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

The human immune system is complex, operates through the innate and adaptive systems and protects the human body from a wide range of pathogens and diseases including the common cold and COVID-19. The adaptive system extensively applies T cells which recognise peptides (short amino acid polymers) presented by antigen presenting molecules belonging to the Major Histocompatibility Complex (MHC) to respond to pathogens detected. Other 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. The exact nature of the ligands capable of both binding MR1 and stimulating immune cells has remained relatively elusive. Metabolites of microbial origin from vitamin biosynthetic pathways have been identified in the laboratory and a combination of in silico screening and in vitro functional assays have revealed that non-microbial endogenous ligands also bind to MR1. In summary, a wide range of ligands could be recognised by MR1T cells, however, the exact nature of these molecules remains to be fully characterised.
In this research project, as a collaboration between the University of Birmingham and the biotechnology company Immunocore Ltd, we will: (1) develop an integrated laboratory-computational workflow to identify new ligands - both self and non-self- forming complexes with MR1; (2) apply the laboratory-computational workflow to a range of biological studies to identify new and biologically important ligands related to human health; and (3) characterise the structure and function of isolated MR1-antigen complexes.