title: Axons are injured by antigen-specific CD8(+) T cells through a MHC class I- and granzyme B-dependent mechanism.
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.
authors.affiliation: 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.
authors.forename: Brian M
authors.initials: BM
authors.lastname: Sauer
authors.forename: William F
authors.initials: WF
authors.lastname: Schmalstieg
authors.forename: Charles L
authors.initials: CL
authors.lastname: Howe
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D016827:CD8 Antigens / Q000378:metabolism*; D002540:Cerebral Cortex / Q000166:cytology; D004622:Embryo, Mammalian; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D053804:Granzymes / Q000235:genetics / Q000378:metabolism*; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000378:metabolism*; D007371:Interferon-gamma / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009457:Neuroglia / Q000166:cytology / Q000648:ultrastructure; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010047:Ovalbumin / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000648:ultrastructure
chemical_list: D016827:CD8 Antigens; D015395:Histocompatibility Antigens Class I; D009419:Nerve Tissue Proteins; C110366:OVA-8; D010446:Peptide Fragments; D007371:Interferon-gamma; D010047:Ovalbumin; D053804:Granzymes
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
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