Human Galectin-2: Novel Inducer of T Cell Apoptosis with Distinct Profile of Caspase Activation

Abstract

Galectin-2 is structurally closely related to galectin-1, but has a distinct expression profile primarily confined to the gastrointestinal tract. Prominent differences in the proximal promoter regions between galectins-2 and -1 concern Sp1-, hepatocyte NF-3, and T cell-specific factor-1 binding sites. Of note, these sequence elements are positioned equally in the respective regions for human and rat galectins-2. Labeled galectin-2 binds to T cells in a β-galactoside-specific manner. In contrast to galectin-1, the glycoproteins CD3 and CD7 are not ligands, while the shared affinity to β1 integrin (or a closely associated glycoprotein) accounts for a substantial extent of cell surface binding. The carbohydrate-dependent binding of galectin-2 induces apoptosis in activated T cells. Fluorogenic substrate and inhibitor assays reveal involvement of caspases-3 and -9, in accordance with cleavage of the DNA fragmentation factor. Enhanced cytochrome c release, disruption of the mitochondrial membrane potential, and an increase of the Bax/Bcl-2 ratio by opposite regulation of expression of both proteins add to the evidence that the intrinsic apoptotic pathway is triggered. Cell cycle distribution and expression of regulatory proteins remained unaffected. Notably, galectins-1 and -7 reduce cyclin B1 expression, defining functional differences between the structurally closely related galectins. Cytokine secretion of activated T cells was significantly shifted to the Th2 profile. Our study thus classifies galectin-2 as proapoptotic effector for activated T cells, raising a therapeutic perspective. Of importance for understanding the complex galectin network, it teaches the lesson that selection of cell surface ligands, route of signaling, and effects on regulators of cell cycle progression are markedly different between structurally closely related galectins.

Structural Features of Galectin-9 and Galectin-1 That Determine Distinct T Cell Death Pathways

“…However, even in the same cell type, different galectins trigger distinct intracellular death pathways, e.g. galectin-1, galectin-2, galectin-3, and galectin-9 all trigger T cell death, but differ in the requirement for caspase activation (6,12,15,17). Similarly, we have found that galectin-1, galectin-3, and galectin-9 kill different subsets of thymocytes and peripheral CD4 T cells (Fig.…”

“…Specific glycoprotein receptors involved in galectin-1 death and specific types of O-and N-glycan ligands required for galectin-1 death have been identified, and galectin-1 has been shown to trigger a novel intracellular death pathway (6 -14). Other galectins have also been reported to trigger death of T cell lines and various T cell subsets, including galectin-2, galectin-3, galectin-8, and galectin-9 (15)(16)(17)(18)(19). Relatively little is known about the glycoprotein receptors, glycan ligands, and intracellular death pathways used by these galectins.…”

Galectin-1 Interacts with the α5β1 Fibronectin Receptor to Restrict Carcinoma Cell Growth via Induction of p21 and p27

“…In previous reports, Gal-1 was demonstrated to interact with ␣7␤1 or ␣1␤1 integrin in mesenchymal cells and ␤1 integrin in T-cells, suggesting that cell type-specific expression patterns of integrins and their glycans contribute to differential effects of Gal-1 in mesenchymal, lymphoid, and epithelial cancer cells (35)(36)(37). In the case of human smooth muscle cells Gal-1 binding did not cross-link ␤1 integrin but nonetheless led to a transient increase in tyrosine phosphorylation of two cytoskeleton-associated proteins and to modulation of cell attachment, possibly due to an effect of Gal-1 on ␤1 conformation (13).…”

Functions of cell surface galectin-glycoprotein lattices

“…Galectin-1, -2, -3 and -9 bind distinct cell surface glycoprotein receptors and trigger distinct intracellular signaling pathways to promote T-cell death [17,19,[35][36][37]. Remarkably, a number of factors determine the responsiveness of cells to galectin-mediated signals which include the repertoire of glycosylated molecules expressed on the cell surface and the activities of specific glycosyltransferases, which are responsible for creating or masking galectin ligands [5,6,18].…”