Journal Article

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

Shin-Young Na, Yi Cao, Catherine Toben, Lars Nitschke, Christine Stadelmann, Ralf Gold, Anneliese Schimpl and Thomas Hünig

in Brain

Published on behalf of The Guarantors of Brain

Volume 131, issue 9, pages 2353-2365
Published in print September 2008 | ISSN: 0006-8950
Published online July 2008 | e-ISSN: 1460-2156 | DOI: http://dx.doi.org/10.1093/brain/awn148
Naïve CD8 T-cells initiate spontaneous autoimmunity to a sequestered model antigen of the central nervous system

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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

Journal Article.  6978 words.  Illustrated.

Subjects: Neurology ; Neuroscience

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