Galectin-1 is a local but not systemic immunomodulatory factor in mesenchymal stromal cells.

BACKGROUND AIMS: Mesenchymal stromal cells (MSCs) have powerful immunosuppressive activity. This function of MSCs is attributed to plethora of the expressed immunosuppressive factors, such as galectin-1 (Gal-1), a pleiotropic lectin with robust anti-inflammatory effect. Nevertheless, whether Gal-1 renders or contributes to the immunosuppressive effect of MSCs has not been clearly established. Therefore, this question was the focus of a complex study. METHODS: MSCs were isolated from bone marrows of wild-type and Gal-1 knockout mice and their in vitro anti-proliferative and apoptosis-inducing effects on activated T cells were examined. The in vivo immunosuppressive activity was tested in murine models of type I diabetes and delayed-type hypersensitivity. RESULTS: Both Gal-1-expressing and -deficient MSCs inhibited T-cell proliferation. Inhibition of T-cell proliferation by MSCs was mediated by nitric oxide but not PD-L1 or Gal-1. In contrast, MSC-derived Gal-1 triggered apoptosis in activated T cells that were directly coupled to MSCs, representing a low proportion of the T-cell population. Furthermore, absence of Gal-1 in MSCs did not affect their in vivo immunosuppressive effect. CONCLUSIONS: These results serve as evidence that Gal-1 does not play a role in the systemic immunosuppressive effect of MSCs. However, a local contribution of Gal-1 to modulation of T-cell response by direct cell-to-cell interaction cannot be excluded. Notably, this study serves a good model to understand how the specificity of a pleiotropic protein depends on the type and localization of the producing effector cell and its target.

How does it act when soluble? Critical evaluation of mechanism of galectin-1 induced T-cell apoptosis.

Galectin-1 (Gal-1), a mammalian lectin induces apoptosis of T lymphocytes. Contradictory data have resulted in confusing knowledge regarding mechanism of Gal-1 induced T-cell apoptosis. In this paper we aimed to resolve this controversy by comparing cell death induced by low (1.8 µM, lowGal-1) and high (18 µM, highGal-1) concentration of soluble Gal-1. We show that lowGal-1 and highGal-1 trigger phosphatidylserine exposure, generation of rafts and mitochondrial membrane depolarization. In contrast, lowGal-1 but not highGal-1 is dependent on the presence of p56lck and ZAP70 and activates caspase cascade. The results allow the conclusion that the cell-death mechanism strictly depends on the concentration of Gal-1.

Mechanism of tumor cell-induced T-cell apoptosis mediated by galectin-1.

Galectin-1 (Gal-1) has been implicated in tumor progression partly via the induction of T-cell apoptosis. However the mechanism of Gal-1 induced T-cell death was mostly studied using recombinant, soluble Gal-1 producing controversial results. To explore the true mechanism of Gal-1 and hence tumor cell-induced T-cell death, we applied co-cultures of tumor cells and T-cells thus avoiding artificial circumstances generated using recombinant protein. T-cells died when co-cultured with Gal-1-expressing but survived with Gal-1 non-expressing tumor cells. Removing tumor cell surface Gal-1 or knocking down Gal-1 expression resulted in diminution of T-cell apoptosis. Gal-1 transgenic or soluble Gal-1 treated HeLa cells became cytotoxic. Stimulation of apoptosis required interaction between the tumor and T-cells, presence of p56lck and ZAP70, decrease of mitochondrial membrane potential and caspase activation. Hence tumor cell-derived Gal-1 might efficiently contribute to tumor self-defense. Moreover this system resolves the discrepancies obtained using recombinant Gal-1 in T-cell apoptosis studies.