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⇱ The Tim-3 ligand galectin-9 negatively regulates T helper type 1 immunity | Nature Immunology

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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-Ξ³-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.
The alternative text for this image may have been generated using AI.
Figure 2: Identification of the Tim-3-binding protein.
The alternative text for this image may have been generated using AI.
Figure 3: Galectin-9 specifically interacts with Tim-3.
The alternative text for this image may have been generated using AI.
Figure 4: Galectin-9 specifically binds to the carbohydrate chains on Tim-3.
The alternative text for this image may have been generated using AI.
Figure 5: Galectin-9-induced cell death in activated mouse TH1 cells is mediated by interaction with Tim-3.
The alternative text for this image may have been generated using AI.
Figure 6: Confocal microscopy of galectin-9-induced cell death in TH1 cells.
The alternative text for this image may have been generated using AI.
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.).

Author information

Authors and Affiliations

  1. Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, 02115, Massachusetts, USA

    Chen Zhu, Ana C Anderson, Anna Schubart, Jaime Imitola, Samia J Khoury & Vijay K Kuchroo

  2. Immunobiology Center, Mount Sinai School of Medicine of New York University, New York, 10029, New York, USA

    Huabao Xiong

  3. Division of Immunology and Transplant Research Center, Beth Israel and Deaconess Hospital, Harvard Medical School, Boston, 02115, Massachusetts, USA

    Xin Xiao Zheng & Terry B Strom

Authors
  1. Chen Zhu
  2. Ana C Anderson
  3. Anna Schubart
  4. Huabao Xiong
  5. Jaime Imitola
  6. Samia J Khoury
  7. Xin Xiao Zheng
  8. Terry B Strom
  9. Vijay K Kuchroo

Corresponding author

Correspondence to Vijay K Kuchroo.

Ethics declarations

Competing interests

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

Supplementary information

Supplementary Table 1 (download PDF )

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

Supplementary Video 1 (download MOV )

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 ΞΌM Gal-9. (MOV 1246 kb)

Supplementary Video 2 (download MOV )

Galectin-9 induced cell aggregation and subsequent cell death in TH1 cells. DO11.10 TH1 cells form tight junctions 1 h after 0.5 ΞΌM Gal-9 stimulation. (MOV 509 kb)

Supplementary Video 3 (download MOV )

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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