Selected publications

• Johnson Louise A, Clasper Steven, Holt Andrew P, Lalor Patricia F, Baban Dilair, and Jackson David G (2006) An inflammation-induced mechanism for leukocyte transmigration across lymphatic vessel endothelium. J Exp Med, 203(12):2763-77.

• Banerji Suneale, Wright Alan J, Noble Martin, Mahoney David J, Campbell Iain D, Day Anthony J, and Jackson David G (2007) Structures of the Cd44-hyaluronan complex provide insight into a fundamental carbohydrate-protein interaction. Nat Struct Mol Biol, 14(3):234-9.

• Gale Nicholas W, Prevo Remko, Espinosa Jorge, Ferguson David J, Dominguez Melissa G, Yancopoulos George D, Thurston Gavin, and Jackson David G (2007) Normal lymphatic development and function in mice deficient for the lymphatic hyaluronan receptor LYVE-1. Mol Cell Biol, 27(2):595-604.

• Witte Marlys H, Jones Kimberly, Wilting Jorg, Dictor Michael, Selg Manuel, McHale Noel, Gershenwald Jeffrey E, and Jackson David G (2006) Structure function relationships in the lymphatic system and implications for cancer biology. Cancer Metastasis Rev, 25(2):159-84.

• Prevo Remko, Banerji Suneale, Ni Jian, and Jackson David G (2004) Rapid plasma membrane-endosomal trafficking of the lymph node sinus and high endothelial venule scavenger receptor/homing receptor stabilin-1 (FEEL-1/CLEVER-1). J Biol Chem, 279(50):52580-92.

David Jackson

The lymphatic system is an integral compartment of the immune system comprising a network of vessels whose primary function is the transport of antigen presenting cells to the lymph nodes where they meet and activate T and B cells to propagate the immune response.   Such events are key not only to the initiation of protective immunity to pathogens but also to the orchestration of inflammation and autoimmunity.  In malignant disease, the lymphatics are both a route for dissemination and a reservoir for metastatic cancers such as cutaneous melanoma and breast carcinoma, where lymph node involvement is an early indicator of prognosis.  Yet, despite such obvious importance in disease, the fundamental biology of the lymphatics is poorly understood and critical mechanisms such as those underlying nodal trafficking of leukocytes and tumour cells have been largely overlooked.

Lymphatic vessels (green) in skin are distinguished from smaller blood vessels (red) using the lymphatic marker LYVE-1 developed in our laboratory.

The HA receptor CD44 regulates leukocyte exit from blood to inflamed tissue. The HA receptor LYVE-1 may be involved in lymphatic function or HA metabolism. Both are under investigation in our laboratory.

We are dedicated to understanding these trafficking mechanisms through detailed adhesion/transmigration studies of lymphatics and primary lymphatic endothelial cells in vitro and in vivo using appropriate gene knockout models together with structure-function analyses of receptor-ligand interactions involved in vascular homing.  Instrumental to such research has been our identification of the lymphatic endothelial specific receptor LYVE-1, a finding that has permitted unambiguous identification of lymphatics in human tissues as well as isolation and culture of lymphatic endothelial cells.  This has allowed us to study the mechanisms by which leukocytes traffic through the lymphatics to initiate the immune response and how tumour cells exploit the lymphatics during nodal metastasis.  

Thus far we have shown that dendritic cells enter the afferent lymphatics following adhesion to the inflammation-induced receptors ICAM-1 and VCAM-1 and transmigration, and that the mechanism is critical to the generation of the T cell response. We have also found evidence that separate mechanisms control tumour cell entry to the afferent lymphatics during lymph node metastasis in murine tumours and human cancers and are now studying the process in more detail as well as assessing its utility in prognosis.

In addition, we are investigating the physiological function of LYVE-1 using gene knockout models as well as the mechanism for regulation of ligand binding activity. Finally, we have characterized the 3D structure of the inflammatory leukocyte homing receptor CD44, a close homologue of LYVE-1, and are pursuing the design of small molecule inhibitors and function-blocking antibodies for anti-inflammatory therapy.

We anticipate that further research in these areas will provide us with the knowledge not only to develop new therapies to block inflammation and metastasis, but also to promote protective immunity to emerging infectious agents by enhancing vaccine delivery.

Crystal structure of the CD44 HA binding domain complexed with HA8 (HA shown in turquoise)