Investigating the basis of MAIT cell antigen potency

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SUMMARY Mucosal Associated Invariant T (MAIT) cells comprise up to 10% of human peripheral blood T cells, and are enriched in the liver, lungs and gastrointestinal mucosa. This indicates that MAIT cells are key players in immunity. However, their roles in immune protection, and in immunopathology are yet to be fully established. Nevertheless, MAIT cells are implicated in chronic inflammatory diseases including tuberculosis, peptic ulceration, periodontal disease and inflammatory bowel disease. Central to the function of MAIT cells is the MAIT T cell antigen receptor (TCR). Consistent with their innate-like phenotype, MAIT cells express a very restricted T cell repertoire. Namely, human MAIT cells are characterized by an invariant TCR a-chain (TRAV1-2-TRAJ33) paired with a limited array of TCR b-chains (TRBV6 or TRBV20). The MAIT TCR is restricted to the monomorphic Major Histocompatibility Complex class I related protein, MR1. A very high level of conservation of MR1 in mammals and the restricted MAIT TCR usage strongly indicate an important and evolutionarily conserved function for the MAIT TCR-MR1 axis in immunity. Based on our previous work and preliminary findings, we aim to: (i) Investigate novel MAIT cell antigens and their impact on MAIT TCR diversity; (ii) Define the cellular machinery involved in acquisition and presentation of MR1 antigens; (iii) Investigate the structural basis of MAIT cell antigen potency and selectivity. Our proposed studies will advance our understanding of MR1 presentation and subsequent recognition by the MAIT TCR, which is a fundamental precursor for harnessing MAIT cells for future immunotherapeutics.