Brain Advance Access originally published online on July 10, 2008
Brain 2008 131(9):2353-2365; doi:10.1093/brain/awn148
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Naïve CD8 T-cells initiate spontaneous autoimmunity to a sequestered model antigen of the central nervous system
1Institute for Virology and Immunobiology, University of Würzburg, D-97078 Würzburg, 2Institute for Neuropathology, University of Göttingen, D-37073 Göttingen and 3Department of Neurology at St Josef Hospital, Ruhr-University Bochum, D-44791 Bochum Bochum, Germany
Correspondence to: Thomas Hünig, Institute for Virology and Immunobiology, University of Würzburg, Verbacher Straße 7, D-97078 Würzburg, Germany E-mail: huenig{at}vim.uni-wuerzburg.de
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-
(IFN-). Release of IFN- 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- dependent. In conclusion, naïve CD8 T-cells gaining access to an ‘immune-privileged’ organ can initiate autoimmunity via an IFN--assisted amplification loop even if the self-antigen in question is not spontaneously released for presentation by professional antigen presenting cells.
Key Words: autoimmune encephalitis; multiple sclerosis; cytotoxic T-cell response; demyelinating disease; blood–brain barrier
Abbreviations: BBB, blood–brain barrier; EAE, experimental autoimmune encephalomyelitis; MBP, myelin basic protein; ODC-OVA mice, mice expressing ovalbumin in oligodendrocytes
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Received April 10, 2008. Revised June 4, 2008. Accepted June 12, 2008.
*Present address: Laboratory of Molecular and Experimental Pathology, Key Laboratory of Animal Models and Human Disease Mechanisms, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, P.R. China.
Present address: Department of Genetics, University of Erlangen, D-91058 Erlangen, Germany.
Shared senior authorship.
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