Galectin-9 and T cell immunoglobulin mucin-3 pathway is a therapeutic target for type 1 diabetes

Motoko Kanzaki, Jun Wada, Koichi Sugiyama, Atsuko Nakatsuka, Sanae Teshigawara, Kazutoshi Murakami, Kentaro Inoue, Takahiro Terami, Akihiro Katayama, Jun Eguchi, Hisaya Akiba, Hideo Yagita, Hirofumi Makino

Research output: Contribution to journalArticlepeer-review

63 Citations (Scopus)


Galectin-9 (Gal-9), a ligand for T cell Ig mucin-3 (Tim-3), induces apoptosis in cluster of differentiation 4 (CD4) + Tim-3 + T helper 1 (T H1) cells via the Gal-9-Tim-3 pathway and negatively regulates T H1 immunity. In turn, Gal-9 activates dendritic cells (DC) to produce TNF-α, which promotes the T H1 response. We investigated the efficacy of Gal-9 against T H1-mediated autoimmune diabetes in NOD mice and compared with anti-Tim-3 monoclonal antibody (RMT3-23), which inhibited the binding between Tim-3-Ig and Gal-9 in a solid-phase binding assay. mRNA expression of Gal-9 was prominently induced by the treatment of interferon-γ in MIN6 cells, and Gal-9 was also expressed in the pancreatic β-cells in NOD mice, suggesting Gal-9 may be released from pancreatic β-cells to terminate T H1-mediated inflammation. Long-term injection of Gal-9 exhibits preventive efficacy for development of diabetes in NOD mice, but RMT3-23 demonstrated further prominent therapeutic potential compared with Gal-9. Gal-9 induced apoptosis of CD4 +Tim-3 + T H1 cells at the concentration of 0.2 μM, whereas RMT3-23 failed to enhance the apoptosis of CD4 +Tim-3 + T H1 cells. In contrast, Gal-9 induced TNF-α production in cultured DC in a dose-dependent manner; however, RMT3-23 inhibited Gal-9-induced TNF-α production in a dose-dependent manner. Although Gal-9 exhibited certain therapeutic potential against autoimmune diabetes by enhancing apoptosis of CD4 +Tim-3 + T H1 cells, RMT3-23 exhibited prominent therapeutic efficacy by suppressing the TNF-α production and activation of DC. Taken together, the inhibition of the Gal-9-Tim-3 pathway on DC, upstream of T H1 response, may be a new target for the treatment of type 1 diabetes.

Original languageEnglish
Pages (from-to)612-620
Number of pages9
Issue number2
Publication statusPublished - Feb 2012

ASJC Scopus subject areas

  • Endocrinology


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