Research
The current paradigm of dendritic cell (DC) activation and function has generally been characterised in vitro using model antigens (Ag), or Ag derived from pathogens that induce a ‘Th1-type’ response (ie bacteria, viruses and protozoa). Comparatively little is known about how DCs interpret pathogen-inherent information to elicit Th2 responses. We investigate DC involvement in immune response induction and development using a combination of in vivo and in vitro model systems, and during active murine infection, focusing particularly on the parasitic helminth Schistosoma mansoni. We have developed a model system to assess DC function in vivo by exposing murine DCs to Ag from helminth or bacterial pathogens in vitro, transferring these cells into recipient mice, then characterising the nature of the immune response induced by the transferred DCs in recipient animals. Comparison of wild-type or gene-deficient DCs transferred into wild-type or gene-deficient recipients provides a tractable system to define the source and importance of key molecules during this process, and the flexibility of this cell transfer system makes it a powerful technique for trying to understand the role of DCs in the immune response to any given pathogen or Ag. Many of the results we have so far produced using this approach have challenged conventional thinking about how DCs become activated by pathogens, and how they function during T cell response polarisation.
Aims:
The main research areas we are currently actively involved in addressing are:
- DC subsets, activation and function during Schistosoma mansoni infection.
- Cytokines and Th2 induction by DCs (focusing on IL-4, IL-13, IL-25 and TSLP).
- Epigenetic regulation of Th2 induction by DCs.
- Multitasking by DCs responding to Schistosoma mansoni and Salmonella typhimurium.
The ultimate goal of this work is to identify the molecular mechanisms underlying the ability of DCs to direct polarised immune responses against pathogens. Further understanding of this area is a vital step towards informed design of vaccines and immunotherapeutics against diseases that are dominated by immune-driven pathology.
Collaborators in Edinburgh:
- Rick Maizels
- Judi Allen
- Rose Zamoyska
- Amy Buck
- Simon Babayan
- David Gray
- Maurice Gallagher
- Steve Anderton
- Matt Taylor
- Andrew Jackson
- Adrian Bird
- Tom Freeman
Collaborators farther afield:
- Gunter Hammerling
- Karl Hoffmann
- Toby Lawrence
- Simon Milling
- Adrian Mountford
- Mark Travis
- Tom Wynn
- Frank Brombacher
- Markus Mohrs
Funding:
This work is only possible because of support provided by:
the Wellcome Trust
