Galectin-4 Controls Intestinal Inflammation by Selective Regulation of Peripheral and Mucosal T Cell Apoptosis and Cell Cycle

Abstract

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.

Galectin-2 Suppresses Contact Allergy by Inducing Apoptosis in Activated CD8+ T Cells

“…Toscano et al demonstrated that systemic treatment of mice with 50 g of galectin-1 per day for 3 days reduced experimental autoimmune uveitis significantly (40), and similar amounts of galectin-9 suppressed allergic asthma (41). However, even higher concentrations of galectin-4 (60 g/day for 8 days) were used to inhibit dextrane sulfate-induced colitis (34). Here we demonstrate that contact allergy can be blocked by i.p.…”

“…Furthermore, the differences in galectin concentrations required to efficiently block inflammatory disorders might also be attributed to different kinds of administration (e.g., galectin-9 and galectin-1 were injected i.v., whereas galectin-4 and galectin-2 were given i.p. (34,40,41)). …”

“…Previous studies demonstrated that galectins, in particular galectin-1, galectin-3, and galectin-4, induced apoptosis in T cells (33,34,36). Therefore, the decreased numbers of activated CD8 ϩ T cells in peripheral lymph nodes of systemically galectin-2-treated and hapten-sensitized C57BL/6 and galectin-2 treated autoimmune-prone CD40L tg mice (Fig.…”

Galectins: Key Players at the Frontiers of Innate and Adaptive Immunity

“…1). In particular, Gal4 reduces intestinal inflammation by inducing apoptosis of mucosal T cells and reducing pro-inflammatory cytokine secretion (96). However, this lectin was also reported to induce IL-6 production in T cells through PKCϕ-dependent pathways, leading to stimulation of an intestinal inflammatory response (97) (Fig.…”

Surface profiles of live colorectal cancer cells and tumor infiltrating lymphocytes from surgical samples correspond to prognostic categories

“…Poor survival Secreted by CRC cells to bind to activated T-cells at the CD3 region, which is translated into a potent inhibition of cell cycle progression and induction of antigen-induced cell death (Paclik et al, 2008) ↑ CA19-9 Poor survival Sialylated Lewis a blood group antigen, secreted in high concentrations into serum of patients with CRC (Yamada et al, 1995) ↑ TSP-1 Poor survival Role in the recruitment, activation and retention of infiltrating T-cells in the lesions of inflammatory diseases.…”