Interferon-gamma prevents death of bystander neurons during CD8 T cell responses in the brain.
T cells restricted to neurotropic viruses are potentially harmful as their activity may result in the destruction of neurons. In the Borna disease virus (BDV) model, antiviral CD8 T cells entering the brain of infected mice cause neurological disease but no substantial loss of neurons unless the animals lack interferon-gamma (IFN-gamma). We show here that glutamate receptor antagonists failed to prevent BDV-induced neuronal loss in IFN-gamma-deficient mice, suggesting that excitotoxicity resulting from glutamate receptor overstimulation is an unlikely explanation for the neuronal damage. Experiments with IFN-gamma-deficient mice lacking eosinophils indicated that these cells, which specifically accumulate in the infected brains of IFN-gamma-deficient mice, are not responsible for CA1 neuronal death. Interestingly, BDV-induced damage of CA1 neurons was reduced significantly in IFN-gamma-deficient mice lacking perforin, suggesting a key role for CD8 T cells in this pathological process. Specific death of hippocampal CA1 neurons could be triggered by adoptive transfer of BDV-specific CD8 T cells from IFN-gamma-deficient mice into uninfected mice that express transgene-encoded BDV antigen at high level in astrocytes. These results indicate that attack by CD8 T cells that cause the death of CA1 neurons might be directed toward regional astrocytes and that IFN-gamma protects vulnerable CA1 neurons from collateral damage resulting from exposure to potentially toxic substances generated as a result of CD8 T cell-mediated impairment of astrocyte function.
Department of Virology, University of Freiburg, Freiburg, Germany.
Kirsten
K
Richter
Jürgen
J
Hausmann
Peter
P
Staeheli
D019264:Adoptive Transfer; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D001890:Borna Disease / Q000378:metabolism / Q000473:pathology / Q000821:virology; D001891:Borna disease virus / Q000502:physiology*; D001921:Brain / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D003602:Cytotoxicity, Immunologic; D004804:Eosinophils / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D005260:Female; D005434:Flow Cytometry; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D007124:Immunoenzyme Techniques; D020287:In Situ Nick-End Labeling; D007249:Inflammation; D007371:Interferon-gamma / Q000502:physiology*; D008214:Lymphocytes / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009474:Neurons / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D054353:Perforin / Q000378:metabolism; D017470:Receptors, Glutamate / Q000737:chemistry / Q000378:metabolism; D013154:Spleen / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D019562:Viral Load
D017470:Receptors, Glutamate; D054353:Perforin; D007371:Interferon-gamma