Nave CD8 T-cells initiate spontaneous autoimmunity to a sequestered model antigen of the central nervous system

作者：Na Shin Young; Cao Yi; Toben Catherine; Nitschke Lars; Stadelmann Christine; Gold Ralf; Schimpl Anneliese; Huenig Thomas

来源：Brain, 2008, 131: 2353-2365.

DOI：10.1093/brain/awn148

• autoimmune encephalitis
• multiple sclerosis
• cytotoxic T-cell response
• demyelinating disease
• blood-brain barrier

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 nave 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 nave OT-I cells in vitro, and both major histocompatibility complex class I expression and the OT-I response are further up-regulated by interferon-gamma (IFN-gamma). Release of IFN-gamma 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-gamma dependent. In conclusion, nave CD8 T-cells gaining access to an immune-privileged organ can initiate autoimmunity via an IFN-gamma assisted amplification loop even if the self-antigen in question is not spontaneously released for presentation by professional antigen presenting cells.

• 出版日期2008-9