Zhu, C. et al. The Tim-3 ligand galectin-9 negatively regulates T helper type 1 immunity. Nat. Immunol. 6, 1245-1252

Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Nature Immunology (Impact Factor: 20). 01/2006; 6(12):1245-52. DOI: 10.1038/ni1271
Source: PubMed


Tim-3 is a T helper type 1 (T(H)1)-specific cell surface molecule that seems to regulate T(H)1 responses and the induction of peripheral tolerance. However, the identity of the Tim-3 ligand and the mechanism by which this ligand inhibits the function of effector T(H)1 cells remain unknown. Here we show that galectin-9 is the Tim-3 ligand. Galectin-9-induced intracellular calcium flux, aggregation and death of T(H)1 cells were Tim-3-dependent in vitro, and administration of galectin-9 in vivo resulted in selective loss of interferon-gamma-producing cells and suppression of T(H)1 autoimmunity. These data suggest that the Tim-3-galectin-9 pathway may have evolved to ensure effective termination of effector T(H)1 cells.

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    • "Although Gal-9 has antitumor properties, it has also been associated with immunoregulatory effects that can favor tumor cell escape to the effector immune mechanisms, for instance, the peripheral expansion of Treg cells via TGF-␤ activating pathways (Lv et al., 2012). Moreover, Gal-9 binding to TIM-3 molecules (ligand for T cell immunoglobulin mucin-3) on the Th1 cell surface induces apoptosis in this cell, thus contributing to the establishment of an immune environment in the area that fosters tumor growth (Zhu et al., 2005). Therefore, further studies should be performed to investigate the role of immune system in this galectin. "
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    • "It has been shown that once T helper cells get activated and differentiate into Th1 lineage, they express TIM-3 [47, 48]. IFN-g leads to the upregulation of Galectin-9, which binds to TIM-3 to create a negative co-stimulatory signal promoting Th1 cell death through apoptosis and necrosis [49]. As expected, it has been shown that TIM-3 blockade accelerates Th1-mediated autoimmune disease in rodent models [48]. "
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    • "Tim-3 has been reported as a well-characterized receptor for galectin-9 (Jayaraman et al., 2010; Reddy et al., 2011; Zhu et al., 2005). The Tim-3-galectin-9 interaction induces signals that can mediate Th1 cell apoptosis and inhibition of cytotoxic T lymphocytes (CTL), leading to the attenuation of autoimmune diseases and prolongation of allograft survival (Sehrawat et al., 2010; Xu et al., 2010; Zhu et al., 2005). Even though it has been reported that the Tim-3-galectin-9 interaction promotes the suppressive activity of Treg cells and induces a higher frequency of Treg cells during allogeneic skin grafts (Rabinovich and Toscano, 2009; Wang et al., 2009), we found no Tim-3 expression on iTreg cells in vitro. "
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