IMPC: Use of IMPC knockout mice and novel transgenic murine models to identify molecular pathways controlling thymic regulatory T cell development

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The immune system provides an essential protective role against bacterial and viral infection, and additionally plays a key surveillance role in guarding against tumour formation. A critical immune cell type involved in this process is the T cell. However, T cells not only play a critical role in protective immunity, but if incorrectly regulated can potentially attack the body's own tissues and cause autoimmune disease. The thymus is an organ located within the upper chest that provides the main anatomical site for T-cell development. During T cell development, T-cells are screened for their potential to mount an immune response against our own tissues. Those T-cells bearing a high likelihood of attacking the body's organs are forced to undergo cell death. However, this process is not 100% efficient, meaning that T-cells with the potential to cause autoimmune disease are able to escape deletion within the thymus. In order to keep autoreactive T-cells in check, the thymus additionally supports the development of a highly specialised type of T-cell, termed regulatory T-cells (also called Treg). Regulatory T-cells possess a unique capacity to supress the activity of other T-cells, including autoreactive T-cells. In addition, regulatory T-cells also curtail protective T-cell responses following the clearance of infections, which if left unchecked may also cause 'friendly-fire' damage to bystander tissues. Regulatory T-cells generated within the thymus therefore play a critical role in controlling the activity of the immune system and therefore impact autoimmune disease. However, the precise mechanisms that control regulatory T-cell development and function remain incompletely understood. This project aims to use novel experimental approaches to identify new molecules that control the development and function of regulatory T cells generated within the thymus. We aim to use innovative methods that will allow us to accurately identify regulatory T cells undergoing development within the thymus and quantitate their output from the thymus into the peripheral circulation when the expression of individual defined genes are defective. The identification of new molecules controlling regulatory T cells development and function may ultimately inform future approaches to therapeutically manipulate regulatory T cell and therefore modulate immune system activity in health and disease.