Unravelling the role of CD46 in T cell fate decisions

点击翻译按钮获取中文摘要

The complement system is a component of the immune system used to recognise and remove invading micro-organisms. As such, it is undeniably of critical importance to immunity and host defense. Hyperactivity of the complement system underlies a number of diseases of humans, such as systemic lupus erythematosus, where there is a need for new, effective and low toxicity treatments.Complement has been traditionally viewed as a serum-restricted system. In the last few years it has become apparent that complement is not restricted to the extracellular space but is also present within immune cells as an autocrine system. The cell surface receptor CD46 is a key regulatory molecule in this newly discovered autocrine system, particularly in T cells, which are key mediators of human autoimmunity and highly responsive to complement. This single molecule causes T cells to first take on inflammatory functions in order to eradicate infections and then to shut down those pathways in order to dampen inflammation and allow restoration of tissue integrity. How CD46 signaling achieves these dual functions is poorly understood and could be key to developing new drug therapies.In this application I propose to study the cell signaling events initiated by engagement of CD46 and uncover how CD46 signals are integrated in the nucleus to drive gene expression and determine disparate T cell functions. We aim to uncover the genes directly bound and regulated by CD46 (Aim 1), the signaling cascade initiated on CD46 engagement (Aim 2) and the outcomes of those events at the single cell level (Aim 3). Broadly, these will be achieved by leveraging unique reagents, cutting-edge massive parallel sequencing, cell and molecular technologies. In the year I have already spent at the National Institutes of Health I have generated the preliminary data to support these aims. Understanding the molecular means by which CD46 determines T cell behaviour is essential for identifying and appropriately targeting this pathway for immunomodulation in the context of inflammatory diseases of humans.