Molecular and Cellular Diversity of the MR1-MR1T Cell Axis in Antimicrobial Immunity

In lieu of peptides, the monomorphic MHC-I-like molecule MR1 is thought to present small molecule antigens to stimulate a semi-invariant, phenotypically distinct subset of ɑβ T cells called MR1-restricted T (MR1T) cells. The MR1 ligands identified to date derive from the riboflavin biosynthesis pathway and their presentation is therefore thought to be an indicator of bacterial infection, including that of Mycobacterium tuberculosis. The MR1-MR1T cell axis was once thought to be a highly conserved, innate-like immune mechanism due to the monomorphic nature of MR1, the small pool of validated ligands, and the bias toward usage of a single TRAV gene by a subset of MR1T cells. However, the data presented in this thesis suggest that the MR1-MR1T cell axis is not a binary sensor of infection, but rather a complex indicator of the cellular metabolome; specifically, this work expands our understanding of the molecular mechanisms underpinning donor-unrestricted T cell biology. In this thesis, I first describe a mass spectrometry-based platform for the investigation of the bacterially-derived ligand repertoire of MR1 which revealed a novel class of indolyl-ribityllumazine MR1 ligands. I then present a case study on MR1T cell selectivity by contrasting MR1T cell clone responses toward a natural ribityllumazine MR1 ligand and its deaza-analogue. Finally, I explore heterogeneity in the TCR diversity, antigen specificity, and phenotype of MR1T cells from the peripheral blood of healthy donors using single-cell multi-omics techniques. Altogether, this work addresses the diversity of MR1-restricted T cell antigen recognition and in doing so, challenges the paradigms of MR1T cell biology