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

Tomoki Kaneyama, Hiroki Tomiki, Sayaka Tsugane, Yuji Inaba, Motoki Ichikawa, Hisaya Akiba, Hideo Yagita, Byung S. Kim, Chang Sung Koh*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

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-? 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.

Original languageEnglish (US)
Pages (from-to)369-381
Number of pages13
JournalInternational Immunology
Volume26
Issue number7
DOIs
StatePublished - Jul 2014

Keywords

  • Demyelination
  • Galectin-9
  • Multiple sclerosis
  • T-cell immunoglobulin and mucin domain-3
  • Theiler's murine encephalomyelitis virus-induced demyelinating disease

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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