Chemokines modulate glycan binding and the immunoregulatory activity of galectins

Abstract

Galectins are versatile glycan-binding proteins involved in immunomodulation. Evidence suggests that galectins can control the immunoregulatory function of cytokines and chemokines through direct binding. Here, we report on an inverse mechanism in which chemokines control the immunomodulatory functions of galectins. We show the existence of several specific galectin-chemokine binding pairs, including galectin-1/CXCL4. NMR analyses show that CXCL4 binding induces changes in the galectin-1 carbohydrate binding site. Consequently, CXCL4 alters the glycan-binding affinity and specificity of galectin-1. Regarding immunomodulation, CXCL4 significantly increases the apoptotic activity of galectin-1 on activated CD8+ T cells, while no effect is observed in CD4+ T cells. The opposite is found for another galectin-chemokine pair, i.e., galectin-9/CCL5. This heterodimer significantly reduces the galectin-9 induced apoptosis of CD4+ T cells and not of CD8+ T cells. Collectively, the current study describes an immunomodulatory mechanism in which specific galectin-chemokine interactions control the glycan-binding activity and immunoregulatory function of galectins.

Galectokines: The Promiscuous Relationship between Galectins and Cytokines

“…In a follow-up study that showed that the binding of anginex increased the galectin-1 binding affinity for specific glycan ligands up to a thousand-fold, it was stated that “… it is hard to believe that an artificial peptide can show such dramatic effects without speculating that there is a natural counterpart in vivo.” [ 126 ]. Indeed, recently we provided evidence that CXCL4 can heterodimerize with galectin-1 while CCL5 heterodimerizes with galectin-9 [ 17 ]. These findings corroborated other studies that recently reported on galectin-cytokine interactions, e.g., galectin-3/IFN-ã [ 15 ] and galectin-3/CXCL12 [ 16 ].…”

“…Moreover, this was not restricted to galectin-1 as anginex could also alter the glycan binding affinity of other galectins [ 126 ]. More recently, we described that the effect on glycan-binding was also induced after heterodimerization of galectin-1 with chemokine CXCL4 [ 17 ]. Like anginex, the heterodimer formation altered glycan-binding affinity, which was accompanied by structural changes in the galectin-1 CRD [ 17 ].…”

“…More recently, we described that the effect on glycan-binding was also induced after heterodimerization of galectin-1 with chemokine CXCL4 [ 17 ]. Like anginex, the heterodimer formation altered glycan-binding affinity, which was accompanied by structural changes in the galectin-1 CRD [ 17 ]. This supports the hypothesis that galectokines represent a mechanism to steer the glycan-binding affinity and specificity of galectins.…”

“…In the study describing the galectin-1/CXCL4 galectokine, we also evaluated the effects of this galectokine on T cell apoptosis. Results indicated that CXCL4 enhanced the apoptotic activity of galectin-1 on activated peripheral blood mononuclear cells (PBMCs), affecting mainly CD8+ T cells [ 17 ]. In the same study, galectin-9 was found to heterodimerize with chemokine CCL5 which hampered the pro-apoptotic activity of galectin-9 on activated PBMCs.…”

“…In addition, emerging evidence indicates that galectins and cytokines can also directly interact and form heterodimers. Such galectin-cytokine heterodimers -here referred to as galectokines- can affect the activity of both proteins, indicative of a mechanism that extends beyond transcriptional regulation [ 15 , 16 , 17 ]. These findings add a new layer of complexity to the regulatory mechanisms that shape the immune response.…”