Article

The Tim-3 ligand galectin-9 negatively regulates T helper type 1 immunity.

Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Nature Immunology (Impact Factor: 24.97). 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.

Download full-text

Full-text

Available from: Terry B. Strom, Jul 01, 2015
1 Follower
 · 
293 Views
  • Source
    [Show abstract] [Hide abstract]
    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 · 3.18 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    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 · 19.75 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Dendritic cells (DCs) are central in maintaining the intricate balance between immunity and tolerance by orchestrating adaptive immune responses. Being the most potent antigen presenting cells, DCs are capable of educating naïve T cells into a wide variety of effector cells ranging from immunogenic CD4 T helper cells and cytotoxic CD8 T cells to tolerogenic regulatory T cells. This education is based on three fundamental signals. Signal I, which is mediated by antigen/major histocompatibility complexes binding to antigen-specific T cell receptors, guarantees antigen specificity. The co-stimulatory signal II, mediated by B7 family molecules, is crucial for the expansion of the antigen-specific T cells. The final step is T cell polarization by signal III, which is conveyed by DC-derived cytokines and determines the effector functions of the emerging T cell. Although co-stimulation is widely recognized to result from the engagement of T cell-derived CD28 with DC-expressed B7 molecules (CD80/CD86), other co-stimulatory pathways have been identified. These pathways can be divided into two groups based on their impact on primed T cells. Whereas pathways delivering activatory signals to T cells are termed co-stimulatory pathways, pathways delivering tolerogenic signals to T cells are termed co-inhibitory pathways. In this review, we discuss how the nature of DC-derived signal II determines the quality of ensuing T cell responses and eventually promoting either immunity or tolerance. A thorough understanding of this process is instrumental in determining the underlying mechanism of disorders demonstrating distorted immunity/tolerance balance, and would help innovating new therapeutic approaches for such disorders.
    Frontiers in Immunology 02/2013; 4:53. DOI:10.3389/fimmu.2013.00053