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

Abstract

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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Figure 1: Tim-3 expression on effector-memory T cells in vivo.
Figure 2: Identification of the Tim-3-binding protein.
Figure 3: Galectin-9 specifically interacts with Tim-3.
Figure 4: Galectin-9 specifically binds to the carbohydrate chains on Tim-3.
Figure 5: Galectin-9-induced cell death in activated mouse TH1 cells is mediated by interaction with Tim-3.
Figure 6: Confocal microscopy of galectin-9-induced cell death in TH1 cells.
Figure 7: Effect of the modulation of galectin-9 on TH1 cells in vivo.

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Acknowledgements

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.).

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Correspondence to Vijay K Kuchroo.

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Patents have been licensed to Telos; V.K.K. is a consultant to Telos.

Supplementary information

Supplementary Table 1

The kinetics of galectin-9 induced cell death in TH1 and TH2 cells. (PDF 97 kb)

Supplementary Video 1

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)

Supplementary Video 2

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)

Supplementary Video 3

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

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