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

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 Kerschensteiner; Daniel D Pinschewer; Doron Merkler

doi:10.1084/jem.20122143

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

J Exp Med. 2013 Sep 23;210(10):2087-103. doi: 10.1084/jem.20122143. Epub 2013 Sep 2.

Authors

Mario Kreutzfeldt¹, 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 Kerschensteiner, Daniel D Pinschewer, Doron Merkler

Affiliation

¹ Department of Pathology and Immunology and 2 World Health Organization Collaborating Centre for Vaccine Immunology, University of Geneva, 1211 Geneva, Switzerland.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

Receptors, Interferon
STAT1 Transcription Factor
fas Receptor
Perforin
Interferon-gamma

Grants and funding

Biotechnology and Biological Sciences Research Council/United Kingdom