期刊
JOURNAL OF EXPERIMENTAL MEDICINE
卷 210, 期 10, 页码 2087-2103出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20122143
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资金
- Klaus-Tschira Stiftung GmbH
- Deutsche Forschungsgemeinschaft (DFG) [SFB 596, EXC 114 CIPSM]
- German Federal Ministry of Research and Education (Bundesministerium fur Bildung und Forschung, BMBF)
- DFG [SFB 571, Transregio 128, SFB 621]
- BMBF (Competence Network Multiple Sclerosis)
- Verein Therapieforschung fur MS-Kranke e.V.
- Munich Cluster for Systems Neurology [EXC 1010 SyNergy]
- Gemeinnutzige Hertie Stiftung
- Roche Research Foundation
- Schweizerische Stiftung fur Medizinisch-Biologische Stipendien foundation (SSMBS) of the Swiss National Science Foundation (SNF)
- BBSRC
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-gamma (IFN-gamma) and neuronal IFN-gamma 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-gamma blocking antibody prevented neuronal deafferentation and clinical disease without reducing CTL responses or CNS infiltration. These findings identify neuronal IFN-gamma signaling as a novel target for neuroprotective interventions in CTL-mediated CNS disease.
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