title: Neuroprotective intervention by interferon-γ blockade prevents CD8+ T cell-mediated dendrite and synapse loss.
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.
authors.affiliation: Department of Pathology and Immunology and 2 World Health Organization Collaborating Centre for Vaccine Immunology, University of Geneva, 1211 Geneva, Switzerland.
authors.forename: Mario
authors.initials: M
authors.lastname: Kreutzfeldt
authors.forename: Andreas
authors.initials: A
authors.lastname: Bergthaler
authors.forename: Marylise
authors.initials: M
authors.lastname: Fernandez
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Brück
authors.forename: Karin
authors.initials: K
authors.lastname: Steinbach
authors.forename: Mariann
authors.initials: M
authors.lastname: Vorm
authors.forename: Roland
authors.initials: R
authors.lastname: Coras
authors.forename: Ingmar
authors.initials: I
authors.lastname: Blümcke
authors.forename: Weldy V
authors.initials: WV
authors.lastname: Bonilla
authors.forename: Anne
authors.initials: A
authors.lastname: Fleige
authors.forename: Ruth
authors.initials: R
authors.lastname: Forman
authors.forename: Werner
authors.initials: W
authors.lastname: Müller
authors.forename: Burkhard
authors.initials: B
authors.lastname: Becher
authors.forename: Thomas
authors.initials: T
authors.lastname: Misgeld
authors.forename: Martin
authors.initials: M
authors.lastname: Kerschensteiner
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Pinschewer
authors.forename: Doron
authors.initials: D
authors.lastname: Merkler
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002467:Cell Nucleus / Q000378:metabolism; D002648:Child; D003712:Dendrites / Q000276:immunology*; D006801:Humans; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008216:Lymphocytic Choriomeningitis / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D054353:Perforin / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D021381:Protein Transport; D017471:Receptors, Interferon / Q000235:genetics / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D013116:Spinal Cord / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D013569:Synapses / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D055815:Young Adult; D019014:fas Receptor / Q000235:genetics / Q000378:metabolism; D000096743:Interferon gamma Receptor
chemical_list: D007371:Interferon-gamma; D054353:Perforin; D017471:Receptors, Interferon; D050794:STAT1 Transcription Factor; D019014:fas Receptor; D000096743:Interferon gamma Receptor