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

PLoS One

Whitney A. Manhart¹  Robin C. Willenbring¹  Aaron J. Johnson¹  Istvan Pirko¹  Holly L. Johnson²  Fang Jin³  Stephanie J. LaFrance⁴ 

[1] Department of Immunology, Mayo Clinic, Rochester, Minnesota, United States of America;Department of Neurology, Mayo Clinic, Rochester, Minnesota, United States of America;Neurobiology of Disease Graduate Program, Mayo Graduate School, Rochester, Minnesota, United States of America;Virology and Gene Therapy Graduate Program, Mayo Graduate School, Rochester, Minnesota, United States of America

关键词: Cytotoxic T cells;    T cells;    Vascular permeability;    Central nervous system;    Astrocytes;    Cell disruption;    Magnetic resonance imaging;    Tight junctions;   

DOI  :  10.1371/journal.pone.0111401

学科分类：医学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY