Naive CD8 T-cells initiate spontaneous autoimmunity to a sequestered model antigen of the central nervous system.
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-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, naïve 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.
Na
Shin-Young
SY
Institute for Virology and Immunobiology, University of Würzburg, Würzburg, Germany.
Cao
Yi
Y
Toben
Catherine
C
Nitschke
Lars
L
Stadelmann
Christine
C
Gold
Ralf
R
Schimpl
Anneliese
A
Hünig
Thomas
T
D019264:Adoptive Transfer; D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D015551:Autoimmunity; D001402:B-Lymphocytes / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002531:Cerebellum / Q000276:immunology / Q000473:pathology; D018450:Disease Progression; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000473:pathology; D007371:Interferon-gamma / Q000276:immunology; D008198:Lymph Nodes / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009836:Oligodendroglia / Q000276:immunology; D010047:Ovalbumin / Q000276:immunology; D013116:Spinal Cord / Q000276:immunology / Q000473:pathology
D007371:Interferon-gamma; D010047:Ovalbumin