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

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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.