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Int Immunol. 2014 Jul;26(7):369-81. doi: 10.1093/intimm/dxt056. Epub 2014 Jan 31.

The TIM-3 pathway ameliorates Theiler's murine encephalomyelitis virus-induced demyelinating disease.

Author information

1
Department of Biomedical Laboratory Sciences, Graduate School of Medicine, Shinshu University, Matsumoto, Nagano 390-8621, Japan Research Fellow of the Japan Society for the Promotion of Science, Chiyoda-ku, Tokyo 102-0083, Japan.
2
Department of Biomedical Laboratory Sciences, Graduate School of Medicine, Shinshu University, Matsumoto, Nagano 390-8621, Japan.
3
Department of Pediatrics, School of Medicine, Shinshu University, Matsumoto, Nagano 390-8621, Japan.
4
Department of Immunology, Juntendo University Graduate School of Medicine, Bunkyo-ku, Tokyo 113-8421, Japan.
5
Department of Microbiology-Immunology, Northwestern University Finberg Medical School, Chicago, IL 60611, USA.
6
Department of Biomedical Laboratory Sciences, Graduate School of Medicine, Shinshu University, Matsumoto, Nagano 390-8621, Japan kshosei@shinshu-u.ac.jp.

Abstract

Infection by Theiler's murine encephalomyelitis virus (TMEV) in the central nervous system (CNS) induces an immune-mediated demyelinating disease in susceptible mouse strains and serves as a relevant infection model for human multiple sclerosis. T-cell immunoglobulin and mucin domain-3 (TIM-3) has been demonstrated to play a crucial role in the maintenance of peripheral tolerance. In this study, we examined the regulatory role of the TIM-3 pathway in the development of TMEV-induced demyelinating disease (TMEV-IDD). The expression of TIM-3 was increased at both protein and mRNA levels in the spinal cords of mice with TMEV-IDD compared with naive controls. In addition, by utilizing a blocking mAb, we demonstrate that TIM-3 negatively regulates TMEV-specific ex vivo production of IFN-γ and IL-10 by CD4(+) T cells and IFN-γ by CD8(+) T cells from the CNS of mice with TMEV-IDD at 36 days post-infection (dpi). In vivo blockade of TIM-3 by using the anti-TIM-3 mAb resulted in significant exacerbation of the development of TMEV-IDD both clinically and histologically. The number of infiltrating mononuclear cells in the CNS was also increased in mice administered with anti-TIM-3 mAb both at the induction phase (10 dpi) and at the effector phase (36 dpi). Flow cytometric analysis of intracellular cytokines revealed that the number of CD4(+) T cells producing TNF, IL-4, IL-10 and IL-17 was significantly increased at the effector phase in the CNS of anti-TIM-3 mAb-treated mice. These results suggest that the TIM-3 pathway plays a critical role in the regulation of TMEV-IDD.

KEYWORDS:

T-cell immunoglobulin and mucin domain-3; Theiler’s murine encephalomyelitis virus-induced demyelinating disease.; demyelination; galectin-9; multiple sclerosis

PMID:
24486565
DOI:
10.1093/intimm/dxt056
[Indexed for MEDLINE]

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