Zhu, C. et al. The Tim-3 ligand galectin-9 negatively regulates T helper type 1 immunity. Nature 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

ABSTRACT 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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Available from: Terry B. Strom, Sep 28, 2015
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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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    ABSTRACT: To evaluate the expression of Galectins (Gal) 1, 3 and 9, Metalloproteinase 3 (MMP-3) and mast cell density in oral lesions of patients with potentially malignant disorders (PMD) and oral squamous cell carcinomas (OSCC) by comparison with the controls. We selected 40 cases of PMD, 40 OSCC and 13 with normal histopathological profile. Immunohistochemistry was performed for Gal-1, Gal-3, Gal-9 and MMP-3. Gal-9 was significantly higher in patients with OSCC than in others groups (p<0.001). Gal-1 expression was significantly lower in patients with leukoplakia than those with OSCC and controls (p=0.0001). Gal-3 was significantly lower in patients with OSCC than those with leukoplakia (p=0.03). MMP-3 was lower in patients with leukoplakia in comparison with the lichen planus group (p=0.013). The increased expression of Gal-9 may be helpful to differentiate of OSCC from other oral cavity lesions. Copyright © 2015. Published by Elsevier GmbH.
    Immunobiology 04/2015; 220(8). DOI:10.1016/j.imbio.2015.04.004 · 3.04 Impact Factor
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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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    ABSTRACT: T cell differentiation is dictated by a combination of T cell receptor (TCR) interaction with an antigen-bound major histocompatibility complex (MHC), and co-stimulatory molecules signal. The co-stimulatory signal can be positive or negative, and amplifying or diminishing the initial signal. However, the secondary co-stimulatory signal is not obligatory and its necessity is dictated, in part, by the stage of T cell development. In the field of transplantation, directing the T cell differentiation process can lead to therapeutic possibilities that promote allograft tolerance, and hinder unfavorable alloimmune responses. Therefore, understanding the details of T cell differentiation process, including the influence of co-stimulatory signals, is of paramount importance. It is important to note there is functional overlap between co-stimulatory molecules. It has been observed that some co-stimulatory signals have different effects on different T cell subsets. Hence, blockade of a co-stimulatory signal pathway, as part of a therapeutic regimen in transplantation, may have far reaching effects beyond the initial therapeutic intent and inhibit co-stimulatory signals necessary for desirable regulatory responses. In this review, co-stimulatory molecules involved in the differentiation of naïve T cells into T helper 1 (Th1), T helper 2 (Th2), T helper 17 (Th17), inducible regulatory T cells (iTregs), and T helper 9 (Th9) cells and their overlap are discussed.
    International Journal of Organ Transplantation Medicine 08/2014; 5(3):97-110.
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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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    ABSTRACT: The β-galactoside-binding protein galectin-9 is critical in regulating the immune response, but the mechanism by which it functions remains unclear. We have demonstrated that galectin-9 is highly expressed by induced regulatory T cells (iTreg) and was crucial for the generation and function of iTreg cells, but not natural regulatory T (nTreg) cells. Galectin-9 expression within iTreg cells was driven by the transcription factor Smad3, forming a feed-forward loop, which further promoted Foxp3 expression. Galectin-9 increased iTreg cell stability and function by directly binding to its receptor CD44, which formed a complex with transforming growth factor-β (TGF-β) receptor I (TGF-βRI), and activated Smad3. Galectin-9 signaling was further found to regulate iTreg cell induction by dominantly acting through the CNS1 region of the Foxp3 locus. Our data suggest that exogenous galectin-9, in addition to being an effector molecule for Treg cells, acts synergistically with TGF-β to enforce iTreg cell differentiation and maintenance.
    Immunity 07/2014; 41(2). DOI:10.1016/j.immuni.2014.06.011 · 21.56 Impact Factor
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