Perforin competent CD8 T cells are sufficient to cause immune-mediated blood-brain barrier disruption

PLoS One. 2014 Oct 22;9(10):e111401. doi: 10.1371/journal.pone.0111401. eCollection 2014.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adoptive Transfer
  • Animals
  • Astrocytes / metabolism
  • Blood-Brain Barrier / immunology*
  • Blood-Brain Barrier / metabolism*
  • Blood-Brain Barrier / pathology
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / metabolism*
  • Capillary Permeability / genetics
  • Capillary Permeability / immunology
  • Diffusion
  • Fluorescent Dyes / metabolism
  • Gene Expression
  • Glial Fibrillary Acidic Protein
  • Magnetic Resonance Imaging
  • Male
  • Mice
  • Mice, Knockout
  • Models, Animal
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Perforin / genetics
  • Perforin / metabolism*
  • Tight Junction Proteins / genetics
  • Tight Junction Proteins / metabolism

Substances

  • Fluorescent Dyes
  • Glial Fibrillary Acidic Protein
  • Nerve Tissue Proteins
  • Tight Junction Proteins
  • glial fibrillary astrocytic protein, mouse
  • Perforin