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

Brück, Wolfgang
Vorm, Mariann
Coras, Roland
Blümcke, Ingmar
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Published in The journal of experimental medicine. 2013, vol. 210, no. 10, p. 2087-103
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 AdolescentAdultAnimalsAntigens, CD95/genetics/metabolismCD8-Positive T-Lymphocytes/immunologyCell Nucleus/metabolismChildDendrites/immunologyHumansInterferon-gamma/antagonists & inhibitors/metabolismLymphocytic Choriomeningitis/immunology/metabolism/prevention & controlLymphocytic choriomeningitis virus/immunologyMiceMice, TransgenicNeurons/immunology/metabolism/virologyPerforin/genetics/metabolismPhosphorylationProtein TransportReceptors, Interferon/genetics/metabolismSTAT1 Transcription Factor/metabolismSignal TransductionSpinal Cord/immunology/metabolism/pathologySynapses/immunologyT-Lymphocytes, Cytotoxic/immunologyYoung Adult
PMID: 23999498
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Research group La Sclérose en plaques (908)
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KREUTZFELDT, Mario et al. Neuroprotective intervention by interferon-γ blockade prevents CD8+ T cell-mediated dendrite and synapse loss. In: Journal of Experimental Medicine, 2013, vol. 210, n° 10, p. 2087-103. doi: 10.1084/jem.20122143 https://archive-ouverte.unige.ch/unige:33447

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Deposited on : 2014-01-20

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