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

• DOI: 10.1084/jem.20122143
• Publication Date: 2013-09-03T04:38:46Z
• Authors: Mario Kreutzfeldt; Andreas Bergthaler; Marylise Fernandez; Wolfgang Brück; Karin Steinbach; Mariann Vorm; Roland Coras; Ingmar Blümcke; Weldy V. Bonilla; Anne Fleige; Ruth Forman; Werner Müller; Burkhard Becher; Thomas Misgeld; Martin Kerschenst...; Daniel D. Pinschewer; Doron Merkler
• Keywords: 0301 basic medicine; immunology [T-Lymphocytes, Cytotoxic]; metabolism [Lymphocytic Choriomeningitis]; info:eu-repo/classification/ddc/616.07; ddc:616.07; CD8-Positive T-Lymphocytes; 10263 Institute of Experimental Immunology; Mice; Lymphocytic choriomeningitis virus; Receptors, Interferon/genetics/metabolism; Phosphorylation; Child; genetics [Perforin]; Receptors, Interferon; Neurons; Interferon-gamma/antagonists & inhibitors/metabolism; immunology [Lymphocytic choriomeningitis virus]; metabolism [Perforin]; Neurons/immunology/metabolism/virology; immunology [Lymphocytic Choriomeningitis]; 3. Good health; genetics [Receptors, Interferon]; Protein Transport; Antigens, CD95; immunology [Dendrites]; STAT1 Transcription Factor; Spinal Cord; metabolism [Neurons]; 2723 Immunology and Allergy; metabolism [Interferon-gamma]; STAT1 Transcription Factor/metabolism; Signal Transduction; Adult; metabolism [Spinal Cord]; Lymphocytic Choriomeningitis/immunology/metabolism/prevention & control; virology [Neurons]; Adolescent; metabolism [fas Receptor]; prevention & control [Lymphocytic Choriomeningitis]; Perforin/genetics/metabolism; 610 Medicine & health; Mice, Transgenic; pathology [Spinal Cord]; Lymphocytic Choriomeningitis; CD8-Positive T-Lymphocytes/immunology; antagonists & inhibitors [Interferon-gamma]; Article; Dendrites/immunology; Synapses/immunology; Young Adult; Interferon-gamma; 03 medical and health sciences; genetics [fas Receptor]; Animals; Humans; Lymphocytic choriomeningitis virus/immunology; ddc:610; fas Receptor; metabolism [Cell Nucleus]; immunology [Spinal Cord]; Spinal Cord/immunology/metabolism/pathology; Cell Nucleus; 2403 Immunology; immunology [Synapses]; metabolism [Receptors, Interferon]; Perforin; immunology [CD8-Positive T-Lymphocytes]; Dendrites; T-Lymphocytes, Cytotoxic/immunology; interferon gamma receptor; Antigens, CD95/genetics/metabolism; metabolism [STAT1 Transcription Factor]; Cell Nucleus/metabolism; Synapses; 570 Life sciences; biology; immunology [Neurons]; T-Lymphocytes, Cytotoxic

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.