CD8(+) T Cells Cause Disability and Axon Loss in a Mouse Model of Multiple Sclerosis

BACKGROUND: The 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 FINDINGS: To 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/SIGNIFICANCE: In 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.