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Fundamental to generating a host immune response to infection is the mobilisation of antigen loaded dendritic cells (DCs) in the affected tissues and their migration via afferent lymph to draining nodes where they prime and activate T cells in the paracortex. The trafficking of DCs through afferent lymphatic vessels is vital to such immunity, and involves a series of co-ordinated steps driven by chemokines, including CCL21 and CX3CL1 secreted from initial lymphatic capillaries and supported by a plethora of adhesion receptors (see Fig 1) whose expression is frequently upregulated during inflammation.

Besides DCs, other leucocyte populations such as macrophages and neutrophils also migrate through lymphatics, and such migration is important for their clearance from the tissues during the resolution of inflammation. The precise choreography of directional guidance, endothelial adhesion and transmigration, and downstream trafficking to lymph nodes are however unclear. Most leucocytes  are thought to access lymphatic  capillaries  in the tissues at specialised  overlapping junctions,  distinct  from the tight junctions  of blood capillaries.  Here, the flap-like  edges of oakleaf shaped endothelial cells interdigitate to form button-like portals, whose tips are decorated with the lymphatic  vessel  specific  hyaluronan  receptor  LYVE-1  (reviewed in Jackson 2014), and whose sides are pinned by adherens and tight junction receptors VE- cadherin, claudins and JAMs (Fig 2). The implication is that engagement of migrating cells with these portals leads to loosening of the junctions and entry to the vessel lumen (Fig 3). Recent  work  in my laboratory  using  a combination  of in vitro and in vivo approaches  has yielded compelling evidence that DCs initially adhere to lymphatic endothelium via LYVE-1, and that the interaction involves reversible avidity-dependent binding to hyaluronan arranged appropriately within the DC surface glycocalyx (Lawrance et al 2016; Johnson et al 2017), thus enabling the migrating cells to dock via transmigratory cups and transit to the vessel lumen. An analogous mechanism appears to mediate systemic spread of virulent strains of Group A streptococci, the agents of bacterial tonsillitis and necrotizing fasciitis, whose dense hyaluronan capsule mediates both lymphatic tropism and protection against host phagocytosis (Lynskey et al. 2015). Ongoing work suggests that monocyte/macrophages may also utilize LYVE-1 to navigate the lymphatics, during the course of tissue inflammation. How LYVE-1 selectively binds  The  project  on  offer  will  provide  an  exciting  opportunity  to  explore  the  in vivo  anatomy of LYVE-1  mediated  leucocyte  interactions  during leucocyte  trafficking  in more detail, using intravital video microscopic  imaging  as well as in vitro analytical  approaches.  Questions to be addressed may include the following -

  • How does the LYVE-1:HA axis integrate with chemotaxis for vessel entry ?
  • Are LYVE-1:HA interactions involved primarily in leucocyte docking or do they also assist in DC crawling within the vessel lumen ?
  • Do they also mediate subsequent interactions with the subcapsular cortical or medullary sinuses in downstream lymph nodes ?

The successful candidate will have the benefit of supervision both from the PI, and from a dedicated senior research scientist, as well as close Unit support and international collaborations with other leading scientists in the field. We anticipate the new insights gained in these preclinical studies to seed future development of novel therapeutic strategies for inflammatory diseases. The work will involve the use of animal models of inflammation,  ex vivo tissue explants and in vitro culture  models  to  visualize, characterise,  manipulate and  quantify  leucocyte  trafficking,  hyaluronan  glycocalyx/complex  formation and tissue vasculature by confocal and intravital imaging. Experiments will take advantage of constitutive and conditional LYVE-1-/-  mice, LYVE-1 function blocking mAbs and appropriate fluorescent reporter mice that will be available in the host laboratory

Training Opportunities

The successful candidate will receive training in flow cytometry, confocal/intravital microscopy, endothelial  cell culture and characterization,  ex vivo/in vitro transmigration  assays, in vivo studies in animal inflammatory disease models, immunoassays, molecular biology techniques and protein analysis.The  host Institute,  and the MRC  Human  Immunology  Unit have  world  class,  cutting  edge facilities for microscopic imaging, including super-resolution (STED) microscopy and a dedicated suite for intravital imaging.

As well as the specific training detailed above, students will have access to a wide-range of seminars and training opportunities through the many research institutes and centres based in Oxford. Students are also able to attend the Methods and Techniques course run by the MRC Weatherall Institute of Molecular Medicine. This course runs through the year, ensuring that students have the opportunity to build a broad-based understanding of differing research techniques.

Generic skills training is offered through the Medical Sciences Division's Skills Training Programme. This programme offers a comprehensive range of courses covering many important areas of researcher development: knowledge and intellectual abilities, personal effectiveness, research governance and organisation, and engagement, influence and impact. Students are actively encouraged to take advantage of the training opportunities available to them.

The Department has a successful mentoring scheme, open to graduate students, which provides an additional possible channel for personal and professional development outside the regular supervisory framework. We hold an Athena SWAN Silver Award in recognition of our efforts to support the careers of female students and staff.

Publications

1 "Dendritic cells enter lymphatic vessels by hyaluronan-mediated docking to the endothelial hyaluronan receptor LYVE-1" Johnson LA. Banerji S Lawrance W, Gileadi, U, Prota, G. Holder, K, Roshorm Y, Hanke T, Cerundolo, V, Gale, N. & Jackson DG. (2017) Nat. Immunol. 18, 762-770.
2 “Binding of hyaluronan to the native lymphatic vessel endothelial receptor LYVE-1 is critically dependent on surface clustering and hyaluronan organisation” Lawrance, W, Banerji, S, Day, A.J., Bhattacharjee, S. & Jackson, D.G. (2016). J. Biol. Chem. 291, 8014-8030.
3 “Lymphatic regulation of Cell trafficking” Jackson, DG. (2014) J. Clin. Cell. Immunol. 5, 258 (Special issue “Role of lymphatics in Immunity”)
4 “Control of dendritic cell trafficking in lymphatics by chemokines” Johnson, L.A. and Jackson, D.G. (2014) Angiogenesis 17, 335-345
5 “Rapid Lymphatic dissemination of encapsulated group A streptococci via lymphatic vessel endothelial receptor-1 interaction” Lynskey, N. Banerji, S, Johnson, L. Jackson, DG. & Sriskandan, S. (2015) PLoS Pathogens  11

Research Themes, Tools and Technologies

Supervisors

Additional Supervisors

Dr Louise Johnson, Postdoctoral Researcher, Radcliffe Department of Medicine

Key Dates for October 2018 Entry

Application deadline:  12 noon GMT on Monday 8 January 2018

Interviews for shortlisted candidates: Week commencing Monday 22 January 

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How to apply

To apply for a place on the DPhil in Medical Sciences you will need to submit an application using the online application form.

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