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WIMM PI
Curriculum Vitae
Personal Data
Name
Nationality
Email
David Gerald Jackson
Irish
[email protected]
Present Position
Tenure Track, MRC Human Immunology Unit / Nuffield Department of Medicine, Institute of
Molecular Medicine, John Radcliffe Hospital, Headington,Oxford OX3 9DS.
Tenured Group Leader, MRC Human Immunology Unit / Nuffield Department of Medicine,
Institute of Molecular Medicine, John Radcliffe Hospital,Headington, Oxford OX3 9DS.
Previous Positions
1983-1987
University of Dublin, Post-Doctoral Fellow (Cancer Research Advancement
Board).
Project- Studies on the biochemistry of membrane Glycoprotein’s from the
protozoan parasite Trypanosoma Brucei, the causative agent of African
sleeping sickness in man. Identified, purified, characterized and quantitated
new surface glycoprotein antigens as targets for diagnosis and therapy.
Head of laboratory: Dr. H.P. Voorheis Ph.D (Cantab.) M.D., D.C.M.T.
1987-1992
University of Oxford, Nuffield Department of Medicine, Molecular
Immunology group, Institute of Molecular Medicine
Wellcome Post-Doctoral Research Assistant (grade 1A).
Project - Development of a COS cell expression cloning technique for
isolating cDNAs encoding leucocyte surface polypeptides. Cloned and
characterized cDNAs for CD24, CD38, CD44 and a novel member of the Ig
superfamily. Identified differentially spliced isoforms of CD44 glycoprotein in
different cell types and initiated research project to Investigate the
physiological roles of CD44 glycoproteins in Health and disease.
1992-1995
University of Oxford, Nuffield Department of Medicine, Molecular
Immunology group, Institute of Molecular Medicine.
Yamanouchi Research Fellow in Cell Biology, Wolfson College Oxford.
Project - The expression of CD44 splice variants from activated lymphocytes
and analysis of their ligand binding properties.
1995-2000
University of Oxford, Nuffield Department of Medicine, Molecular Sciences
Division, John Radcliffe Hospital, Headington, Oxford OX3 9DU.
M.R.C. Senior Fellowship.
Research Project - Cell surface heparan sulphate proteoglycans as
presenters of growth factors and chemokines.
Research Achievements
My research has focussed largely on the topic of cell adhesion in the immune system. This
began in the early 90s with my construction of cDNA libraries and their use in expression
cloning strategies to isolate and sequence important leukocyte receptors including CD38, an
ADP ribosyl cyclase associated with T cell activation, CD24, a GPI anchored receptor in B
cells, CMRF35 an Ig superfamily immunoregulatory receptor and CD44, the primary receptor
for hyaluronan involved in inflammatory trafficking. My work on CD44 revealed the intron/exon
structure of the CD44 gene and its unusually complex degree of alternative splicing and went
on to characterize the function of discrete heparan sulphate modified CD44 splice variants in
sequestering growth factors and chemokines. I also applied similar technology to clone cDNAs
for surface antigens in the insect stages of Trypanosoma brucei, the parasite responsible for
African sleeping sickness, revisiting an earlier interest gained during my PhD and initial postdoctoral research.
Following from such research in 1999 I went on to identify LYVE-1, a gene closely related to
CD44 that encodes a hyaluronan receptor expressed preferentially in lymphatic endothelium.
This discovery provided clinical researchers, pathologists and scientists with a powerful
marker to distinguish lymphatic from blood vessels and was instrumental in moving the field of
lymphatic vascular biology forwards. For example over the subsequent period my group was
involved in key collaborations that led to the current understanding of how the lymphatics
derive from the blood vasculature during embryonic development and how mutations in key
genes can lead to vascular abnormalities in the adult, how the lymphatics control the
trafficking of antigen presenting cells to lymph nodes for the generation of immune responses
in inflammation and how tumours exploit/manipulate the lymphatics for metastasis. We also
developed methods to isolate and culture primary lymphatic endothelial cells in vitro and study
mechanisms for adhesion and transmigration. Closely intercalated within this work has been
our continued interest in the specific role of hyaluronan receptors, notably LYVE-1 in lymphatic
trafficking, its structure and likely function as a gatekeeper for cell entry to initial lymphatic
vessels. This has led to key publications including those describing the basic phenotype of
LYVE-1 knockout mice, the crystal and NMR structure of CD44 in complex with hyaluronan
and its conformational transition between on and off binding states, and the mechanism for
regulating LYVE-1 receptor function through glycosylation.
Current and ongoing work involving my lab and our national and international collaborators is
revealing the molecular details of how LYVE-1:HA interactions mediate not only leukocyte
transmigration but also adherence and dissemination of HA encapsulated pathogens such as
Strep pyogenes, the causative agent of tonsillar pharyngitis and necrotizing fasciitis.
What are the Future Aims of Your Current Group?)
Our goals for the next five years have been formulated for the MRC quinquennial review
process and were approved by the review committee and MRC IIB during their site visit in
December 2011. These represent a logical progression from previous studies and may be
summarised as follows
1. To elucidate the structure of the natively glycosylated CD44 ligand binding domain in order
to better understand the allosteric regulation of hyaluronan binding and to generate a crystal
structure for the LYVE-1 homodimer.
2. To investigate the molecular basis by which LYVE-1 functions as a gatekeeper for
leukocyte entry to lymphatic vessels through interaction with its ligand HA, with a particular
focus on how HA presented by leukocytes may trigger receptor clustering and intracellular
signalling that would lead to changes in junctional permeability.
3. To study the involvement of LYVE-1 in regulating the trafficking of leukocytes and tumour
cells via lymphatics using LYVE-1 and CD44 knockout mice, fluorescent reporter mice and
function blocking mAbs in new models of inflammatory disease and cancer, and determine
the importance of hyaluronan interactions in such processes
4. To investigate the role of LYVE-1 within the pulmonary vasculature in effecting resolution of
lung inflammation
5. To exploit intravital microscopy and new high-resolution imaging techniques including
STED to study the detailed choreography of cell trafficking (ie aims 3 and 4) in vivo and the
dynamics of LYVE-1 surface distribution in vitro (aim 2).
6. To investigate the role of LYVE-1 as a receptor for lymphatic dissemination of the
hyaluronan encapsulated pathogen Strep pyogenes, the causative agent of tonsillar
pharyngitis and necrotizing fasciitis.
How do the aims of your research fit with the aims of the WIMM and Division of
Medicine
The research carried out by my group is based on a core of fundamental, curiosity driven
scientific research, which has consistently delivered findings applicable to preclinical
translation. The work proposed for the coming five years is likely to further strengthen this
latter aspect. According to my understanding of the aims, this is precisely what the WIMM was
established to do.
Lay Summary of Research
Our immune system provides constant surveillance against microorganisms that occasionally
breach the body surfaces and enter as a result of infection or physical injury. What actually
happens is that specialized cells called phagocytes and dendritic cells close to these surfaces
engulf the foreign invaders and carry them to the lymph nodes - glands in which white cells
termed lymphocytes reside. When lymphocytes meet these invaders, they respond by
multiplying their numbers and moving from the lymph nodes via the blood to the tissues where
they seek out and destroy any surviving microorganisms. The route by which engulfed
invaders reach the lymph nodes to trigger this critical series of events is quite intricate. It
consists of a network of small vessels termed lymphatics that are distinct from blood vessels
and that carry cells in a clear fluid called lymph. Without this network there would be no route
to alert lymph node lymphocytes to the presence of infection and hence we would not survive.
Surprisingly, scientists still understand little about the workings of the lymphatic system
despite its importance. The research in my laboratory is aimed at understanding how
phagocytes and dendritic cells enter and navigate within lymphatic vessels, which molecules
assist them in the process, and how cancer cells hijack the system to spread to lymph nodes
while avoiding destruction by the host immune response. It is hoped that this will allow us to
develop future drugs that manipulate lymphatic trafficking, promoting helpful immune
responses to vaccines on the one hand and blocking harmful responses that produce chronic
inflammation or autoimmunity on the other.
All Publications Over the Past 5 Years
“Lymphatics and bone.” Edwards JR, Williams K, Kindblom LG, Meis-Kindblom JM, Hogendoorn
PC, Hughes D, Forsyth RG, Jackson D, Athanasou NA. (2008) Hum Pathol. 39, 49-55.
“Absence of lymphatics at the bone-implant interface: implications for periprosthetic osteolysis.”
Edwards J, Schulze E, Sabokbar A, Gordon-Andrews H, Jackson D, Athanasou NA. Acta Orthop.
(2008), 79, 289-94.
“Renal cells activate the platelet receptor CLEC-2 through podoplanin.” Christou CM, Pearce AC,
Watson AA, Mistry AR, Pollitt AY, Fenton-May AE, Johnson LA, Jackson DG, Watson SP,
O'Callaghan CA. (2008) Biochem. J. 411, 133-140.
“A novel gene expression profile in lymphatics associated with tumor growth and nodal metastasis.”
Clasper S, Royston D, Baban D, Cao Y, Ewers S, Butz S, Vestweber D, Jackson DG. (2008) Cancer
Res. 68, 7293-7303.
“Intratumoural lymphatics in benign and malignant soft tissue tumours.” Mahendra G, Kliskey K,
Williams K, Hollowood K, Jackson D, Athanasou NA (2008) Virchows Arch. 2453:457-464.
"The presence and absence of lymphatic vessels in the adult human intervertebral disc: relation to disc
pathology." Kliskey K, Williams K, Yu J, Jackson D, Urban J, Athanasou N. (2009) Skeletal
Radiol. 38, 1169-1173.
“A mechanism of sialylation functionally silences the hyaluronan receptor LYVE-1 in lymphatic
endothelium.” Nightingale T, Frayne MEF, Clasper S, Banerji S, Jackson DG. (2009) J. Biol. Chem.
284, 3935-3945.
“Cell traffic and the lymphatic endothelium” Johnson LA, Jackson DG. (2008) Ann N Y Acad Sci.
1131, 119-133.
“Mechanisms of lymphatic metastasis in colorectal carcinoma” Royston, D Jackson DG. (2009) J.
Pathol. 217; 608-619.
“Blockade of a CD8+ T cell response by targeting lymphatic recruitment of antigen presenting cells”
Teoh, D., Johnson, LA., Hanke, T., McMichael, AJ. Jackson, DG. (2009) J. Immunol. 182: 24252431.
"Immunohistochemical methods for measuring tissue lymphangiogenesis." Clasper S, Jackson DG
(2009) Methods Mol Biol. 467:79-91.
"Immunological functions of Hyaluronan and its receptors in the lymphatics" Jackson, D.G. (2009)
Immunol. Rev. 230; 216-231.
“Distinctive features of the hyaluronan binding domain in the lymphatic endothelial receptor LYVE-1
and their implications for receptor function” Banerji, S. Hide B., James, J., Noble, M. and Jackson,
DG. (2010) J. Biol. Chem. 285, 10724-10735.
"Inflammation-induced secretion of CCL21 in lymphatic endothelium is a key regulator of integrinmediated dendritic cell transmigration" Johnson, L.A. and Jackson, D.G. (2010) Int. Immunol. 10,
839-849.
"Analysis of CD44-hyaluronan interactions in an artificial membrane system, insights into the distinct
binding properties of high and low molecular weight hyaluronan" (2010) Wolny PM, Banerji S,
Gounou C, Brisson AR, Day AJ, Jackson DG, Richter RP. J Biol Chem. 285, 30170-30180.
"Molecular characterization of dermal lymphatic endothelial cells from primary lymphedema skin."
Ogunbiyi S, Chinien G, Field D, Humphries J, Burand K, Sawyer B, Jeffrey S, Mortimer P, Clasper
S, Jackson D, Smith A; London Lymphedema Consortium. (2011) Lymphat Res Biol. 9, 19-30.
"Lymph vessel density in seminomatous testicular cancer assessed with the specific lymphatic
endothelium cell markers D2-40 and LYVE-1: Correlation with pathologic parameters and clinical
outcome". Heinzelbecker J, Kempf KM, Kurz K, Steidler A, Weiss C, Jackson DG, Bolenz C,
Haecker A, Trojan L. (2011) Urol. Oncol. 7, 1386-1394.
“The chemokine CX3CL1 (Fractalkine) promotes trafficking of dendritic cells through
inflamed lymphatics" Johnson L.A. & Jackson D.G. (2013) J. Cell Sci. 126, 5159-5270
"Progression of Carcinogen-Induced Fibrosarcomas is Associated with the Accumulation of Naive
CD4+ T cells via Blood Vessels and Lymphatics" Ondondo, B. Jones, E, Hindley, J. Cutting, S.
Smart, K. Bridgeman, H. Matthews, K. Ladell, K. Price, D. Jackson, D. Godkin,A. Ager, A &
Gallimore, A. (2013) Int. J. Cancer. 134, 2156-2167
“Control of dendritic cell trafficking in lymphatics by chemokines” Johnson, L.A. and Jackson, D.G.
(2014) Angiogenesis 17, 335-345.
“CLEC-2 signalling regulates clustering of Podoplanin and platelet adhesion” Pollitt A, Gitz F.
Hughes C.E.,Wang YJ, Thomas SG, Douglas M, Jackson DG, Dustin ML & Watson SP..
(2014) J. Biol. Chem In revision.
“Prostaglandin D2 and leukotriene E4 synergise to stimulate diverse Th2 function and Th2
cell/neutrophil crosstalk” Xue L, Fergusson J, Salimi M, Panse I, Ussher J, Hegazy A, Vinall SL,
Jackson DG, Hunter MG. Pettipher R. Ogg G, Klenerman P. (2014) J. Allergy Clin Immunol. In
revision.
“Lymphatic regulation of cellular trafficking” Jackson, DG. (2014) J. Clin Cell Immunol Under
review.
Ten Key Publications Throughout your Career
"Release of the variable surface coat glycoprotein from Trypanosoma brucei requires cleavage
of a phosphate ester" Jackson D.G & Voorheis H.P. (1984) J. Biol. Chem. 260, 5179-5183.
“LYVE-1, a new homologue of the CD44 glycoprotein is a lymph-specific receptor for
hyaluronan”. Banerji, S., Clasper, S., Ni, J., Wang, S.X., Su, J., Jones, M. & Jackson, D.G.
(1999) J. Cell Biol. 144, 789-801.
“Mouse LYVE-1 is an endocytic receptor for hyaluronan in lymphatic endothelium.” Prevo,
R., Banerji, S., Ferguson, D.J.P., Clasper, S. & Jackson, D.G. (2001) J. Biol. Chem. 276,
19420-19430.
“Induction of tumour lymphangiogenesis by VEGF-C promotes breast cancer metastasis.”
Skobe, M, Hawighorst, T., Jackson, D., Prevo, R., Janes, L., Velasco, P., Riccardi, L.,
Alitalo, K., Claffey, K. & Detmar, M. (2001) Nature Med. 7, 192-198.
“An essential role for Prox-1 in the induction of the lymphatic endothelial cell phenotype.”
Wigle, J.T.., Harvey, N., Detmar, M., Lagutina, I., Grosveld, G., Gunn, M.D., Jackson,
D.G. & Oliver, G. (2002) EMBO. J. 21, 1505-1513.
“Regulation of blood and lymphatic vascular network separation by signalling proteins SLP-76
and SYK” Abtahian, F., Guerriero, A., Lu, M-M., Zhou, R., Mocsai, A., Myers, E.E.,
Huang, B., Jackson, D.G., Ferrari, V.A., Tybulewicz, V., Lowell, C.A., Lepore, J.J.,
Koretzky, G.A., & Kahn, M.L. (2003) Science 299, 247-251.
“Structure of the regulatory hyaluronan-binding domain in the inflammatory leukocyte homing
receptor CD44.” Teriete, P., Banerji, S., Noble, M., Blundell, C.D., Wright , A.J., Pickford,
A.R., Lowe, E., Mahoney, D.J., Tammi, M.I., Kahmann, J.D., Campbell, I.D., Day, A.J. &
Jackson, D.G. (2004) Mol Cell. 13, 483-496.
“An inflammation-induced mechanism for leukocyte transmigration of lymphatic
endothelium.” Johnson, L.A., Clasper, S. Holt, A., Lalor, P., Baban, D. & Jackson, D.G.
(2006) J. Exp. Med. 203, 2763-2777.
“A novel gene expression profile in lymphatics associated with tumor growth and nodal
metastasis.” Clasper S, Royston D, Baban D, Cao Y, Ewers S, Butz S, Vestweber D,
Jackson DG. (2008) Cancer Res. 68, 7293-7303.
“A mechanism of sialylation functionally silences the hyaluronan receptor LYVE-1 in
lymphatic endothelium.” Nightingale T, Frayne MEF, Clasper S, Banerji S, Jackson DG.
(2009) J. Biol. Chem. 284, 3935-3945.
“The chemokine CX3CL1 (Fractalkine) promotes trafficking of dendritic cells through
inflamed lymphatics" Johnson L.A. & Jackson D.G. (2013) J. Cell Sci. Sept 4 epubl ahead
of print.
Distinctions / Merit Awards
February 2003
Appointed University Research Lectureship, University of Oxford
October 2004
Appointed University Professor of Human Immunology, University of
Oxford
October 2009
Awarded Additional Salary Reward Scheme, for significant personal
contributions MRC Human Immunology Unit, University of Oxford
Current Grant Support
MRC Unit Core Funding (alpha A rated researcher 2003
Quinquennial review) 1998- present. Renewed 2011-2016
MRC Project grant (G1100134) November 2011- 2014.
Project title "Mechanisms and immune consequences of neutrophil trafficking in lymphatics"
MRC Project grant (MR/L008610) December 2013- 2016.
Project title “Streptococcus pyogenes interaction with the lymphatic hyaluronan receptor
LYVE-1 as a mechanism for lymphatic dissemination and disease progression”