Chemokines modulate glycan binding and immunoregulatory activity of galectins

Abstract

Galectins are versatile glycan-binding proteins involved in immunomodulation. Increasing evidence suggests that galectins can control the immunoregulatory function of cytokines and chemokines through direct binding. Here, we report a new inverse mechanism by which chemokines control the immunomodulatory function of galectins. In a galectin-chemokine interaction screen we identified several specific galectin-chemokine binding pairs, including galectin-1/CXCL4. NMR analyses showed that CXCL4 binds on the surface edge of the galectin-1 ß-sheet causing changes in the galectin-1 carbohydrate binding site. Consequently, the interaction with CXCL4 altered the glycan binding affinity and specificity of galectin-1. With regard to immunomodulation, CXCL4 potentiated the apoptotic activity of galectin-1 on activated peripheral blood mononuclear cells. The potentiation of apoptosis specifically affected CD8+ T cells, while no effect was observed in CD4+ T cells. An opposite regulatory activity was found for another galectin-chemokine pair, i.e., galectin-9/CCL5. While CCL5 reduced the apoptosis induction by galectin-9 in activated PBMCs, this was only statistically significant for CD4+ T cells and not for CD8+ T cells. Collectively, the current study describes a novel immunomodulatory mechanism in which specific galectin-chemokine interactions control the glycan-binding activity and immunoregulatory function of galectins.

Pre-B cell receptor acts as a selectivity switch for Galectin-1 at the pre-B cell surface

“…Beyond the pre-BCR case, our results raise a fundamental question: is there a universal mechanism of allosteric modulation of glycan binding that is conserved across all Galectins through binding to non-glycosylated protein partners? Indeed, there are increasing evidence for direct protein interactions with Galectins [16][17][18]47 . We also demonstrated that CXCL4 interacts with Gal-1 and control its glycan binding activities at the base of the immunoregulatory function of galectins 47 .…”

“…Indeed, there are increasing evidence for direct protein interactions with Galectins [16][17][18]47 . We also demonstrated that CXCL4 interacts with Gal-1 and control its glycan binding activities at the base of the immunoregulatory function of galectins 47 . The pre-BCR case and these latter examples all involve the three different Galectin subfamilies (prototype, chimera and tandem-repeat) 4 .…”