Neuroprotective intervention by interferon-γ blockade prevents CD8+ T cell-mediated dendrite and synapse loss

J Exp Med. 2013 Sep 23;210(10):2087-103. doi: 10.1084/jem.20122143. Epub 2013 Sep 2.

Abstract

Neurons are postmitotic and thus irreplaceable cells of the central nervous system (CNS). Accordingly, CNS inflammation with resulting neuronal damage can have devastating consequences. We investigated molecular mediators and structural consequences of CD8(+) T lymphocyte (CTL) attack on neurons in vivo. In a viral encephalitis model in mice, disease depended on CTL-derived interferon-γ (IFN-γ) and neuronal IFN-γ signaling. Downstream STAT1 phosphorylation and nuclear translocation in neurons were associated with dendrite and synapse loss (deafferentation). Analogous molecular and structural alterations were also found in human Rasmussen encephalitis, a CTL-mediated human autoimmune disorder of the CNS. Importantly, therapeutic intervention by IFN-γ blocking antibody prevented neuronal deafferentation and clinical disease without reducing CTL responses or CNS infiltration. These findings identify neuronal IFN-γ signaling as a novel target for neuroprotective interventions in CTL-mediated CNS disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Animals
  • CD8-Positive T-Lymphocytes / immunology*
  • Cell Nucleus / metabolism
  • Child
  • Dendrites / immunology*
  • Humans
  • Interferon-gamma / antagonists & inhibitors
  • Interferon-gamma / metabolism*
  • Lymphocytic Choriomeningitis / immunology
  • Lymphocytic Choriomeningitis / metabolism
  • Lymphocytic Choriomeningitis / prevention & control
  • Lymphocytic choriomeningitis virus / immunology
  • Mice
  • Mice, Transgenic
  • Neurons / immunology*
  • Neurons / metabolism
  • Neurons / virology
  • Perforin / genetics
  • Perforin / metabolism
  • Phosphorylation
  • Protein Transport
  • Receptors, Interferon / genetics
  • Receptors, Interferon / metabolism
  • STAT1 Transcription Factor / metabolism
  • Signal Transduction
  • Spinal Cord / immunology
  • Spinal Cord / metabolism
  • Spinal Cord / pathology
  • Synapses / immunology*
  • T-Lymphocytes, Cytotoxic / immunology
  • Young Adult
  • fas Receptor / genetics
  • fas Receptor / metabolism

Substances

  • Receptors, Interferon
  • STAT1 Transcription Factor
  • fas Receptor
  • interferon gamma receptor
  • Perforin
  • Interferon-gamma