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

免疫系统对细菌和病毒感染提供了重要的保护作用，并在防止肿瘤形成方面发挥了关键的监督作用。参与这一过程的关键免疫细胞类型是T细胞。然而，T细胞不仅在保护性免疫中发挥关键作用，而且如果调节不当，可能会攻击人体自身组织并导致自身免疫性疾病。胸腺是位于上胸部内的器官，为T细胞发育提供主要解剖部位。在T细胞发育过程中，T细胞被筛选出它们对我们自己的组织产生免疫反应的潜力。那些具有攻击身体器官的高可能性的T细胞被迫经历细胞死亡。然而，这个过程并不是100%有效的，这意味着有可能导致自身免疫性疾病的T细胞能够在胸腺内逃脱删除。为了控制自身反应性T细胞，胸腺还支持高度特化类型的T细胞的发育，称为调节性T细胞（也称为Treg）。调节性T细胞具有抑制其他T细胞（包括自身反应性T细胞）活性的独特能力。此外，调节性T细胞也会在感染清除后减少保护性T细胞反应，如果不加以控制，也可能对旁观者组织造成“友好”损伤。因此，胸腺内产生的调节性T细胞在控制免疫系统的活性方面发挥关键作用，从而影响自身免疫性疾病。然而，控制调节性T细胞发育和功能的确切机制仍不完全清楚。该项目旨在使用新的实验方法来识别控制胸腺内产生的调节性T细胞的发育和功能的新分子。我们的目标是使用创新的方法，这将使我们能够准确地识别调节性T细胞在胸腺内的发展，并定量其输出从胸腺到外周循环时，个别定义的基因的表达是有缺陷的。控制调节性T细胞发育和功能的新分子的鉴定可能最终为未来治疗性操纵调节性T细胞的方法提供信息，从而调节健康和疾病中的免疫系统活性。

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.