Structural Features of Galectin‐9 and Galectin‐1 that Determine Distinct T cell Death Pathways

Abstract

Galectin‐9 and galectin‐1 both kill thymocytes, peripheral T cells and T cell lines. However, differences in target cell specificity, glycoprotein receptor requirements, and intracellular death pathways for these two galectins are not well understood. We found that galectin‐9 and galectin‐1 required different glycan ligands and glycoprotein receptors to trigger T cell death. They also triggered different intracellular death pathways, as only galectin‐9 T cell death was blocked by intracellular bcl‐2, while only galectin‐1 T cell death was blocked by intracellular galectin‐3. Galectin‐9 and galectin‐1 were both expressed in murine thymus, but killed different thymocyte subsets, with mature thymocytes more susceptible to galectin‐9. To define the structural features responsible for distinct activities of galectin‐1 and galectin‐9, we created a series of bivalent neo‐galectins with galectin‐1 and galectin‐9 carbohydrate recognition domains on different peptide linkers. The N‐terminal carbohydrate recognition domain and linker peptide contributed to potency of the galectins. Strikingly, the C‐terminal carbohydrate recognition domain determined receptor recognition, death pathway signaling and target cell susceptibility. Thus, carbohydrate recognition domain specificity, presentation, and valency all contribute to specific effects of different galectins in regulating T cell death.