Molecular insight into the mechanism of antigen presentation: Role of transmembrane domains in MHC Class-II assembly

获得性免疫系统通过选择性地攻击受感染的或癌细胞，使有机体能够保护自己免受入侵的病原体的攻击，例如细菌或病毒。为了定位和摧毁这些受感染的细胞，在最重要的免疫细胞--辅助T细胞的指导下，发生了一系列复杂的事件。辅助T细胞对外来病原体的存在做出反应，释放一系列化学物质来调节免疫系统的各个方面。辅助T细胞本身受第二类主要组织相容性复合体(MHC第二类)的控制，这是一种由抗原提呈细胞表面的两种膜蛋白组成的复合体。MHC第二类负责结合和呈递来自外来蛋白的小肽抗原在细胞表面。MHC第二类抗原呈递的这一过程激活辅助T细胞，并触发免疫反应。第二类MHC未能以正常方式激活辅助T细胞，导致免疫系统严重崩溃。这是自身免疫性疾病以及其他严重人类疾病的关键因素。因此，正确地将负载多肽的第II类分子转运到细胞表面对于健康的免疫反应至关重要。这种转运是由一种称为MHC第二类相关不变链(II)的伴侣分子启动的。II的三聚体与内质网中的三个II类异源二聚体结合形成一个九链复合体，并且只有作为该复合体的一部分，II类分子才能靶向细胞表面。因此，九链复合体的组装是抗原呈递的重要第一步。九链复合体的组装涉及大量特定的蛋白质-蛋白质相互作用，最近的证据表明，这三种蛋白质跨膜结构域之间的特定相互作用具有重要的生物学意义。本研究的重点是研究这些结构域的结构和相互作用，以更好地了解复合体的组装及其在细胞过程和疾病中的作用。这一阶段的工作主要是基本的，然而，我们将描述的相互作用可以用于针对TM结构域相互作用的分子设计，并可以应用于针对MHC II类和MHC II涉及的大量自身免疫性疾病和癌症的药物和疗法的设计。

The acquired immune system enables an organism to defend itself against assaults from invading pathogens, such as bacteria or viruses, by selectively attacking infected or cancerous cells. In order to locate and destroy these infected cells, a complex symphony of events takes place which is directed by the most important of immune cells, the helper T-cells. Helper T-cells respond to the presence of a foreign pathogen by releasing a range of chemicals that regulate all aspects of the immune system. Helper T-cells are themselves controlled by the Class II Major Histocompatibility Complex (MHC Class II), a complex composed of two membrane proteins found on the surface of antigen presenting cells. MHC Class II is responsible for binding and presenting small peptide antigens, derived from foreign proteins, on the surface of cells. This process of antigen presentation by MHC Class II activates helper T-cells and triggers an immune response. The failure of MHC Class II to activate helper T-cells in a normal way results in a severe collapse of the immune system. This is a key factor in autoimmune diseases as well as other serious human diseases. Therefore, correct transport of peptide-loaded Class II molecules to the cells surface is essential to healthy immune response. This transport is initiated by a chaperone molecule called the MHC Class II-associated invariant chain (Ii). A trimer of Ii binds three Class II heterodimers in the endoplasmic reticulum to form a nine-chain complex, and only as part of this complex are Class II molecules targeted to the cells surface. The assembly of the nine-chain complex is therefore an essential first step in antigen presentation. Assembly of the nine-chain complex involves a large number of specific protein-protein interactions, and recent evidence indicates that specific interactions between the transmembrane domains of all three proteins are of significant biological importance. The focus of this research is investigation of the structures and interactions of these domains in order to better understand the assembly of the complex and its role in cellular processes and disease. Work at this stage is primarily fundamental, however the interactions we will characterise can be used in design of molecules that target TM domain interactions and could be applied to design of drugs and therapeutics that target the large number of autoimmune diseases and cancers in which MHC Class II and MHC Ii are implicated.