JVI Accepts, published online ahead of print on 6 August 2008

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J. Virol. doi:10.1128/JVI.00734-08
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Regulatory Role of CD1d in Neurotropic Virus Infection

Ikuo Tsunoda^*, Tomoko Tanaka, and Robert S. Fujinami

Department of Pathology, Division of Cell Biology & Immunology, University of Utah School of Medicine, 30 North 1900 East, Salt Lake City, Utah 84132-2305

^* To whom correspondence should be addressed. Email: ikuo.tsunoda{at}hsc.utah.edu.

The GDVII strain of Theiler's murine encephalomyelitis virus (TMEV) causes an acute fatal polioencephalomyelitis in mice. Infection of susceptible mice with the DA strain of TMEV results in an acute polioencephalomyelitis followed by chronic immune-mediated demyelination with virus persistence in the central nervous system (CNS); DA virus infection is used as an animal model for multiple sclerosis. CD1d-restricted natural killer T (NKT) cells can contribute to viral clearance and regulation of autoimmune responses. To investigate the role of CD1d in TMEV infection, we first infected CD1d-deficient mice (CD1^-/-) and wild-type BALB/c mice with GDVII virus. Wild-type mice were more resistant to virus than CD1^-/- mice (LD₅₀ titer: wild-type mice, 10 plaque forming units (PFU); CD1^-/- mice, 1.6 PFU). Wild-type mice had fewer viral antigen positive cells with greater inflammation in the CNS than CD1^-/- mice. Second, an analysis of DA virus infection in CD1^-/- mice was conducted. Although both wild-type and CD1^-/- mice had similar clinical signs during the first 2 weeks after infection, CD1^-/- mice had an increase in neurological deficits over those observed in wild-type mice, 3 to 5 weeks after infection. Although wild-type mice had no demyelination, 20 and 60% of CD1^-/- mice developed demyelination at 3 and 5 weeks after infection, respectively. TMEV-specific lymphoproliferative responses, interleukin (IL)-4 production and IL-4/interferon- ratios were higher in CD1^-/- mice than in wild-type mice. Thus, CD1d-restricted NKT cells may play a protective role in TMEV-induced neurological disease by alteration of the cytokine profile and virus-specific immune responses.