Understanding the regulation of thymus function to control self-tolerant T-cell production

The immune system of all vertebrate animals is made up of a series of cells and organs. Of the cells that make up the immune system, T-cells are an essential component as they fulfil multiple essential aspects of an immune response. They have the ability to recognise and destroy invading organisms such as viruses and bacteria during infection. T-cells also directly help other important immune cell types, such as B-cells that make antibodies. The functional ability of T-cells to recognise pathogens underpins the success of vaccination. Of the immune organs, termed lymphoid tissues, the thymus represents an essential, non-redundant component of the immune system. It is the only place in the body that supports the development of T-cells. It is also the last part of the body to be given a function, with its immunological importance being discovered in 1961. The importance of the thymus can be seen in situations where it is absent from animals and man, due to defects that occurred during development. This leads to fatal immunodeficiency, a situation where a fully functional immune system is absent. Additionally, abnormal thymus function can lead to the generation of T-cells that recognise and destroy our own body tissues, instead of invading agents. This is the basis of multiple forms of autoimmune diseases including diabetes. From our work and that of others, we know that distinct types of epithelial cells in the thymus are necessary for the formation of T-cells that recognise pathogens and do not recognise our own tissues. This is called self-tolerance. What we don't know is how the epithelial cells of the thymus are able to impose such a complex process. Equally, we don't know how the epithelial cells of the thymus develop, and how they become specialised to support a full programme of T-cell development. The aim of this research, which represents a programme of work of over 25 years carried out by the Anderson group in Birmingham, is to understand how the thymus is uniquely specialised to produce T-cells that keep us healthy. We will examine how the epithelial cells in thymus develop, and how they interact and guide the development of T-cells. This research is important as the function of the thymus is critically important in a range of clinical settings, not only autoimmunity and immunodeficiency. For example, functional thymus tissue is lost as we grow older, with the thymus reaching maximal size early in life, followed by a progressive decline. This means that the thymus of elderly people is very inefficient at producing new T-cells. In addition, the loss of normal thymus function impedes the success of bone marrow transplantation for the treatment of certain cancers. So, although transplanted bone marrow provides the seed of a new immune system, deteriorating thymus function means there is an inability to efficiently process the transplant to produce new T-cells. If we can understand how the thymus develops and functions normally, we may be able to generate approaches to restore thymus function and T-cell development that improve immune responses and enhance vaccination success in the elderly, and enable more effective production of essential T-cells following the treatment of cancer.

Building on our long term research interests, we propose to investigate the cellular and molecular regulators of self-tolerant T-cell production in the thymus. Having established the functional dichotomy of the cortical and medullary epithelial lineages, and shown that they derive from a common precursor pool, we will seek to define the precursor pool in both mouse and man, the molecular mechanisms that determine their lineage specificity, and study how these microenvironments select the developing T-cell receptor repertoire. We will build on our recent discovery of the impact of CD1d-restricted iNKT-cells on the thymus medulla, to understand how these cells and their products influence thymus function and tolerance induction. Finally, we will extend our knowledge of the mouse thymus to study and manipulate human thymic epithelial cells and their progenitors, and define novel approaches to measure thymus function in man. Such studies will facilitate future therapeutic manipulation of human thymus function for effective T-cell production in man.

Our specific goals are as follows:
1. To use newly generated RANK-Venus reporter mice to isolate and define the TEC progenitor populations that give rise to cortical and medullary TEC compartments across the life-course in the mouse.
2. To understand the impact of immunoregulatory CD1d-restricted iNKT-cells and their products on the formation of tolerogenic thymic microenvironments.
3. To determine whether induction of the Unfolded Protein Response by mTEC is linked to their ability to induce T-cell tolerance.
4. To extend our murine studies towards the identification of human thymic epithelial progenitors and establish approaches that enable the analysis and manipulation of thymus function in man.

Our research aims to understand the cellular and molecular mechanisms that control the production of T-cells in the thymus. Given the exclusive ability of the thymus to support T-cell development, and the key role of T-cells in the ability of the immune system to fight infection and target cancers, our research has the potential to impact on several distinct beneficiaries. The clinical importance of T-cell production in the treatment of cancer means our research is relevant to clinical colleagues, and will inform clinical practice by improving strategies to restore or enhance T-cell mediated immunity. Being based in the Institute of Biomedical Research, and close to the Queen Elizabeth Hospital and Wellcome Trust Clinical Research Facility, we have regular contact with clinicians and nurses, which provides a platform to discuss the potential clinical impact our findings may have. Our studies aimed at identifying novel molecular regulators of tolerance induction will be of interest to the commercial sector, where pharmaceutical companies are aiming to generate novel therapeutics that can block unwanted immune responses in autoimmune disease. We are already collaborating with a US based company (nKT Therapeutics), testing the ability of their novel agents to impact on innate T-cell populations and thymus function. Of equal importance is our research in relation to the age-related decline in thymus function that is seen during ageing, that has a direct impact on the quality of life of an ageing population. Through links with the MRC/ARUK Centre for Musculoskeletal Ageing Research and the Medawar Centre for Healthy Ageing Research, we discuss our research at organised workshops (eg AgeWell). While the timescale of the impact of our research at a clinical level will be difficult to determine, we have close association with the clinical community in Birmingham, including a major bone marrow transplantation programme in Birmingham (Craddock, Chen and Moss). This means that our findings have the potential to be rapidly progressed towards clinical translation through the clinical research facilities described above.

At a public level, we ensure that the advances we make through our research reach as wide an audience as possible. We actively engage with local High Schools in the community, and are part of the Science, Technology, Engineering and Mathematics (STEM) network. We regularly provide week-long work experience to High School pupils, and have organized 12 work placements over the past 2 years. Here, we are able to communicate our findings with young science students, and we regularly discuss with High School science teachers the impact of our research and the progress being made in understanding the immune system. As an example of this, our laboratory participated in the Big Bang Fair 2014, where 3 lab members manned the BSI stand, explaining the Secret Life of Snot. In addition, we have piloted a Skype based scheme with a primary school in California, giving pupils a live insight into laboratory-based research. We feel that communicating our research through these outreach approaches is important as it is an opportunity to introduce school pupils to the excitement of science, and see how practical science can lead to potentially important discoveries. In relation to timescale, we believe that this approach has already allowed benefit to be realized: feedback from teachers indicates that our placements are becoming increasingly popular with students, and many students state that their subject choices at school are influenced by the experience gained in our laboratory.