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

Brian M. Sauer; William F. Schmalstieg; Charles L. Howe

doi:10.1016/j.nbd.2013.07.010

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

Brian M. Sauer, William F. Schmalstieg, Charles L. Howe

Neurology

Research output: Contribution to journal › Article › peer-review

36 Scopus citations

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.

Original language	English (US)
Pages (from-to)	194-205
Number of pages	12
Journal	Neurobiology of Disease
Volume	59
DOIs	https://doi.org/10.1016/j.nbd.2013.07.010
State	Published - Nov 2013

Bibliographical note

Funding Information:
This work was supported by a generous gift from Donald and Frances Herdrich to C.L.H., grant RG3636 from the United States National Multiple Sclerosis Society to C.L.H., grant FG 1922-A-1 from the United States National Multiple Sclerosis Society to W.F.S., the Mayo Foundation for Medical Research and United States National Institutes of Health Medical Scientist Training Program grant GM065841 to B.M.S. We thank Rachel Bergstrom for providing technical assistance with the microfluidic neuron culture platform, Joseph Trapani and Vivien Sutton of the Peter MacCallum Cancer Center, Melbourne, Australia for providing the OT-IGzAB −/− and OT-Ipfp −/− mouse strains and Trace Christensen and Scott Gamb for technical assistance with the electron microscopy experiments. We also thank Joshua Burda and Joshua Piotrowski for assistance with manuscript preparation.

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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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.",

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",

author = "Sauer, {Brian M.} and Schmalstieg, {William F.} and Howe, {Charles L.}",

note = "Funding Information: This work was supported by a generous gift from Donald and Frances Herdrich to C.L.H., grant RG3636 from the United States National Multiple Sclerosis Society to C.L.H., grant FG 1922-A-1 from the United States National Multiple Sclerosis Society to W.F.S., the Mayo Foundation for Medical Research and United States National Institutes of Health Medical Scientist Training Program grant GM065841 to B.M.S. We thank Rachel Bergstrom for providing technical assistance with the microfluidic neuron culture platform, Joseph Trapani and Vivien Sutton of the Peter MacCallum Cancer Center, Melbourne, Australia for providing the OT-IGzAB −/− and OT-Ipfp −/− mouse strains and Trace Christensen and Scott Gamb for technical assistance with the electron microscopy experiments. We also thank Joshua Burda and Joshua Piotrowski for assistance with manuscript preparation.",

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AB - 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.

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KW - Multiple sclerosis

KW - OT-I

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