Targeting New Mechanisms In The Control Of Thymus Function To Restore Balanced T-cell Production

The immune system is a mixture of cells and tissues in our body that has multiple essential functions. First, immune cells fight infection by viruses, bacteria and parasites, which are collectively called pathogens. Indeed, as scientists we have hijacked this remarkable ability of the immune system to identify and target foreign invaders by creating the process of immunization, where harmless forms of pathogens can be used as vaccines that then protect us from potentially life threatening diseases. Second, our immune systems are important in recognizing and mounting responses to tumours that form during cancer. Most recently, effective therapies for cancer treatment use approaches to boost the ability of immune cells to recognize and target cancers, which again highlights the importance of the immune system in health and disease.

For all aspects of immune system function, T-cells are considered as essential orchestra conductors. T-cells are a specialized type of white blood cell with multiple functions. For example, they can can either directly kill pathogens, or help other immune cells to function. Importantly, T-cells are only made in one site in the body, an organ called the thymus. This organ lies above the heart in the chest, and its sole purpose is to support the complex process of T-cell development. As such, understanding how the thymus works is fundamentally important in understanding how our immune systems work. Without a functional thymus, the immune system is severely compromised, and we are left vulnerable to pathogens that would otherwise be innocuous. Despite the known importance of the thymus, we still do not understand how the thymus develops and functions. This limitation is a major bottleneck in being able to manipulate the immune system to generate better treatments for diseases where T-cell development is absent or reduced (immunodeficiency) or targeted against our own body (autoimmunity). In addition, as the thymus gets smaller with age, the immune system in elderly life becomes compromised. This provides multiple major obstacles. First, it limits the success of vaccination in the elderly. Second, it impacts upon the successful use of bone marrow transplantation for cancer patients, where recovery of normal immune function depends on a functional thymus.

We believe that by understanding the thymus, we will be able to limit life-threatening diseases, and improve the treatment of cancer. We know that epithelial cells present in the thymus are important for its function, but we don't know how these cells work. By identifying new types of epithelial cell, we will work out which parts of the thymus are responsible for its function. In addition, by discovering how the thymus produces different types of T-cell, in both health and following bone marrow transplant, we will be able to manipulate and monitor thymus function. Through the identification of mechanisms that control the thymus in health, we will be able to identify new targets to boost thymus function in disease. Ultimately, our research will mean that we will have a far deeper understanding of the way in which an essential organ works in our immune systems, which we can then use to design better, more effective and specific therapies that correct or improve multiple immune disorders.

This proposal continues towards our long-term goal of dissecting mechanisms of thymus function that will inform future therapies to restore and replace defective immunity. To examine the role of thymic epithelial cells (TEC) in T-cell development, we have generated novel TEC reporter tools to dissect poorly understood pathways in TEC development that will lead to a better understanding of how epithelial thymic microenvironments develop and function. Building on our novel observation that eosinophils are essential for thymus regeneration, we will identify mechanisms controlling endogenous recovery of thymus function that following insult, including ablative therapy. We will also examine thymus reconstitution following bone marrow transplant, and identify mechanisms that limit the recovery of self-tolerant T-cell production. Finally, we will develop an in-depth definition of conventional and Foxp3+ regulatory Recent Thymus Emigrants (RTE), to provide accurate qualitative and quantitative measurement of thymus function. By defining mechanisms of thymus function and identifying processes that influence the recovery of thymus function, our findings will be important to inform future strategies that aim to improve thymus-dependent immune reconstitution. Our specific goals are:

1. Use newly produced RANKVenus/CCL21Tomato TEC reporter mice to define developmental pathways controlling the formation of functionally distinct medullary TEC subsets that relate to distinct functions of the thymus medulla.
2. Examine mechanisms that control endogenous thymus recovery following ablative therapy, by focussing on a proposed tuft cell/ILC2/eosinophil axis for thymus regeneration.
3. Identify mechanisms that limit the recovery of self-tolerant T-cell production following bone marrow transplantation.
4. Define a molecular signature for mouse and human conventional and Foxp3+ Regulatory RTE, to enable accurate analysis of how therapeutic interventions impact thymus function.

The work described in this proposal has two interconnected aims. First, we aim to identify new mechanisms that control thymus function in health. As the thymus is the exclusive site of T-cell production, understanding the processes that control T-cell production in the thymus is essential in understanding how the immune system develops and functions. This aspect of our work will impact numerous research groups locally (within the College of Medical and Dental Sciences), and internationally. For example the local laboratories of Withers (ILC biology), Toellner (germinal centre reactions), Cunningham (bacterial infection) and the laboratories of international collaborators (Hollander, Oxford) and (Takahama, NIH) will benefit from our newly generated animal models that can be used in their own individual research programmes. Second, we aim to examine the mechanisms that control the process of thymus regeneration following damage. As reconstitution of the immune system is required following therapies that include bone marrow transplantation for haematological malignancies, this will offer exciting possibilities for improved disease treatments, and has the potential to impact on multiple distinct beneficiaries. The clinical importance of our work is relevant to clinical colleagues based in the University. For example, ongoing collaborations with Dr Alex Richter (Director of the Birmingham Clinical Immunology Service) and Professor Paul Moss (Head of Research and Knowledge Transfer) provides an opportunity to discuss our research findings with clinical colleagues who oversee the treatment and monitoring of cancer patients undergoing bone marrow transplantation at the Queen Elizabeth Hospital. The site of my laboratory (Institute of Biomedical Research) is located within 100 metres of this major transplant site, where approximately 200 bone marrow transplants take place each year. Through ongoing collaborative links with Prof Janet Lord to examine rates of thymus function in man, we will impact progress made by the MRC/ARUK Centre for Musculoskeletal Ageing Research. Collectively, by maximizing the impact of our research programme in fundamental immunology through interactions with clinical colleagues sharing similar research interests, our work has the potential to improve therapeutic manipulation of the immune system.

At a public level, we are very active in ensuring that our research programme and findings are accessible to a wide audience to maximise the impact of our discoveries. For example, my lab plays an active role in the Science, Technology, Engineering and Mathematics (STEM) network. By continuing close links with local High Schools, we offer research taster placements to GCSE and A level students. This provides them with an opportunity to get a hands-on feel for laboratory based experimental research. We believe this is important because it demonstrates to prospective students the excitement of scientific discovery, and helps them in choosing the right career paths that match their interests. It also helps lab members to become familiar with discussing their research in lay terms, and to understanding the importance of communicating complex biology in a simple way. This ongoing interaction with high school students typically involves around 5-10 work placements each year. This approach has already enabled benefit to be realized: feedback from students and teachers indicate how these placements have motivated students in their work, and many students state how their choice of subjects at school and university are impacted by their visits to my lab.