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

2.50
Hdl Handle:
http://hdl.handle.net/10033/306168
Title:
Neuroprotective intervention by interferon-γ blockade prevents CD8+ T cell-mediated dendrite and synapse loss.
Authors:
Kreutzfeldt, Mario; Bergthaler, Andreas; Fernandez, Marylise; Brück, Wolfgang; Steinbach, Karin; Vorm, Mariann; Coras, Roland; Blümcke, Ingmar; Bonilla, Weldy V; Fleige, Anne; Forman, Ruth; Müller, Werner; Becher, Burkhard; Misgeld, Thomas; Kerschensteiner, Martin; Pinschewer, Daniel D; Merkler, Doron
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.
Affiliation:
Department of Pathology and Immunology and 2 World Health Organization Collaborating Centre for Vaccine Immunology, University of Geneva, 1211 Geneva, Switzerland.
Citation:
Neuroprotective intervention by interferon-γ blockade prevents CD8+ T cell-mediated dendrite and synapse loss. 2013, 210 (10):2087-103 J. Exp. Med.
Journal:
The Journal of experimental medicine
Issue Date:
23-Sep-2013
URI:
http://hdl.handle.net/10033/306168
DOI:
10.1084/jem.20122143
PubMed ID:
23999498
Type:
Article
Language:
en
ISSN:
1540-9538
Appears in Collections:
publications of the division experimentelle Immunologie (EXIM)

Full metadata record

DC FieldValue Language
dc.contributor.authorKreutzfeldt, Marioen
dc.contributor.authorBergthaler, Andreasen
dc.contributor.authorFernandez, Maryliseen
dc.contributor.authorBrück, Wolfgangen
dc.contributor.authorSteinbach, Karinen
dc.contributor.authorVorm, Mariannen
dc.contributor.authorCoras, Rolanden
dc.contributor.authorBlümcke, Ingmaren
dc.contributor.authorBonilla, Weldy Ven
dc.contributor.authorFleige, Anneen
dc.contributor.authorForman, Ruthen
dc.contributor.authorMüller, Werneren
dc.contributor.authorBecher, Burkharden
dc.contributor.authorMisgeld, Thomasen
dc.contributor.authorKerschensteiner, Martinen
dc.contributor.authorPinschewer, Daniel Den
dc.contributor.authorMerkler, Doronen
dc.date.accessioned2013-12-03T13:57:21Z-
dc.date.available2013-12-03T13:57:21Z-
dc.date.issued2013-09-23-
dc.identifier.citationNeuroprotective intervention by interferon-γ blockade prevents CD8+ T cell-mediated dendrite and synapse loss. 2013, 210 (10):2087-103 J. Exp. Med.en
dc.identifier.issn1540-9538-
dc.identifier.pmid23999498-
dc.identifier.doi10.1084/jem.20122143-
dc.identifier.urihttp://hdl.handle.net/10033/306168-
dc.description.abstractNeurons 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.en
dc.language.isoenen
dc.rightsArchived with thanks to The Journal of experimental medicineen
dc.subject.meshAdolescenten
dc.subject.meshAdulten
dc.subject.meshAnimalsen
dc.subject.meshAntigens, CD95en
dc.subject.meshCD8-Positive T-Lymphocytesen
dc.subject.meshCell Nucleusen
dc.subject.meshChilden
dc.subject.meshDendritesen
dc.subject.meshHumansen
dc.subject.meshInterferon-gammaen
dc.subject.meshLymphocytic Choriomeningitisen
dc.subject.meshLymphocytic choriomeningitis virusen
dc.subject.meshMiceen
dc.subject.meshMice, Transgenicen
dc.subject.meshNeuronsen
dc.subject.meshPerforinen
dc.subject.meshPhosphorylationen
dc.subject.meshProtein Transporten
dc.subject.meshReceptors, Interferonen
dc.subject.meshSTAT1 Transcription Factoren
dc.subject.meshSignal Transductionen
dc.subject.meshSpinal Corden
dc.subject.meshSynapsesen
dc.subject.meshT-Lymphocytes, Cytotoxicen
dc.subject.meshYoung Adulten
dc.titleNeuroprotective intervention by interferon-γ blockade prevents CD8+ T cell-mediated dendrite and synapse loss.en
dc.typeArticleen
dc.contributor.departmentDepartment of Pathology and Immunology and 2 World Health Organization Collaborating Centre for Vaccine Immunology, University of Geneva, 1211 Geneva, Switzerland.en
dc.identifier.journalThe Journal of experimental medicineen
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