Tim-3 is a T helper type 1 (TH1)–specific cell surface molecule that seems to regulate TH1 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 TH1 cells remain unknown. Here we show that galectin-9 is the Tim-3 ligand. Galectin-9-induced intracellular calcium flux, aggregation and death of TH1 cells were Tim-3-dependent in vitro, and administration of galectin-9 in vivo resulted in selective loss of interferon-γ-producing cells and suppression of TH1 autoimmunity. These data suggest that the Tim-3–galectin-9 pathway may have evolved to ensure effective termination of effector TH1 cells.
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Mosmann, T.R. & Coffman, R.L. TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu. Rev. Immunol. 7, 145–173 (1989).
Paul, W.E. & Seder, R.A. Lymphocyte responses and cytokines. Cell 76, 241–251 (1994).
Street, N.E. & Mosmann, T.R. Functional diversity of T lymphocytes due to secretion of different cytokine patterns. FASEB J. 5, 171–177 (1991).
Romagnani, S. Lymphokine production by human T cells in disease states. Annu. Rev. Immunol. 12, 227–257 (1994).
Kamradt, T. & Mitchison, N.A. Tolerance and autoimmunity. N. Engl. J. Med. 344, 655–664 (2001).
Abbas, A.K., Murphy, K.M. & Sher, A. Functional diversity of helper T lymphocytes. Nature 383, 787–793 (1996).
Sher, A. & Coffman, R.L. Regulation of immunity to parasites by T cells and T cell-derived cytokines. Annu. Rev. Immunol. 10, 385–409 (1992).
Monney, L. et al. Th1-specific cell surface protein Tim-3 regulates macrophage activation and severity of an autoimmune disease. Nature 415, 536–541 (2002).
Khademi, M. et al. T cell Ig- and mucin-domain-containing molecule-3 (TIM-3) and TIM-1 molecules are differentially expressed on human TH1 and TH2 cells and in cerebrospinal fluid-derived mononuclear cells in multiple sclerosis. J. Immunol. 172, 7169–7176 (2004).
McIntire, J.J. et al. Identification of Tapr (an airway hyperreactivity regulatory locus) and the linked Tim gene family. Nat. Immunol. 2, 1109–1116 (2001).
Chae, S.C., Park, Y.R., Shim, S.C., Yoon, K.S. & Chung, H.T. The polymorphisms of TH1 cell surface gene Tim-3 are associated in a Korean population with rheumatoid arthritis. Immunol. Lett. 95, 91–95 (2004).
Sabatos, C.A. et al. Interaction of Tim-3 and Tim-3 ligand regulates T helper type 1 responses and induction of peripheral tolerance. Nat. Immunol. 4, 1102–1110 (2003).
Sanchez-Fueyo, A. et al. Tim-3 inhibits T helper type 1-mediated auto- and alloimmune responses and promotes immunological tolerance. Nat. Immunol. 4, 1093–1101 (2003).
Wada, J. & Kanwar, Y.S. Identification and characterization of galectin-9, a novel β-galactoside-binding mammalian lectin. J. Biol. Chem. 272, 6078–6086 (1997).
Rabinovich, G.A. et al. Galectins and their ligands: amplifiers, silencers or tuners of the inflammatory response? Trends Immunol. 23, 313–320 (2002).
Oda, Y. et al. Soluble lactose-binding lectin from rat intestine with two different carbohydrate-binding domains in the same peptide chain. J. Biol. Chem. 268, 5929–5939 (1993).
Hernandez, J.D. & Baum, L.G. Ah, sweet mystery of death! Galectins and control of cell fate. Glycobiology 12, 127R–136R (2002).
Matsushita, N. et al. Requirement of divalent galactoside-binding activity of ecalectin/galectin-9 for eosinophil chemoattraction. J. Biol. Chem. 275, 8355–8360 (2000).
Wada, J., Ota, K., Kumar, A., Wallner, E.I. & Kanwar, Y.S. Developmental regulation, expression, and apoptotic potential of galectin-9, a β-galactoside binding lectin. J. Clin. Invest. 99, 2452–2461 (1997).
Kashio, Y. et al. Galectin-9 induces apoptosis through the calcium-calpain-caspase-1 pathway. J. Immunol. 170, 3631–3636 (2003).
Lam, M. et al. Evidence that BCL-2 represses apoptosis by regulating endoplasmic reticulum-associated Ca2+ fluxes. Proc. Natl. Acad. Sci. USA 91, 6569–6573 (1994).
Matsumoto, R. et al. Human ecalectin, a variant of human galectin-9, is a novel eosinophil chemoattractant produced by T lymphocytes. J. Biol. Chem. 273, 16976–16984 (1998).
Sturm, A. et al. Human galectin-2: novel inducer of T cell apoptosis with distinct profile of caspase activation. J. Immunol. 173, 3825–3837 (2004).
Vercammen, D. et al. Dual signaling of the Fas receptor: initiation of both apoptotic and necrotic cell death pathways. J. Exp. Med. 188, 919–930 (1998).
Weiner, H.L. Oral tolerance: immune mechanisms and the generation of TH3-type TGF-β-secreting regulatory cells. Microbes Infect. 3, 947–954 (2001).
Yoshida, H. et al. Interleukin-1β stimulates galectin-9 expression in human astrocytes. Neuroreport 12, 3755–3758 (2001).
Imaizumi, T. et al. Interferon-γ stimulates the expression of galectin-9 in cultured human endothelial cells. J. Leukoc. Biol. 72, 486–491 (2002).
Asakura, H. et al. Selective eosinophil adhesion to fibroblast via IFN-γ-induced galectin-9. J. Immunol. 169, 5912–5918 (2002).
Pender, M.P., McCombe, P.A., Yoong, G. & Nguyen, K.B. Apoptosis of αβ T lymphocytes in the nervous system in experimental autoimmune encephalomyelitis: its possible implications for recovery and acquired tolerance. J. Autoimmun. 5, 401–410 (1992).
Ferber, I.A. et al. Mice with a disrupted IFN-γ gene are susceptible to the induction of experimental autoimmune encephalomyelitis (EAE). J. Immunol. 156, 5–7 (1996).
Salama, A.D. et al. Critical role of the programmed death-1 (PD-1) pathway in regulation of experimental autoimmune encephalomyelitis. J. Exp. Med. 198, 71–78 (2003).
Rabinovich, G.A. et al. Recombinant galectin-1 and its genetic delivery suppress collagen-induced arthritis via T cell apoptosis. J. Exp. Med. 190, 385–398 (1999).
We thank J. Meyers for reading the manuscript and B. Zhu for technical assistance. Supported by the National Institutes Health, National Multiple Sclerosis Society, Juvenile Diabetes Research Foundation, Forest Health and the Javits Neuroscience Investigator Award from the National Institutes of Health (V.K.K.).
Patents have been licensed to Telos; V.K.K. is a consultant to Telos.
The kinetics of galectin-9 induced cell death in TH1 and TH2 cells. (PDF 97 kb)
Galectin-9 induced cell aggregation and subsequent cell death in TH1 cells. DO11.10 TH1 cell aggregation began at 15 minutes after addition of 0.5 μM Gal-9. (MOV 1246 kb)
Galectin-9 induced cell aggregation and subsequent cell death in TH1 cells. DO11.10 TH1 cells form tight junctions 1 h after 0.5 μM Gal-9 stimulation. (MOV 509 kb)
Galectin-9 induced cell aggregation and subsequent cell death in TH1 cells. Induction of cell death in the aggregated DO11.10 TH1 cells. (MOV 698 kb)
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Zhu, C., Anderson, A., Schubart, A. et al. The Tim-3 ligand galectin-9 negatively regulates T helper type 1 immunity. Nat Immunol 6, 1245–1252 (2005). https://doi.org/10.1038/ni1271