Unravelling the role of CD46 in T cell fate decisions

补体系统是免疫系统的一个组成部分，用于识别和清除入侵的微生物。因此，不可否认，它对免疫和宿主防御至关重要。补体系统的过度活跃是人类许多疾病的基础，如系统性红斑狼疮，需要新的、有效的、低毒性的治疗方法。补体传统上被认为是一种血清限制系统。近年来，补体不仅局限于细胞外，还作为自分泌系统存在于免疫细胞内。细胞表面受体CD46是这个新发现的自分泌系统的关键调控分子，特别是在T细胞中，T细胞是人类自身免疫的关键介质，对补体具有高度反应。这个单分子导致T细胞首先承担炎症功能，以根除感染，然后关闭这些途径，以抑制炎症，并允许恢复组织完整性。CD46信号如何实现这些双重功能尚不清楚，这可能是开发新药物治疗的关键。在本应用中，我建议研究由CD46参与引发的细胞信号转导事件，并揭示CD46信号如何在细胞核中整合以驱动基因表达并决定不同的T细胞功能。我们的目标是揭示CD46直接结合和调节的基因（目标1），CD46接合时启动的信号级联（目标2）以及这些事件在单细胞水平上的结果（目标3）。总的来说，这些将通过利用独特的试剂、尖端的大规模平行测序、细胞和分子技术来实现。在美国国立卫生研究院（National Institutes of Health）工作的这一年里，我已经获得了支持这些目标的初步数据。了解CD46决定T细胞行为的分子手段对于在人类炎症性疾病的背景下识别和适当靶向这一免疫调节途径至关重要。

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.