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

获得性免疫系统使生物体能够通过选择性地攻击感染或癌细胞来防御来自入侵病原体（如细菌或病毒）的攻击。为了定位和破坏这些受感染的细胞，发生了一系列复杂的事件，这些事件由最重要的免疫细胞，辅助T细胞指导。辅助T细胞通过释放一系列调节免疫系统各个方面的化学物质来应对外来病原体的存在。辅助T细胞本身由II类主要组织相容性复合物（MHC II类）控制，这是一种由抗原呈递细胞表面上发现的两种膜蛋白组成的复合物。MHC II类负责在细胞表面上结合和呈递源自外源蛋白的小肽抗原。这种由MHC II类抗原呈递的过程激活辅助性T细胞并引发免疫应答。MHCII类以正常方式激活辅助性T细胞的失败导致免疫系统的严重崩溃。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，将装载肽的II类分子正确转运至细胞表面对于健康的免疫应答是必不可少的。这种转运是由一种称为MHC II类相关不变链（Ii）的分子伴侣启动的。Ii的三聚体结合内质网中的三个II类异二聚体以形成九链复合物，并且仅作为该复合物的一部分的是靶向细胞表面的II类分子。因此，九链复合物的组装是抗原呈递中必不可少的第一步。九链复合物的组装涉及大量的特异性蛋白质-蛋白质相互作用，最近的证据表明，所有三种蛋白质的跨膜结构域之间的特异性相互作用具有重要的生物学意义。本研究的重点是调查这些结构域的结构和相互作用，以便更好地了解复合物的组装及其在细胞过程和疾病中的作用。这个阶段的工作主要是基础性的，但是我们将研究的相互作用可以用于设计靶向TM结构域相互作用的分子，并且可以应用于设计靶向大量自身免疫性疾病和癌症的药物和治疗剂，其中涉及MHC II类和MHC Ii。

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.