclerosis (Johnson et al 2014). These neurological diseases lead to both widespread and sparse BBB disruption.…”

Crimean-Congo Hemorrhagic Fever in Humanized Mice Reveals Glial Cells as Primary Targets of Neurological Infection

“…Astrocytes may also play a role in disrupting CNS barriers in response to T-cell activation. CD8 + T-cell activation of astrocytes is a well-described mechanism of BBB disruption [36,37]. We were able to detect only rare human CD8 + T cells in the brains of these mice by immunohistochemistry; however, it is unclear whether their presence, although in low numbers, directly contributes to alterations in CNS barriers or is secondary to disruption permitting cellular infiltration.…”