Identification and characterisation of novel ligands presented by the Major Histocompatibility Complex class I-related gene protein (MR1)

The human immune system is complex, it protects the human body from a wide range of diseases. The adaptive system, can apply T cells carrying receptor molecules that usually recognise peptides presented by antigen presenting cells (APCs), belonging to the extended family of the Major Histocompatibility Complex (MHC). However, additional classes of T cells, include the invariable natural killer T (iNKT) cells and mucosal-associated invariant T (MAIT) cells, which differ in the sense that they recognise non-peptide antigens presented to them by MHC-like molecules, such as CD1d and MR1, respectively. Focusing on MR1, the exact nature of the ligands capable of both binding MR1 and stimulating MAIT cells has remained elusive until recently, with the identification of MR1-presented metabolites of microbial origin from the vitamin biosynthetic pathways. Recently, non-microbial ligands have also been shown to bind to MR1. These results, have been further substantiated by the discovery of a distinct T cell population (MR1T cells), with MR1 presenting most likely endogenous ligands. The above represents the first steps towards describing a repertoire of ligands recognised by MR1T cells, however, the exact nature of these molecules remains to be fully characterised. The objectives of this research are to: (1) develop an integrated laboratory-computational workflow to identify new ligands - both self and non-self- forming complexes with MR1; (2) to apply the laboratory-computational workflow to a range of biological studies to identify new and biologically important ligands related to human health; (3) the chemical synthesis of newly identified ligands; and (4) to characterise the structure and function of isolated MR1-antigen complexes to mechanistically understand the MR1 antigen presentation pathway.