en
Scientific article
English

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

Published inThe Journal of experimental medicine, vol. 210, no. 10, p. 2087-2103
Publication date2013
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.

Keywords
  • Adolescent
  • Adult
  • Animals
  • Antigens, CD95/genetics/metabolism
  • CD8-Positive T-Lymphocytes/immunology
  • Cell Nucleus/metabolism
  • Child
  • Dendrites/immunology
  • Humans
  • Interferon-gamma/antagonists & inhibitors/metabolism
  • Lymphocytic Choriomeningitis/immunology/metabolism/prevention & control
  • Lymphocytic choriomeningitis virus/immunology
  • Mice
  • Mice, Transgenic
  • Neurons/immunology/metabolism/virology
  • Perforin/genetics/metabolism
  • Phosphorylation
  • Protein Transport
  • Receptors, Interferon/genetics/metabolism
  • STAT1 Transcription Factor/metabolism
  • Signal Transduction
  • Spinal Cord/immunology/metabolism/pathology
  • Synapses/immunology
  • T-Lymphocytes, Cytotoxic/immunology
  • Young Adult
Citation (ISO format)
KREUTZFELDT, Mario et al. Neuroprotective intervention by interferon-γ blockade prevents CD8+ T cell-mediated dendrite and synapse loss. In: The Journal of experimental medicine, 2013, vol. 210, n° 10, p. 2087–2103. doi: 10.1084/jem.20122143
Main files (1)
Article (Accepted version)
accessLevelRestricted
Identifiers
ISSN of the journal0022-1007
535views
3downloads

Technical informations

Creation01/20/2014 12:49:00 PM
First validation01/20/2014 12:49:00 PM
Update time03/14/2023 8:52:14 PM
Status update03/14/2023 8:52:13 PM
Last indexation01/16/2024 1:57:32 PM
All rights reserved by Archive ouverte UNIGE and the University of GenevaunigeBlack