Our immune system operates as a highly efficient surveillance network, continuously monitoring tissues for foreign molecules. Immune cells, known as leukocytes, play a crucial role in this defense, patrolling the body and transporting microbial fragments to lymph nodes via lymphatic vessels. But how do these cells enter the lymphatic system? At the heart of this entry process lies LYVE-1, a receptor that lines the portals of lymphatic vessels.
LYVE-1 acts as a gatekeeper, interacting with long hyaluronan sugar chains present on the surface of leukocytes. This interaction facilitates immune cell migration, but the precise molecular details of how leukocytes traverse the lymphatic barrier have until now remained elusive.
Using a combination of state-of-the-art biophysical, structural, and computational techniques, Martin Lepšík from IOCB Prague and researchers from the University of Oxford and the University of Leeds, have unraveled the mechanics of LYVE-1 binding to hyaluronan in unprecedented detail. Their findings show a new mechanism: immune cells move along hyaluronan chains like curtains sliding on a rail, engaging multiple LYVE-1 receptors in a dynamic, back-and-forth motion. This sliding mechanism enhances the efficiency of leukocyte migration, allowing immune cells to squeeze through the lymphatic entry portals with remarkable ease.
This discovery opens new possibilities for medical applications. Understanding how immune cells enter lymphatic vessels at the molecular level provides a foundation for designing new drugs to regulate immune responses. Targeting the LYVE-1-hyaluronan interaction could lead to therapies that block autoimmunity and inflammation or prevent tumor cells from metastasizing through the lymphatic system.
Read more: https://www.imm.ox.ac.uk/news/jackson-nat-comms
Read the paper: Bano, F.; Banerji, S.; Ni, T.; Green, D. E.; Cook, K. R.; Manfield, I. W.; DeAngelis, P. L.; Paci, E.; Lepšík, M.; Gilbert, R. J. C.; Richter, R. P.; Jackson, D. G. Structure and Unusual Binding Mechanism of the Hyaluronan Receptor LYVE-1 Mediating Leucocyte Entry to Lymphatics. Nat. Commun. 2025, 16, 2754. https://doi.org/10.1038/s41467-025-57866-8
