期刊
NEUROBIOLOGY OF DISEASE
卷 59, 期 -, 页码 194-205出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.nbd.2013.07.010
关键词
Multiple sclerosis; Axon injury; CDS+ T cell; OT-I; Microfluidic neuron culture; Major histocompatibility complex class I (MHC I); Interferon gamma (IFN gamma); Granzyme B
资金
- United States National Multiple Sclerosis Society [RG3636, FG 1922-A-1]
- Mayo Foundation for Medical Research and United States National Institutes of Health Medical Scientist Training Program [GM065841]
Axon injury is a central determinant of irreversible neurological deficit and disease progression in patients with multiple sclerosis (MS). CD8(+) lymphocytes (CTLs) within inflammatory demyelinated MS lesions correlate with acute axon injury and neurological deficits. The mechanisms of these correlations are unknown. We interrogated CTL-mediated axon injury using the transgenic OT-I antigen-specific CTL model system in conjunction with a chambered cortical neuron culture platform that permitted the isolated manipulation of axons independent of neuron cell bodies and glia. Interferon gamma upregulated, through a dose dependent mechanism, the axonal expression of functional major histocompatibility complex class I (MHC I) molecules competent to present immunologically-relevant antigens derived from endogenously expressed proteins. Antigen-specific CTLs formed cytotoxic immune synapses with and directly injured axons expressing antigen-loaded MHC I molecules. CTL-mediated axon injury was mechanistically dependent upon axonal MHC I antigen presentation, T cell receptor specificity and axoplasmic granzyme B activity. Despite extensive distal CTL-mediated axon injury, acute neuron cell body apoptosis was not observed. These findings present a novel model of immune-mediated axon injury and offer anti-axonal CTLs and granzyme B as targets for the therapeutic protection of axons and prevention of neurological deficits in MS patients. (C) 2013 Elsevier Inc. All rights reserved.
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