What is the molcular basis of CTLA-4 trans-endocytosis?

免疫系统拥有强大的武器库，用于对抗和摧毁引起疾病的不同入侵生物体。其中一种武器叫做T细胞。像大多数武器一样，它会对周围区域造成一些附带伤害，在这种情况下是我们的身体。因此，有必要调节T细胞，当这些控制失去时，关节炎和糖尿病等疾病就会发生。我们希望了解在T细胞上发现的基本调节因子是如何起作用的。这种调节因子是一种叫做CTLA-4的蛋白质，它以某种方式关闭T细胞。如果CTLA-4缺失，则会迅速导致自身免疫死亡，尽管我们不知道为什么会发生这种情况。CTLA-4与树突状细胞上的两种蛋白质CD80和CD86结合。本课题将研究CTLA-4与这些蛋白相互作用的机制。我们最近发现了一种新的机制，CTLA-4可以从树突状细胞中撕裂其相互作用的伙伴CD86。由于CD86可以通过与另一种蛋白质（CD28）结合来刺激免疫反应，因此去除CD86具有阻止其他T细胞被激活的作用。这导致了免疫反应的抑制，并解释了为什么CTLA-4不断地从T细胞表面移除并被带入细胞内。这也解释了为什么CTLA-4与CD28共享CD86，以便窃取CD86。在这个项目中，我们将通过观察CTLA-4蛋白的哪些部分是必需的以及它们在细胞内与什么相互作用来探索CTLA-4如何实现这种配体的去除。这项工作是重要的数据，因为了解CD28/CTLA-4系统如何工作具有许多意义，例如，目前正在测试干扰该途径的药物。此外，如果我们找到新的途径，这可能会被用来制造新药。最终，该项目将进一步加深我们对免疫系统中最强大的调节因子之一的基本生物学理解，这在癌症生物学、自身免疫和HIV感染中很重要。

The immune system contains a powerful arsenal of weapons used to fight and destroy different invading organisms that cause disease. One type of weapon is called a T cell. Like most weapons, there can be some collatoral damage to surrounding areas, in this case our bodies. There is therefore a need to regulate T cells and when these controls are lost, diseases such as arthritis and diabetes can occur. We wish to understand how an essential regulator found on a T cell actually functions. The regulator is a protein called CTLA-4 which acts to turn T cells off in some way. If CTLA-4 is missing then death from autoimmunity rapidly results, although we don't know why this occurs. CTLA-4 binds to two proteins, CD80 and CD86, on a different immune cell called a dendritic cell. This proposal will study the mechanisms by which CTLA-4 interacts with these proteins. We have very recently discovered a new mechanism whereby CTLA-4 can literally rip its interacting partner, CD86, from dendritic cells. Since CD86 can stimulate immune responses by binding to another protein (CD28) removing CD86 has the effect of preventing other T cells becoming activated. This results in suppression of immune responses and provides an explanation for why CTLA-4 is continually removed from the surface of T cells and brought inside cells. It also explains why CTLA-4 shares CD86 with the CD28, in order to allow it to steal CD86. In this project we will explore how CTLA-4 achieves this removal of ligands, by seeing which bits of the CTLA-4 protein are required and what these interact with inside the cell. This work is important data since understanding how the CD28/CTLA-4 system works has many implications, for example, medicines are currently being tested which interfere with this pathway. Furthermore if we find new pathways this might be used to make new drugs. Ultimately this project will further our basic biological understanding of one of the most powerful regulators in our immune system which is important in cancer biology, autoimmunity and HIV infection.