Chemokines modulate glycan binding and the immunoregulatory activity of galectins

Lucía Sanjurjo,Rory R Koenen,Pauline Touarin,Victor L J L Thijssen,Ed Aanhane,Hakon Leffler,Iris A Schulkens,Ulf J Nilsson,Tanja D De Gruijl,Kitty C M Castricum,Latifa Elantak,Arjan W Griffioen,Roy Heusschen

doi:10.1038/s42003-021-02922-4

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.

Highlights

Galectins are versatile glycan-binding proteins involved in immunomodulation
The current study aimed to explore whether galectin-chemokine interactions could serve as a mechanism to modulate galectin glycan-binding and function
Based on our recent work showing complementary platelet responses induced by galectin-1 and platelet factor 4 (PF4 or CXCL4), we focused our investigation on this galectin-chemokine pair[8]

Summary

Introduction

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. The current study describes an immunomodulatory mechanism in which specific galectinchemokine interactions control the glycan-binding activity and immunoregulatory function of galectins. Modulation of glycan-binding activity was observed in response to the interaction of galectin-1 with a specific fragment of the pre-B-cell receptor[6,7]. These findings suggest that heterodimerization of galectins with other proteins could represent a mechanism to regulate galectin-glycan interactions. Such a mechanism would extend the functionality of this glycomedecoding protein family. Our findings provide evidence of galectinchemokine cross-talk which can serve as a regulatory mechanism to guide and fine-tune glycoconjugate-galectin interactions leading to specific cellular responses

Methods

Results

Conclusion