title: 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.
authors.affiliation: Department of Neurology, Mayo Clinic, Rochester, Minnesota, United States of America; Department of Immunology, Mayo Clinic, Rochester, Minnesota, United States of America; Neurobiology of Disease Graduate Program, Mayo Graduate School, Rochester, Minnesota, United States of America.
authors.forename: Holly L
authors.initials: HL
authors.lastname: Johnson
authors.affiliation: Department of Immunology, Mayo Clinic, Rochester, Minnesota, United States of America; Virology and Gene Therapy Graduate Program, Mayo Graduate School, Rochester, Minnesota, United States of America.
authors.forename: Robin C
authors.initials: RC
authors.lastname: Willenbring
authors.affiliation: Department of Immunology, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: Fang
authors.initials: F
authors.lastname: Jin
authors.affiliation: Department of Immunology, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: Whitney A
authors.initials: WA
authors.lastname: Manhart
authors.affiliation: Department of Immunology, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: Stephanie J
authors.initials: SJ
authors.lastname: LaFrance
authors.affiliation: Department of Neurology, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: Istvan
authors.initials: I
authors.lastname: Pirko
authors.affiliation: Department of Neurology, Mayo Clinic, Rochester, Minnesota, United States of America; Department of Immunology, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: Aaron J
authors.initials: AJ
authors.lastname: Johnson
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D002199:Capillary Permeability / Q000235:genetics / Q000276:immunology; D004058:Diffusion; D005456:Fluorescent Dyes / Q000378:metabolism; D015870:Gene Expression; D005904:Glial Fibrillary Acidic Protein; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D054353:Perforin / Q000235:genetics / Q000378:metabolism*; D062725:Tight Junction Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D005456:Fluorescent Dyes; D005904:Glial Fibrillary Acidic Protein; D009419:Nerve Tissue Proteins; D062725:Tight Junction Proteins; C528900:glial fibrillary astrocytic protein, mouse; D054353:Perforin