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

Research output: Contribution to journalArticlepeer-review

20 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 languageEnglish (US)
Pages (from-to)194-205
Number of pages12
JournalNeurobiology of Disease
Volume59
DOIs
StatePublished - Nov 2013

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

ASJC Scopus subject areas

  • Neurology

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