CD8+ T Cells Cause Disability and Axon Loss in a Mouse Model of Multiple Sclerosis |
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Authors: | Chandra Deb Reghann G. LaFrance-Corey William F. Schmalstieg Brian M. Sauer Huan Wang Christopher L. German Anthony J. Windebank Moses Rodriguez Charles L. Howe |
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Affiliation: | 1. Department of Neurology, Mayo Clinic College of Medicine, Rochester, Minnesota, United States of America.; 2. Neurosurgery, Mayo Clinic College of Medicine, Rochester, Minnesota, United States of America.; 3. Neuroscience, Mayo Clinic College of Medicine, Rochester, Minnesota, United States of America.; 4. Neurobiology of Disease PhD Program, Mayo Clinic College of Medicine, Rochester, Minnesota, United States of America.;Julius-Maximilians-Universität Würzburg, Germany |
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Abstract: | BackgroundThe objective of this study was to test the hypothesis that CD8+ T cells directly mediate motor disability and axon injury in the demyelinated central nervous system. We have previously observed that genetic deletion of the CD8+ T cell effector molecule perforin leads to preservation of motor function and preservation of spinal axons in chronically demyelinated mice.Methodology/Principal FindingsTo determine if CD8+ T cells are necessary and sufficient to directly injure demyelinated axons, we adoptively transferred purified perforin-competent CD8+ spinal cord-infiltrating T cells into profoundly demyelinated but functionally preserved perforin-deficient host mice. Transfer of CD8+ spinal cord-infiltrating T cells rapidly and irreversibly impaired motor function, disrupted spinal cord motor conduction, and reduced the number of medium- and large-caliber spinal axons. Likewise, immunodepletion of CD8+ T cells from chronically demyelinated wildtype mice preserved motor function and limited axon loss without altering other disease parameters.Conclusions/SignificanceIn multiple sclerosis patients, CD8+ T cells outnumber CD4+ T cells in active lesions and the number of CD8+ T cells correlates with the extent of ongoing axon injury and functional disability. Our findings suggest that CD8+ T cells may directly injure demyelinated axons and are therefore a viable therapeutic target to protect axons and motor function in patients with multiple sclerosis. |
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