Galectin-4 controls intestinal inflammation by selective regulation of peripheral and mucosal T cell apoptosis and cell cycle

Galectin-4 is a carbohydrate-binding protein belonging to the Galectin family. Here we provide novel evidence that Galectin-4 is selectively expressed and secreted by intestinal epithelial cells and binds potently to activated peripheral and mucosal lamina propria T-cells at the CD3 epitope. The carbohydrate-dependent binding of Galectin-4 at the CD3 epitope is fully functional and inhibited T cell activation, cycling and expansion. Galectin-4 induced Apoptosis of activated peripheral and mucosal lamina propria T cells via calpain-, but not caspase-dependent, pathways. Providing further evidence for its important role in regulating T cell function, Galectin-4 blockade by Antisense Oligonucleotides reduced TNF-alpha inhibitor induced T cell death. Furthermore, in T cells, Galectin-4 reduced pro-inflammatory cytokine secretion including IL-17. In a model of experimental colitis, Galectin-4 ameliorated mucosal inflammation, induced Apoptosis of mucosal T-cells and decreased the secretion of pro-inflammatory cytokines. Our results show that Galectin-4 plays a unique role in the intestine and assign a novel role of this protein in controlling intestinal inflammation by a selective induction of T cell Apoptosis and cell cycle restriction. Conclusively, after defining its biological role, we propose Galectin-4 is a novel anti-inflammatory agent that could be therapeutically effective in diseases with a disturbed T cell expansion and Apoptosis such as inflammatory bowel disease.