Orchestration of the Th2 response by dendritic cells

Key questions remain to be answered as to the relative contribution that specific components of the immune system make in shaping the nature of the developing immune response. Dendritic cells (DC) represent a highly specialised type of immune cell that play a decisive role in orchestration of this process. Such direction is critical, since the consequences of mounting an inappropriate immune response can be extremely damaging. However, in contrast to increasing awareness of the mechanisms by which pathogens such as bacteria or viruses activate DC, little is known about how they respond to more complex organisms. Schistosome worms are complex multicellular parasites that cause chronic disease in millions of people and the distinctive type of immune response that they induce is intimately involved in the development of many of the symptoms that accompany infection. The goal of our studies is to identify the fine detail of the mechanisms by which DC are able to direct the immune response to schistosomes and other pathogens that induce a similar type of reaction. Once we have this information, it will enable us to design novel drugs and vaccines against any condition in which the immune response is ‘unbalanced‘.

Dendritic cells (DC) are the orchestrators of the immune response, able to assess the nature and context of encountered pathogens and to direct T cells appropriately. DC play a decisive role in activation, polarisation, and even regulation of the immune system. While there is an increasing understanding of how they carry out this role when they respond to pathogens such as bacteria, protozoa, or viruses, much less is known about how DC are activated and function in response to metazoan pathogens.
Building upon the foundation I have established during my MRC Career Development Fellowship, I intend to address some outstanding fundamental questions about T cell response induction and modulation by DC, focussing on the Th2 response to the parasitic trematode Schistosoma mansoni. Specifically: 1) what are the mechanisms of Th2 induction by DC? 2) what is the impact of the local environment on DC activation in a Th2 setting? 3) how do DC multitask in the face of stimulation by diverse pathogens? 4) what is the impact of DC depletion on Th2 development in vivo? 5) what is the functionality of Th2 cells induced by DC?
We will address these defined questions using a combination of in vivo and in vitro model systems, and during active murine infection: We will identify core mechanisms utilised by DC to direct T cell polarisation, and address the influence of epigenetics on this process using ChIP and Solexa sequencing; We will determine the impact of the tissue environment on DC activation and function in response to pathogens; We will gain a clear picture of the behaviour of DC and differently polarised effector T cells in single and co-infection settings using state-of-the-art confocal and multi-photon microscopy; We will identify at which stage DC are integral for Th2 induction and development in vivo using CD11c-DTR transgenic mice, and provide new insight into the heterogeneity and functionality of DC-driven effector Th2 cells with the aid of S. mansoni-specific TCR transgenic mice.
In addition to providing novel information about multiple facets of basic DC biology, this approach will provide a platform for rational design of vaccination and immunotherapy strategies.