Journal Article

DZNE-2020-03370

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Neuroprotective intervention by interferon-γ blockade prevents CD8+ T cell-mediated dendrite and synapse loss.

Kreutzfeldt, M. ; Bergthaler, A. ; Fernandez, M. ; Brück, W. ; Steinbach, K. ; Vorm, M. ; Coras, R. ; Blümcke, I. ; Bonilla, W. V. ; Fleige, A. ; Forman, R. ; Müller, W. ; Becher, B. ; Misgeld, T.DZNE* ; Kerschensteiner, M. ; Pinschewer, D. D. ; Merkler, D. (Corresponding author)

2013
Rockefeller Univ. Press New York, NY

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Please use a persistent id in citations: doi:10.1084/jem.20122143

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.

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

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Contributing Institute(s):

1. Neuronal Cell Biology (AG Misgeld)

Research Program(s):

1. 341 - Molecular Signaling (POF3-341) (POF3-341)

Appears in the scientific report 2013

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Database coverage:
; BIOSIS Previews ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; IF >= 10 ; JCR ; NCBI Molecular Biology Database ; PubMed Central ; SCOPUS ; Science Citation Index ; Science Citation Index Expanded ; Web of Science Core Collection

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