Differential antigenic requirements by diverse MR1-restricted T cells.

MHC-related protein 1 (MR1) presents microbial riboflavin metabolites to mucosal-associated invariant T (MAIT) cells for surveillance of microbial presence. MAIT cells express a semi-invariant T-cell receptor (TCR), which recognizes MR1-antigen complexes in a pattern-recognition-like manner. Recently, diverse populations of MR1-restricted T cells have been described that exhibit broad recognition of tumor cells and appear to recognize MR1 in association with tumor-derived self-antigens, though the identity of these antigens remains unclear. Here, we have used TCR gene transfer and engineered MR1-expressing antigen-presenting cells to probe the MR1 restriction and antigen reactivity of a range of MR1-restricted TCRs, including model tumor-reactive TCRs. We confirm MR1 reactivity by these TCRs, show differential dependence on lysine at position 43 of MR1 (K43) and demonstrate competitive inhibition by the MR1 ligand 6-formylpterin. TCR-expressing reporter lines, however, failed to recapitulate the robust tumor specificity previously reported, suggesting an importance of accessory molecules for MR1-dependent tumor reactivity. Finally, MR1-mutant cell lines showed that distinct residues on the α1/α2 helices were required for TCR binding by different MR1-restricted T cells and suggested central but distinct docking modes by the broad family of MR1-restricted αß TCRs. Collectively, these data are consistent with recognition of distinct antigens by diverse MR1-restricted T cells.

MR1: a multi-faceted metabolite sensor for T cell activation.

The major histocompatibility complex class I-related molecule MR1 captures and presents small metabolites to MR1-restricted T cells including Mucosal Associated Invariant T (MAIT) cells. The first MR1 ligands discovered were intermediates of microbial riboflavin synthesis, antigens presented to alert inflammatory MAIT cells to bacterial infection. Recent advances have expanded the range of MR1 ligands to include extracellular metabolites released by the commensal microbiome, and yet undefined antigens presented by cancer cells to mediate MR1-dependent anti-tumor activity. MR1 thus exhibits a multifaceted ability to display a diverse range of ligands for immune surveillance in a variety of contexts. The mechanisms of antigen presentation by MR1 are of central importance to understanding metabolite-mediated immune homeostasis, immunity to infection and tumor surveillance.

MR1 antigen presentation to MAIT cells: new ligands, diverse pathways?

The major histocompatibility complex class I-related molecule MR1 is the only antigen (Ag) presenting molecule that captures and displays vitamin B-derived metabolites that are unique to a wide array of microbes. Presentation of these metabolite Ag at the cell surface activates mucosal-associated invariant T (MAIT) cells, a highly abundant innate-like T cell population, and represents a recently-described mechanism used by the mammalian immune system to sense pathogenic or commensal microbes. Our understanding of the cell biology of how MR1 accomplishes this unique task is still evolving, but recent advances are allowing a general picture to emerge. Further, the list of metabolites presented by MR1 is expanding both by identification of natural metabolites and the design of synthetic ligands. Here we review the latest studies contributing to our growing understanding of this rapidly expanding field.