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

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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.