Antigen recognition by MR1-restricted T cells

T cells recognize antigens when associated with dedicated antigen-presenting molecules. Conventional T cells recognize peptides presented by polymorphic MHC molecules, whereas unconventional T cells recognize non-peptide antigens bound to non-polymorphic antigen-presenting molecules. These latter ones include cluster differentiation 1 (CD1), butyrophilin 3A1 (BTN3A1) and MHC class-I related molecule (MR1). Due to their unique structural properties, CD1 molecules bind and present an array of self-, bacteria-, and plant-derived lipid antigens recognized by TCR αβ and γδ T cells. A major population of TCR γδ cells react to phosphoantigens interacting with BTN3A1, whereas other rare TCR γδ cells react to CD1-presented lipids or to MR1-self-antigen complexes. Finally, small metabolites generated during riboflavin synthesis in microbes, are presented by MR1 and stimulate mucosal-associated invariant-T cells (MAITs). Recently our laboratory isolated a novel population of MR1-restricted T (MR1T) cells from healthy donors. MR1T cells are distinct from MAIT cells as they do not recognize riboflavin-related metabolites, exhibit polyclonal TCRs and are adaptive-like T cells. Strikingly, they demonstrate preferential recognition of tumour cells and not of healthy cells. Their role in health and disease remains poorly characterized. The aim of my PhD project was to study the physiology of MR1T cells, and mostly, to characterize the antigens that stimulate MR1T cells. I participated in the characterization and identification of the tumour-derived antigens which stimulate MR1T cells. These antigens belong to a new class of T cell-stimulatory antigens and are represented by nucleobases adducts, generated during different stress conditions and accumulating in tumour cells. I also established methods to synthesize and purify nucleobase adducts which I used to investigate their T cell-stimulatory activities. In my studies I then investigated how large is the repertoire of stimulatory nucleobase adducts, including molecules derived from both DNA and RNA. In summary, this dissertation describes a novel class of T cell-stimulatory antigens made of nucleobases adducts. The nucleobase adducts accumulate upon combined alterations in the metabolism of nucleobases, carbonyls and reactive oxygen species. These molecules bind and form stable complexes with MR1 and stimulate MR1T cells. The metabolic changes generating nucleobase adducts preferentially occur in tumour cells, explaining MR1T cell recognition of many different cancer types. This novel type of antigen specificity suggests that MR1T cells survey cells for metabolic alterations, laying the groundwork for novel genetically-unrestricted T cell-based immunotherapies targeting the altered metabolome