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|Title:||Naive CD8 T-cells initiate spontaneous autoimmunity to a sequestered model antigen of the central nervous system|
|Citation:||Brain, 2008; 131(9):2353-2365|
|Publisher:||Oxford University Press|
|Shin-Young Na, Yi Cao, Catherine Toben, Lars Nitschke, Christine Stadelmann, Ralf Gold, Anneliese Schimpl, and Thomas Hünig|
|Abstract:||In multiple sclerosis, CD8 T-cells are thought play a key pathogenetic role, but mechanistic evidence from rodent models is limited. Here, we have tested the encephalitogenic potential of CD8 T-cells specific for the model antigen ovalbumin (OVA) sequestered in oligodendrocytes as a cytosolic molecule. We show that in these ‘ODC-OVA’ mice, the neo-self antigen remains invisible to CD4 cells expressing the OVA-specific OT-II receptor. In contrast, OVA is accessible to naïve CD8 T-cells expressing the OT-I T-cell receptor, during the first 10 days of life, resulting in antigen release into the periphery. Introduction of OT-I as a second transgene leads to fulminant demyelinating experimental autoimmune encephalomyelitis with multiple sclerosis-like lesions, affecting cerebellum, brainstem, optic nerve and spinal cord. OVA-transgenic oligodendrocytes activate naïve OT-I cells in vitro, and both major histocompatibility complex class I expression and the OT-I response are further up-regulated by interferon-γ (IFN-γ). Release of IFN-γ into the circulation of ODC-OVA/OT-I double transgenic mice precedes disease manifestation, and pathogenicity of OT-I cells transferred into ODC-OVA mice is largely IFN-γ dependent. In conclusion, naïve CD8 T-cells gaining access to an ‘immune-privileged’ organ can initiate autoimmunity via an IFN-γ-assisted amplification loop even if the self-antigen in question is not spontaneously released for presentation by professional antigen presenting cells.|
|Keywords:||autoimmune encephalitis; multiple sclerosis; cytotoxic T-cell response; demyelinating disease; blood-brain barrier|
|Rights:||© The Author (2008).|
|Appears in Collections:||Medicine publications|
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