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Journal of Virology, December 2002, p. 12834-12844, Vol. 76, No. 24
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.24.12834-12844.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Induction of Autoreactive CD8+ Cytotoxic T Cells during Theiler's Murine Encephalomyelitis Virus Infection: Implications for Autoimmunity

Ikuo Tsunoda, Li-Qing Kuang, and Robert S. Fujinami*

Department of Neurology, University of Utah School of Medicine, Salt Lake City, Utah 84132

Received 22 May 2002/ Accepted 3 September 2002

Theiler's murine encephalomyelitis virus (TMEV) belongs to the family Picornaviridae and causes demyelinating disease in the spinal cords of infected mice. Although immune responses have been shown to play an important role in demyelination, the precise effector mechanism(s) is unknown. Potentially autoreactive cytotoxic cells could contribute to the destruction. We tested whether an autoreactive cell induced by TMEV infection mediated cytotoxicity by using a 5-h 51Cr release assay in SJL/J mice. Spleen cells from TMEV-infected mice were stimulated with irradiated TMEV antigen-presenting cells and used as effector cells. The effector cells differed from conventional cytotoxic T cells since these cells could kill both TMEV-infected and uninfected syngeneic or semisyngenic cell lines (PSJLSV and BxSF11gSV) but could not kill an allogeneic cell line (C57SV). The TMEV-induced autoreactive cells were also different from conventional natural killer (NK) cells or lymphokine-activated killer (LAK) cells, because they could kill neither NK cell-sensitive YAC-1 nor NK cell-resistant P815 and EL4 cells. Induction of autoreactive cells was not detected in vaccinia virus infection. The autoreactive killing required direct cell-to-cell contact and was mediated by a Fas-FasL pathway but not by a perforin pathway. The phenotype of the killer cells was CD3+ CD4- CD8+. Intracerebral inoculation of the effector cells into naive mice caused meningitis and perivascular cuffing not only in the brain parenchyma but also in the spinal cord, with no evidence of viral antigen-positive cells. This is the first report demonstrating that TMEV can induce autoreactive cytotoxic cells that induce central nervous system pathology.

* Corresponding author. Mailing address: Department of Neurology, University of Utah School of Medicine, 30 North 1900 East, Room 3R330, Salt Lake City, UT 84132. Phone: (801) 585-3305. Fax: (801) 585-3311. E-mail: Robert.Fujinami{at}hsc.utah.edu.

Journal of Virology, December 2002, p. 12834-12844, Vol. 76, No. 24
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.24.12834-12844.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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