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

免疫系统包含一个强大的武器库，用于对抗和摧毁不同的入侵生物体，这些生物体会导致疾病。一种武器被称为T细胞。像大多数武器一样，可能会对周围区域造成一些胶状损伤，在这种情况下是我们的身体。因此，有必要调节T细胞，当失去这些控制时，可能会发生关节炎和糖尿病等疾病。我们希望了解在T细胞上发现的一个必要的调节因子是如何发挥作用的。这种调节剂是一种名为CTLA-4的蛋白质，它能以某种方式关闭T细胞。如果CTLA-4丢失，那么很快就会死于自身免疫，尽管我们不知道为什么会发生这种情况。CTLA-4与CD80和CD86这两种蛋白质结合在一种不同的免疫细胞上，称为树突状细胞。这项提议将研究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，通过这种机制，CTLA-4可以从树突状细胞上撕裂其相互作用的伙伴CD86。由于CD86可以通过与另一种蛋白(CD28)结合来刺激免疫反应，因此去除CD86具有防止其他T细胞被激活的效果。这导致了免疫反应的抑制，并为为什么CTLA-4不断从T细胞表面移除并进入细胞内提供了解释。这也解释了为什么CTLA-4与CD28共享CD86，以便允许它窃取CD86。在这个项目中，我们将通过观察CTLA-4蛋白的哪些片段是必需的，以及这些片段在细胞内与什么相互作用来探索CTLA-4是如何实现这种配体的去除的。这项工作是重要的数据，因为了解CD28/CTLA-4系统是如何工作的具有许多意义，例如，目前正在测试干扰这一途径的药物。此外，如果我们找到新的途径，这可能会被用来制造新药。最终，这个项目将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，它在癌症生物学、自身免疫和艾滋病毒感染中非常重要。

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.