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Using state-of-the-art structural, biophysical and computational approaches, a team of researchers from Oxford, Leeds, Prague and Oklahoma City have advanced understanding of a key mechanism by which immune cells enter and move through the lymphatic system – an important process for immune surveillance and generating protective immune responses.
In immune surveillance, the immune system constantly looks for and identifies foreign pathogens such as bacteria and viruses or pre-cancerous or cancerous cells in the body. Specialised immune cells known as antigen presenting cells (APCs) play an important role in this by transporting pathogen fragments through the lymphatic system.
New crystal structures combined with Dynamic Force Spectroscopy measurements described in this Nature Communications study reveal how these APCs interact with a receptor called LYVE-1 to facilitate their entry into the lymphatic system. The international research team showed that long chains of the ubiquitous sugar polymer, hyaluronan, on the surface of APCs can thread through deep clefts on LYVE-1 molecules, which line portals used by the APCs to enter the lymphatic system. This allows the hyaluronan chains on the APCs to slide back and forth like curtains on a rail, making it easier for the APCs to move through their entry portals.
Disrupting this system of lymphatic trafficking could block unwanted immune and inflammatory responses, so the mechanistic details uncovered in this study could help in the future development of drugs for the treatment of autoimmunity, inflammation and potentially tumour metastasis.
Professor David Jackson, one of the lead authors of the study, said: 'Our paper marks an important advance in understanding how cells enter and migrate through the lymphatics via dedicated receptors and adds to the knowledge of how this relatively neglected vascular network helps orchestrate immune responses. I also think our study shows the power of a multi-disciplinary approach to science as well as emphasising the importance of basic research for identifying new therapeutic targets.'