Following adoptive transfer of these specific numbers of CD8+ cells within the context of 105 other cell types in the SCILs, we found that even 1000 CD8+ cells were sufficient to permanently disrupt motor function in demyelinated perforin-deficient hosts (P 0
Posted On April 3, 2023
Following adoptive transfer of these specific numbers of CD8+ cells within the context of 105 other cell types in the SCILs, we found that even 1000 CD8+ cells were sufficient to permanently disrupt motor function in demyelinated perforin-deficient hosts (P 0.001 vs CD8-depleted SCILs) (Figure 6E). GUID:?608408CC-DD78-4116-8F70-9FA44ADD5DC1 Movie S2: Runway video analysis demonstrates preservation of motor function in perforin deficient mice and impairment of motor function in perforin qualified mice at 90 dpi.(3.53 MB MOV) pone.0012478.s005.mov (3.3M) GUID:?43D4774A-75C6-4796-ABF3-66FA500E50CE Movie S3: Runway video analysis demonstrates loss of motor function in perforin deficient hosts after adoptive transfer of SCILs from perforin qualified donors.(3.81 MB MOV) pone.0012478.s006.mov (3.6M) GUID:?57CC538E-8745-499E-9B9E-6BBA92FAD133 Movie S4: Open field video analysis demonstrates motor impairment in perforin deficient hosts after adoptive transfer of total SCILs from perforin qualified donors, whereas no impairment occurs in perforin deficient hosts after adoptive transfer of CD8+ depleted SCILs from perforin qualified donors.(5.20 MB MOV) pone.0012478.s007.mov (4.9M) GUID:?381FEE59-5A1A-4CF8-9046-7F2F2A1AD9A5 Abstract 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 RO4929097 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. Introduction The identification of cellular and molecular mediators of axon injury during chronic demyelination is critical to understanding and preventing or repairing the loss of function associated with multiple sclerosis (MS) and CD117 other demyelinating diseases of the central nervous system. At present, the MS field has defined the following possible mechanisms for axon injury : 1) demyelination is the necessary RO4929097 and sufficient inciting pathology in MS, with axons lost as a direct consequence of failed glial support; 2) demyelination is necessary but not sufficient for axon injury C the loss of myelin exposes axons to a cytotoxic mileu; 3) demyelination is necessary but not sufficient for axon injury C the loss of myelin exposes axons to axopathic immune effectors such as T cells; 4) neurons and axons are the primary locus for the initiation of MS pathology, and demyelination follows the injury of axons. These mechanisms are not mutually exclusive and each is likely to play an overlapping role in some patients, in some lesions, and at some stage of disease evolution. Here we focus on the hypothesis that the loss of RO4929097 myelin is a necessary predisposing factor for axon injury in MS, but demyelination itself is usually insufficient to cause axon loss. Rather, loss of myelin renders the axolemma accessible to CNS infiltrating immune effectors such as CD8+ T cells C. CD8+ T cells are the most frequent T cell subset observed in MS lesions, outnumbering CD4+ T cells by up to 10-fold at sites of active inflammation , . The number of CD8+ T cells found within acute lesions correlates very well with the extent of ongoing axon injury exhibited by MS patients . Unlike CD4+ T cells in MS lesions, CD8+ T cells exhibit clonal expansion, suggesting the recruitment and local proliferation of a distinct, epitope-specific repertoire in the brain , C. Importantly, MHC class I is usually upregulated on axons within active MS lesions . Finally, while anti-CD4 monoclonal antibody treatment failed to alter disease course in MS patients , treatment with alemtuzumab , a monoclonal antibody that depletes both CD8+ and CD4+ T cells, or treatment with natalizumab , , which prevents both CD8+ and CD4+ T cell trafficking into the CNS, resulted in a reduction in relapse rate. The cytotoxic mechanisms used by CD8+ T cells include cytokine-mediated toxicity, FasL induction of target cell apoptosis, and target cell killing mediated by perforin and granzyme . Recent evidence suggests that.