Investigating diversity within the MR1-restricted T cell repertoire in humans

Studies in T cell mediated immunity have focused on understanding the presentation of peptides by the Major Histocompatibility Complex (MHC), and their recognition by αβ T cell receptors (TCRs). However, αβ T cells can respond to other classes of antigen (Ag) associated with both protective and aberrant immunity. Moreover, a distinct lineage of T cells, termed γδ T cells, exhibits diverse Ag-specificity, functional roles, and tissue localisation. However, our understanding of non-peptide-centric αβ T cell immunity, and γδ T cell mediated immunity in humans, remains germinal. Mucosal-associated invariant T (MAIT) cells play a central role in immunity by mediating the recognition of vitamin B metabolites that are presented by the MHC class I-related molecule, MR1. MAIT cells are emerging as key players in antimicrobial immunity, autoimmunity, cancer and metabolic diseases. However, many aspects of MR1-mediated immunity, such as the extent of the MR1 restricted T cell repertoire, and the potential for recognising other MR1-bound Ags, are unknown. Here, we will address 1 pressing question in MR1-mediated immunity, namely: What are the molecular mechanisms that underpin the recognition of MR1-Ag by these ‘atypical’ αβ and γδ T cell subsets? The project will involve a number of biochemistry- and biophysical-based techniques including the recombinant expression, purification of αβ and γδ TCRs, and MR1 molecule; crystallization of αβ and γδ TCRs in complex with MR1 presenting Ag and 3D structure determination of TCRs-MR1-Ag ternary complexes; affinity measurements using Surface Plasmon Resonance (SPR) technique.