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CD8(+) T cells from Theiler's virus-resistant BALB/cByJ mice downregulate pathogenic virus-specific CD4(+) T cells
L M Haynes1, C L Vanderlugt, M C Dal Canto
1Department of Microbiology-Immunology, Northwestern University Medical School, 303 East Chicago Avenue, Chicago, IL 60611, USA.
Abstract:
Theiler's murine encephalomyelitis virus (TMEV) is a picornavirus which induces an immune-mediated demyelinating disease in susceptible strains of mice and serves as a relevant animal model for multiple sclerosis. Treatment with low dose irradiation prior to infection with the BeAn strain of TMEV renders the genetically resistant BALB/cByJ (C/cByJ) mice susceptible to disease. Previous studies have shown that disease resistance in the C/cByJ is mediated by a 'regulatory' CD8(+) T cell population, which does not appear to function via a cytolytic mechanism. We show here that TMEV-specific CD4(+) T cell blasts transferred into susceptible, irradiated C/cByJ accelerate clinical disease and enhance TMEV-specific DTH and proliferation in these animals. Significantly, CD8(+) cells from infected, resistant C/cByJ mice specifically downregulate the in vivo disease potentiation and diminish virus specific DTH, and proliferative and pro-inflammatory cytokine responses (IFNgamma and IL-2) in recipients of TMEV-specific CD4(+) T cell blasts. These results indicate that TMEV infection of resistant C/cByJ mice induces a radiosensitive population of regulatory CD8(+) T cells which actively downregulate inherent Th1 responses which have disease initiating potential.
Insights
Regulatory CD8(+) T cells in mice infected with Theiler's murine encephalomyelitis virus (TMEV) actively suppress immune responses. These cells are radiosensitive and downregulate T-helper 1 (Th1) responses, preventing demyelinating disease.
Area of Science:
- Immunology
- Virology
- Neuroscience
Background:
- Theiler's murine encephalomyelitis virus (TMEV) causes immune-mediated demyelinating disease in mice, modeling multiple sclerosis.
- BALB/cByJ (C/cByJ) mice are genetically resistant to TMEV disease, with resistance mediated by regulatory CD8(+) T cells.
- Low-dose irradiation can render resistant C/cByJ mice susceptible to TMEV-induced disease.
Purpose of the Study:
- To investigate the role of regulatory CD8(+) T cells in TMEV-induced demyelinating disease.
- To determine the mechanism by which regulatory CD8(+) T cells suppress immune responses to TMEV.
- To assess the radiosensitivity of regulatory CD8(+) T cells in TMEV infection.
Main Methods:
- Transfer of TMEV-specific CD4(+) T cell blasts into irradiated C/cByJ mice.
- Administration of CD8(+) T cells from infected, resistant C/cByJ mice into recipients.
- Assessment of clinical disease, delayed-type hypersensitivity (DTH), proliferation, and cytokine responses (IFN-gamma, IL-2).
Main Results:
- TMEV-specific CD4(+) T cell blasts accelerated clinical disease and enhanced TMEV-specific DTH and proliferation in susceptible mice.
- CD8(+) T cells from infected, resistant mice downregulated disease potentiation and diminished virus-specific DTH, proliferation, and pro-inflammatory cytokine responses.
- These regulatory effects were observed in recipients of TMEV-specific CD4(+) T cell blasts.
Conclusions:
- TMEV infection induces a radiosensitive population of regulatory CD8(+) T cells in resistant mice.
- These regulatory CD8(+) T cells actively suppress Th1 responses that have disease-initiating potential.
- This mechanism highlights a novel regulatory pathway in TMEV-induced demyelinating disease.