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

免疫系统包含一个强大的武器库，用于对抗和摧毁导致疾病的不同入侵生物。其中一种武器叫做T细胞。像大多数武器一样，可能会对周围区域造成一些附带损害，在这种情况下，我们的身体。因此，需要调节T细胞，当这些控制丧失时，可能会发生关节炎和糖尿病等疾病。我们希望了解T细胞上的一个重要调节因子是如何发挥作用的。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性死亡，尽管我们不知道为什么会发生这种情况。CTLA-4与称为树突状细胞的不同免疫细胞上的两种蛋白质CD 80和CD 86结合。该提案将研究CTLA-4与这些蛋白质相互作用的机制。我们最近发现了一种新的机制，CTLA-4可以从树突状细胞中剥离其相互作用的伴侣CD 86。由于CD 86可以通过与另一种蛋白质（CD 28）结合来刺激免疫应答，因此去除CD 86具有防止其他T细胞被激活的作用。这导致免疫反应的抑制，并解释了为什么CTLA-4不断从T细胞表面去除并进入细胞内部。这也解释了为什么CTLA-4与CD 28共享CD 86，以允许它窃取CD 86。在这个项目中，我们将探索CTLA-4如何实现这种配体的去除，通过观察CTLA-4蛋白的哪些部分是必需的，以及这些蛋白在细胞内与什么相互作用。这项工作是重要的数据，因为了解CD 28/CTLA-4系统如何工作具有许多意义，例如，目前正在测试干扰这一途径的药物。此外，如果我们发现新的途径，这可能被用来制造新药。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器之一的基本生物学理解，这在癌症生物学，自身免疫和HIV感染中非常重要。

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.