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Neurobiol Dis. 2013 Nov;59:194-205. doi: 10.1016/j.nbd.2013.07.010. Epub 2013 Jul 27.

Axons are injured by antigen-specific CD8(+) T cells through a MHC class I- and granzyme B-dependent mechanism.

Author information

1
Medical Scientist Training Program, College of Medicine, Mayo Clinic, Rochester, MN 55905, USA; Department of Neurology, College of Medicine, Mayo Clinic, Rochester, MN 55905, USA; Neurobiology of Disease Training Program, College of Medicine, Mayo Clinic, Rochester, MN 55905, USA; Department of Neuroscience, College of Medicine, Mayo Clinic, Rochester, MN 55905, USA.

Abstract

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.

KEYWORDS:

Axon injury; CD8(+) T cell; Granzyme B; Interferon gamma (IFNγ); Major histocompatibility complex class I (MHC I); Microfluidic neuron culture; Multiple sclerosis; OT-I

PMID:
23899663
PMCID:
PMC3788647
DOI:
10.1016/j.nbd.2013.07.010
[Indexed for MEDLINE]
Free PMC Article

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