Discovery of novel, microbial antigens that could modulate T cell function

Metabolite based T cell immunity is emerging as a major player in antimicrobial immunity, autoimmunity, metabolic diseases, and cancer. Namely, vitamin B-based derivatives were identified to be captured and presented by the major histocompatibility complex (MHC) class-I related molecule MR1 to T cells, namely Mucosal Associated Invariant T cells (MAIT), and diverse MR1-restricted T cells. During microbial infection, MAIT cells are modulated by intermediate metabolites derived from the riboflavin synthesis pathway in bacteria, whereby 5-OP-RU is the most potent MAIT agonist recognised so far. Recently, we have addressed the molecular basis underpinning the activation and responsiveness of MAIT cells toward 5-OP-RU (Awad et al. Nature Immunology 2020 and Howson, Awad, et al. Science Immunology 2020). In this project, we will explore the diversity within the microbial MR1-ligandome by discovering novel riboflavin and non-riboflavin related molecules that could modulate MAIT immune response. Indeed, such studies improve our understanding of the molecular determinants of T cell immunity and pave the way for the development of innovative therapeutics based on selective modulation of MAIT cell immunity. Our underlying approach is to express and purify proteins, and determine the 3D structure using the expertise in x-ray crystallography. These are complemented by multi-disciplinary and highly innovative approaches including Surface Plasmon Resonance (SPR), Mass Spectrometry (MS), cellular immunology and advanced atomic and molecular imaging where required.