Metabolic Regulation of the Th2 Response

Our immune system is our principal defence against infection, but it is a double-edged sword. Inappropriate or over-exuberant immune responses can be as harmful as no response at all. Th2 immunity is a type of immune response that is associated with intestinal worm infections. It causes swelling, muscle contraction and an increase in the production of watery mucus, all of which contribute to flushing out the pathogen. However, the same Th2 response is also associated with allergies and asthma, and in these contexts the same hallmarks of Th2 immunity are damaging; they can even be fatal. Tissue swelling and watery mucus are behind many of the classic symptoms of hay fever, for example, and deeper in the lungs the same processes are responsible for many, severe asthma attacks.

At the moment, our best treatment strategies for Th2-mediated diseases are drugs that cause generalised suppression of the whole immune system, like corticosteroids. Approaches that would enable us to fine-tune the Th2 response, selectively, would be a significant advance. Our aim in this project is to understand the cell biology behind the Th2 response and to identify key pathways that support or suppress Th2 development, so that in the future we can manipulate these pathways to control Th2 immunity.

The particular pathways that we focus on are metabolic pathways, ones controlling how cells use energy to function. Recent evidence suggests that the activation of immune cells is associated with a dramatic change in their energy usage, as the activated cells begin to burn sugar in a frenetic attempt to fuel their rapid proliferation and increased function. The purpose of this project is to assess whether it is possible to use access to particular energy sources as a method of manipulating the function of immune cells. Our hypothesis is that the cells that participate in a Th2 response, such as one against a parasitic worm infection, are less reliant on sugar than the cells involved in an immune response that defends against a virus, for example. We propose that altering the immune system's patterns of energy use could determine the type of immune response that dominates, and hence whether the pathogen or the person will thrive or die.

We anticipate that the data we produce and the new understanding we provide will not only accelerate the work of other scientists seeking to understand disease processes in infections, but will also benefit our colleagues in biotech and pharmaceutical industry who will move this information forward into drugs and therapeutic interventions. Our aim is that the progress we make will lead to targeted interventions in Th2 immunity and new therapies both for intestinal worm infections, and for allergies and asthma. Our work may also support policy makers and non-governmental organisations who promote action to achieve the best possible advancement in global health.

Immune responses to infection involve a careful balance. Too weak a response allows pathogen replication and persistence; too strong risks immunopathology. The damage caused by misdirected or inappropriate immune responses is evident in chronic inflammatory conditions such as inflammatory bowel disease and allergic lung disease. In Th2 immunity, the prevalence and chronicity of current helminth infections illustrates the pressing need for novel strategies to reinforce Th2 immunity, while the rising incidence of allergy and atopy also points to an urgent need for targeted interventions that restrict Th2 activity. New therapies that control Th2 immunity have the potential to provide significant health and economic benefit.

The activation and differentiation of CD4+ T cells is accompanied by profound changes in cell metabolism, switching from a pattern of catabolic, fatty acid oxidation in naïve T cells, to an anabolic metabolism in activated effector cells that is dominated by aerobic glycolysis. Recent data indicates that the extent of this metabolic shift can influence both the size and the quality of T cell activation. Th2 cells in vitro are reported to be uniquely glycolytic, but Th2 glycolysis has not yet been characterized in vivo or in the context of infection. Our preliminary data suggest that Th2 cells in vivo behave differently to those activated in vitro, using little glycolysis despite being activated, effector cells. Our aim here is to characterise Th2 metabolism in vivo, identifying the factors that control Th2 glycolysis and defining the mechanisms by which metabolism influences Th2 function. We will test the hypothesis that manipulating T cell metabolism can control the strength and impact of the Th2 response. Together, our work will provide new insight into Th2 biology and will evaluate new targets for the therapeutic regulation of Th2 immunity.

Our aims in this proposal are to identify mechanisms that control Th2 immunity, and to manipulate these mechanisms to determine therapeutically the strength and impact of the Th2 response. The data we generate will provide molecular details of immune cell function during infection, including new insight into metabolic regulation of T cell function. The project has exciting potential to identify new pathways for therapeutic exploitation. The impact of this research therefore includes the following:

1) Academic
Data from the proposed research will be of importance to researchers in the UK and internationally and in a wide range of disciplines including immunology, infection biology, and cellular metabolism. Raw and analysed data sets will be made available through publication, pre-publication archiving, and full use of open-access data depositories such as ISAC's FlowRepository. We anticipate the data will be re-used by academics interested in the function and regulation of immune responses, and in the metabolic control of cell fate decisions and system biology. The impact of this proposal on UK based researchers will be to advance the knowledge economy. We also aim to inform and educate, with impact, other beneficiaries in our local and international communities through collaborations, in teaching and via outreach activities.

2) Private sector / biotech industry
This proposal explores new areas of immune regulation and tests new mechanisms of tuning T cell responses. Our findings will be relevant to infections of significant global importance, and to atopic disorders of increasing relevance both globally and here in the UK. The mechanistic detail provided in this proposal is a necessary step toward exploitation of metabolic pathways for therapeutic regulation of Th2 immunity, and our interventionist experiments will provide first proof-of-principle testing of the efficacy of such metabolic targets. Our data therefore has potential for attracting R&D investment and developing intellectual property in this area.

3) Economic and societal impact
More than 2 billion people are currently infected with helminth parasites. The ability of chronic helminth infections to enhance susceptibility to other infections and to abrogate vaccination strategies is a significant global health issue. In addition, many chronic inflammatory diseases of post-industrial countries such as the UK involve the same immune mechanisms as in helminth infections, including allergies and atopic asthma. New understanding of the underlying mechanisms will constitute a significant advance in our ability to treat and mitigate these diseases. This proposal will elucidate the metabolic signals that underlie Th2 immunity and Th2 immune regulation, and offers potential to benefit the quality of life, health and well-being of UK citizens and of communities across the globe.

4) Training of highly skilled personnel
This proposal exploits state-of-the-art techniques in cellular immunology, infection biology, biochemistry and metabolic regulation. The multidisciplinary approach offers exceptional training opportunities. Immunology, immune therapies and animal modelling are all areas in which expertise is currently highly sought in academia, biotech, pharma, and other fields, and this proposal will therefore provide specialised and advanced training of early career researchers.