Galectins. Structure and function of a large family of animal lectins.

Galectins are a family of animal lectins with diverse biological activities. They function both extracellularly, by interacting with cell-surface and extracellular matrix glycoproteins and glycolipids, and intracellularly, by interacting with cytoplasmic and nuclear proteins to modulate signalling pathways. Current research indicates that galectins have important roles in cancer; they contribute to neoplastic transformation, tumour cell survival, angiogenesis and tumour metastasis. They can modulate the immune and inflammatory responses and might have a key role helping tumours to escape immune surveillance. How do the different members of the Galectin family contribute to these diverse aspects of tumour biology?

Galectins as modulators of tumour progression

Galectin-1, a member of the family of beta-galactoside binding proteins, has growth regulatory and immunomodulatory activities. We report here that galectin-1, expressed by stromal cells in human thymus and lymph nodes, is present at sites of cell death by apoptosis during normal T-cell development and maturation. Galectin-1 induced apoptosis of activated human T cells and human T leukaemia cell lines. Resting T cells also bound galectin-1, but did not undergo apoptosis. Human endothelial cells that expressed galectin-1 induced apoptosis of bound T cells. Galectin-1-induced apoptosis required expression of CD45, and was decreased when N-glycan elongation was blocked by treatment of the cells by swainsonine, whereas inhibition of O-glycan elongation potentiated the apoptotic effect of galectin-1. Induction of apoptosis by an endogenous mammalian lectin represents a new mechanism for regulating the immune response.

Apoptosis of T cells mediated by galectin-1

Publisher Summary This chapter discusses the interactions of lectins with animal cell surfaces. Lectin interactions with cell surfaces can be put into a proper framework for understanding complex phenomena such as lectin-induced mitogenic stimulation, cell agglutination, and lectin-mediated cell toxicity. Lectins have been isolated from a wide variety of plants and animals, from legumes to horseshoe crabs. Lectins generally have the property of agglutinating cells through their cell surface oligosaccharide determinants, and in some cases these determinants have been elucidated by determining the sequences or sugars responsible for saccharide inhibition of agglutination. Because of the carbohydrate-binding specificities of lectins, some of these agglutinins have proven to be quite useful for clinical blood typing and structural studies of blood group substances, in analysis of the surface structure of normal and tumor cells, for specific isolation of glycoproteins and oligo- and mucopolysaccharides, in studies on mitogenesis, as antigen-antibody models, and so on. They have also proven to be invaluable as specific molecular probes for studying membrane, cell, and tissue structure and organization.

The interactions of lectins with animal cell surfaces.

The function of deciphering the biological information encoded by the glycome, which is the entire repertoire of complex sugar structures expressed by cells and tissues, is assigned in part to endogenous glycan-binding proteins or lectins. Galectins, a family of animal lectins that bind N-acetyllactosamine-containing glycans, have many roles in diverse immune cell processes, including those relevant to pathogen recognition, shaping the course of adaptive immune responses and fine-tuning the inflammatory response. How do galectins translate glycan-encoded information into tolerogenic or inflammatory cell programmes? An improved understanding of the mechanisms underlying these functions will provide further opportunities for developing new therapies based on the immunoregulatory properties of this multifaceted protein family.

Turning 'sweet' on immunity: galectin-glycan interactions in immune tolerance and inflammation.

Identification of an autocrine negative growth factor: Mouse β-galactoside-binding protein is a cytostatic factor and cell growth regulator

We have used mRNA differential display PCR to search for genes induced in activated T cells and have found the LGALS1 (lectin, galactoside-binding, soluble) gene to be strongly up-regulated in effector T cells. The protein coded by the LGALS1 gene is a beta-galactoside-binding protein (betaGBP), which is released by cells as a monomeric negative growth factor but which can also associate into homodimers (galectin-1) with lectin properties. Northern blot analysis revealed that ex vivo isolated CD8+ effector T cells induced by a viral infection expressed high amounts of LGALS1 mRNA, whereas LGALS1 expression was almost absent in resting CD8+ T cells. LGALS1 expression could be induced in CD4+ and CD8+ T cells upon activation with the cognate peptide antigen and high levels of LGALS1 expression were found in concanavalin A-activated T cells but not in lipopolysaccharide-activated B cells. Gel filtration and Western blot analysis revealed that only monomeric betaGBP was released by activated CD8+ T cells and in vitro experiments further showed that recombinant betaGBP was able to inhibit antigen-induced proliferation of naive and antigen-experienced CD8+ T cells. Thus, these data indicate a role of betaGBP as an autocrine negative growth factor for CD8+ T cells.

β‐Galactoside‐binding protein secreted by activated T cells inhibits antigen‐induced proliferation of T cells

In this paper, the effects of beta-galactoside binding protein (beta GBP), the LGALS1 gene product, on the cell cycle progression and expansion of activated human T lymphocytes were studied. Beta GBP drastically inhibits the IL-2 induced proliferation of PHA-activated T lymphocytes as well as the IL-2 independent proliferation of malignant T lymphocytes by arresting them in the S and G2/M phases of the cell cycle. In addition, beta GBP up-regulates the expression of both the alpha- and the beta-chains of the IFN-gamma R on activated T lymphocyte membrane. None of these effects depend on sugar binding: saturating amounts of lactose do not affect the cell cycle block nor IFN-gamma R up-modulation. The increased expression of both chains renders beta GBP-treated T lymphoblasts sensitive to IFN-y-induced apoptosis. Taken as a whole, these findings suggest that beta GBP plays an important immunoregulatory role by switching off T lymphocyte effector functions. They also provide the first evidence of up-modulation of IFN-gamma R expression on T lymphocytes by a negative cell growth regulator.

Beta-galactoside-binding protein (beta GBP) alters the cell cycle, up-regulates expression of the alpha- and beta-chains of the IFN-gamma receptor, and triggers IFN-gamma-mediated apoptosis of activated human T lymphocytes.

CHANGES in the nature and conformation of the cell membrane have been considered to play a significant role in malignant transformation1. Transformed cells have been reported to have altered surface properties detectable by the binding of some plant derived lectins leading to agglutination2–5. It has been suggested that the surface of transformed cells contains exposed sites where these agglutinins interact, whereas normal cells have such sites in a cryptic form6,7. I now report evidence for the binding of the phytagglutinin concanavalin A (Con A) on the surface of both normal and transformed cells as detectable by immunofluorescence.

Livio Mallucci

Papers

Identification of an autocrine negative growth factor: Mouse β-galactoside-binding protein is a cytostatic factor and cell growth regulator

β‐Galactoside‐binding protein secreted by activated T cells inhibits antigen‐induced proliferation of T cells

Beta-galactoside-binding protein (beta GBP) alters the cell cycle, up-regulates expression of the alpha- and beta-chains of the IFN-gamma receptor, and triggers IFN-gamma-mediated apoptosis of activated human T lymphocytes.

Binding of concanavalin A to normal and transformed cells as detected by immunofluorescence.

Structure and expression of the negative growth factor mouse β-galactoside binding protein gene