The TIM-3 pathway ameliorates Theiler's murine encephalomyelitis virus-induced demyelinating disease.
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.
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.
Tomoki
T
Kaneyama
Department of Biomedical Laboratory Sciences, Graduate School of Medicine, Shinshu University, Matsumoto, Nagano 390-8621, Japan.
Hiroki
H
Tomiki
Department of Biomedical Laboratory Sciences, Graduate School of Medicine, Shinshu University, Matsumoto, Nagano 390-8621, Japan.
Sayaka
S
Tsugane
Department of Pediatrics, School of Medicine, Shinshu University, Matsumoto, Nagano 390-8621, Japan.
Yuji
Y
Inaba
Department of Biomedical Laboratory Sciences, Graduate School of Medicine, Shinshu University, Matsumoto, Nagano 390-8621, Japan.
Motoki
M
Ichikawa
Department of Immunology, Juntendo University Graduate School of Medicine, Bunkyo-ku, Tokyo 113-8421, Japan.
Hisaya
H
Akiba
Department of Immunology, Juntendo University Graduate School of Medicine, Bunkyo-ku, Tokyo 113-8421, Japan.
Hideo
H
Yagita
Department of Microbiology-Immunology, Northwestern University Finberg Medical School, Chicago, IL 60611, USA.
Byung S
BS
Kim
Department of Biomedical Laboratory Sciences, Graduate School of Medicine, Shinshu University, Matsumoto, Nagano 390-8621, Japan kshosei@shinshu-u.ac.jp.
Chang-Sung
CS
Koh
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation; D000072597:Hepatitis A Virus Cellular Receptor 2; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis / Q000378:metabolism; D016753:Interleukin-10 / Q000096:biosynthesis / Q000378:metabolism; D020381:Interleukin-17 / Q000096:biosynthesis / Q000378:metabolism; D015847:Interleukin-4 / Q000096:biosynthesis / Q000378:metabolism; D051379:Mice; D009103:Multiple Sclerosis; D061166:Peripheral Tolerance; D011051:Poliomyelitis / Q000235:genetics* / Q000276:immunology / Q000473:pathology / Q000821:virology; D012333:RNA, Messenger / Q000235:genetics / Q000276:immunology*; D011991:Receptors, Virus / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction; D013116:Spinal Cord / Q000276:immunology* / Q000473:pathology; D017945:Theilovirus / Q000276:immunology* / Q000472:pathogenicity
D000911:Antibodies, Monoclonal; C442241:Havcr2 protein, mouse; D000072597:Hepatitis A Virus Cellular Receptor 2; D020381:Interleukin-17; D012333:RNA, Messenger; D011991:Receptors, Virus; D016753:Interleukin-10; D015847:Interleukin-4; D007371:Interferon-gamma
T-cell immunoglobulin and mucin domain-3; Theiler’s murine encephalomyelitis virus-induced demyelinating disease.; demyelination; galectin-9; multiple sclerosis