Identification of Novel MR1 Ligands Derived from Herbal Medicines by MR1-Presentation Reporter Screening and Their Structure-Activity Relationship

Mucosal-associated invariant T (MAIT) cells are innate-like T cells that are modulated by ligands presented on MHC class I-related proteins (MR1). These cells have attracted attention as potential drug targets because of their involvement in the initial response to infection and various disorders. Herein, we have established the MR1-presentation reporter assay system employing split-luciferase, which enables the efficient exploration of MR1 ligands. Using our screening system, we identified herbal medicine-derived MR1 ligands, including coniferyl aldehyde, which have an ability to inhibit the MR1–MAIT cell axis. Coniferyl aldehyde comprises phenylpropanoids and is a novel motif for MR1 ligands. Further structure-activity relationship study revealed the key structural features of ligands required for MR1 recognition. These results will contribute to uncovering the mode of action of herbal medicines and their analogs, and to developing novel MAIT cell modulators.