Jackson Group: Lymphatic Trafficking Research Group

david.jackson@imm.ox.ac.uk

Investigative Medicine Division MRC Translational Immune Discovery Unit MRC Weatherall Institute of Molecular Medicine

We focus on the mechanisms controlling the migration of leucocytes and tumour cells via lymph in health and disease.

Research in our group focusses on the mechanisms underlying cell migration through the lymphatic system in inflammation and immunity. The process is of critical importance for host defense and tissue repair, as the lymphatic vessels act as conduits for transport of antigen-loaded dendritic cells from the tissues to draining lymph nodes where they prime protective immune responses. The lymphatics also provide an important exit route for the clearance of phagocytes from inflamed tissues during the process of resolution and the return to normal homeostasis. In each case, the entry of cells to the lymphatics occurs in small, often blind-ended capillaries which have specialized overlapping junctions that are quite distinct from those of blood capillaries and that operate under conditions of very low fluid shear, quite unlike that of the blood circulation. The molecular mechanisms that direct cell entry to lymph vessels and migration in lymph nodes are not well understood, although the chemokine CCL21 and its leucocyte receptor CCR7 are known to be essential. Our goal is to define these mechanisms, their component receptors and signaling pathways, and devise strategies to exploit them for future immune therapy.

Current research in the laboratory revolves around our recent discovery that mature dendritic cells and inflammatory macrophages initiate lymphatic vessel entry by docking to the endothelial hyaluronan receptor LYVE-1 via their HA surface glycocalyx, to form discrete transmigratory cups. The unique character of the LYVE-1•HA interaction appears to facilitate locomotion of the migrating cells at the vessel surface, as well as activate signaling pathways that provoke changes in the endothelium to promote diapedesis. We are currently investigating the molecular details of this LYVE-1 mediated entry mechanism both in vitro and in vivo using Lyve1^-/- mice and appropriate disease models. In addition, we are exploring the possibility it may also mediate leucocyte crawling inside lymphatic vessels, and immune cell trafficking within lymph node sinuses. Besides this we are studying the roles played by LYVE-1 and other HA receptors in vascular leucocyte recruitment at sites including the inflamed liver and lung and in lymphogenic tumour metastasis.

An integral part of our research involves structural studies of the LYVE-1 HA binding domain, and its complexes with key function blocking mAbs, using X-ray crystallography and allied biophysical methods. Here the goal is to define the precise nature of the unique avidity dependent LYVE-1•HA interaction so that we can design inhibitors for anti-inflammatory therapy.